by author The year in Infectious Diseases 24th European Congress of Clinical Microbiology and Infectious Diseases Barcelona, May, 2014

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1 24th European Congress of Clinical Microbiology and Infectious Diseases Barcelona, May, 2014 The year in Infectious Diseases Pierluigi Viale Infectious Disease Unit - Teaching Hospital S. Orsola Malpighi Bologna, Italy

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3 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURACY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS 3. THE VALUE OF COMBINATION THERAPIES IN THE MANAGEMENT OF MDR GRAM NEGATIVE SEVERE INFECTION 4. THE CLINICAL VALUE OF A CORRECT ANTIMICROBIALS EXPOSURE 5. THE VARIABILITY OF THE PROSTHETIC JOINT INFECTIONS MANAGEMENT 6. THE DIAGNOSIS and MANAGEMENT OF INVASIVE CANDIDIASIS WITHOUT CANDIDEMIA

4 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES

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6 Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile van Nood E et al, N Engl J Med 2013;368: Rates of Cure without Relapse Because most patients in both control groups had a relapse, the trial was suspended after an interim analysis. At that time 43 patients were enrolled and 42 were analyzed

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8 Microbiota Transplantation Restores Normal Fecal Bile Acid Composition in Recurrent C.difficile Infection. Weingarden AR et al, Am J Physiol Gastrointest Liver Physiol November 27, S rrna gene sequencing was used to determine the bacterial composition of pre- and post- FMT fecal samples. Than general metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. Major bacterial phyla in patients and donors

9 Microbiota Transplantation Restores Normal Fecal Bile Acid Composition in Recurrent C.difficile Infection. Weingarden AR et al, Am J Physiol Gastrointest Liver Physiol November 27, 2013 normal Normal bile acid composition in the colon prevents germination of C. difficile spores. FMT CDI correction of bile acid metabolism is likely one of the major mechanisms by which FMT results in a cure and prevents recurrence of CDI. Antibiotics allow increased levels of primary bile acids promoting germination of C. difficile spores and growth of vegetative forms.

10 Therapy of Clostridium difficile infection: perspectives on a changing paradigm Tran MC, Claros MC, Goldstein EJ Expert Opin. Pharmacother. 2013, Sep 22 FUTURE PHARMACOTHERAPY of CDI : DRUGS UNDER DEVELOPMENT LFF 571 (Novartis) Surotomycin (Cubist) SMT Cadazolid (Actelion) Oritavancin CamSA semisynthetic thiopeptide with high and selective in vitro activity Phase II trials undergoing novel lipopeptide structurally related to daptomycin Phase III trials undergoing bis-benzimidazole tetrahydrate compound with minimal growth inhibition against a large panel of isolates from the gut flora non-absorbable oxazolidinone with very selective actitvity Scheduled for Phase II trials Lipoglycopeptide fourfold more active in vitro than vanco and metro Strong activity against ribotype 027 in a human gut model bile salt analog, inhibits C. difficile spore germination in vitro. In a murine model study a single dose of prevented CDI without any toxicity suggesting a possible new approach for prevention of CDI

11 Bile Salt Inhibition of Host Cell Damage by Clostridium Difficile Toxins Darkoh C et al, PLoS ONE 2013; 8: e79631 The mechanism of taurocholate-mediated inhibition functions at the level of toxin activity since taurocholate did not affect C. difficile growth and toxin production

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13 Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and C. difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial Allen SJ et al, Lancet 2013 ;382: A multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. participants were randomized in a 1:1 ratio to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 101⁰ organisms, one per day for 21 days, or an identical placebo and 1471 subject were included in the analyses of the primary endpoints Do the standard probiotic preparations have a too small bacterial load for a real impact on the microbiota composition?

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15 Epidemiology of Clostridium difficile-associated disease: a shift from hospital-acquired infection to long-term care facility-based infection. Garg S et al, Dig Dis Sci. 2013;58: A retrospective study included 400 randomly selected patients with a diagnosis of CDI Most LTCF patients (84.8%) had nondiarrheal symptoms as their presenting complaint

16 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURACY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS

17 The 2005 ATS/IDSA guidelines for nosocomial pneumonia defined healthcareassociated pneumonia (HCAP) as including patients who had recent contact with healthcare environments through nursing homes, hemodialysis centers, or recent hospitalization, distinguished from CAP because of higher prevalence of drug resistant pathogens, recommending that all patients with HCAP be treated empirically microorganisms. with multiple antibiotics, directed against multidrug resistant

18 HCAP = HAP Aggressive broad spectrum therapy HCAP = hospitalized CAP? Standard CAP therapy

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20 Microbial aetiology of HCAP in Spain: a prospective, multicentre, case control study Polverino E et al, Thorax 2013; 68: A prospective multicentre case control study, comparing clinical presentation, outcomes and microbial aetiology of HCAP and CAP patients matched by age (±10 years), gender and period of admission (±10 weeks): 476 patients (238 cases, 238 controls) were recruited for 2 years Microbiological aetiology of pneumonia among patients with known aetiology HCAP CAP N % N % Streptococcus pneumoniae Respiratory Viruses Legionella pneumophila Gram-negative bacilli Pseudomonas aeruginosa Staphylococcys aureus Atypical pathogens Haemophilus influenza Moraxella catarrhalis P

21 Microbial aetiology of HCAP in Spain: a prospective, multicentre, case control study Polverino E et al, Thorax 2013; 68: Patients main characteristics HCAP CAP N % N % Previous antibiotic therapy (last month) 33% 15% Proton-pump inhibitors, 52% 44%.048 Anti-H2 drugs 17% 7.1%.017 BMI, media±sd Comorbidities 2, 75% 53% <.0001 Neurological diseases, 54% 24% <.0001 Dysphagia 39% 14% <.0001 PSI, mean +SD <.0001 PSI I III, 15% 33% <.0001 P

22 Microbial aetiology of HCAP in Spain: a prospective, multicentre, case control study Polverino E et al, Thorax 2013; 68: Clinical course and outcome HCAP CAP N % N % Altered mental status, <.001 Non-respiratory Mean LOS 9±8 7±8.008 Time to clinical stability 5.7± day readmissions days mortality rate months mortality rate <.001 HCAP corresponds to patients with poor functional status and with multiple comorbidities, who, despite having a similar clinical presentation and similar microbial etiology, show worse clinical outcomes. P

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24 Risk Factors for Drug-Resistant Pathogens in CAP and HCAP Shindo Y et al, Am J Respir Crit Care Med 2013; 188: A prospective observational study conducted in hospitalized patients with pneumonia at ten institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillinsulbactam,macrolides,and respiratory fluoroquinolones were defined as drug resistant pathogens (DRP). In total, 1,413 patients (887 CAP and 526 HCAP) were analyzed. % Identified pathogens (770/1413) according to type of pneumonia: THE TOP THREE

25 Risk Factors for Drug-Resistant Pathogens in CAP and HCAP Shindo Y et al, Am J Respir Crit Care Med 2013; 188: DRPs were more frequently found in patients with HCAP (26.6%) than in patients with CAP (8.6%) Independent risk factors for DRP Variable OR 95% CI prior hospitalization immunosuppression previous antibiotic use use of gastric acid suppressive agents tube feeding non-ambulatory status

26 Risk Factors for Drug-Resistant Pathogens in CAP and HCAP Shindo Y et al, Am J Respir Crit Care Med 2013; 188: Number of risk factors for CAP drug resistance 35.9%

27 Risk Factors for Drug-Resistant Pathogens in CAP and HCAP Shindo Y et al, Am J Respir Crit Care Med 2013; 188: Outcomes according to type of pneumonia HCAP CAP % % drug-resistant pathogens <.001 Inappropriate initial antibiotic treatment <.001 Mechanical ventilation d mortality <.001 In-hospital mortality Building a prediction rule based on well defined Risk Factors and not on a simple disease definition, is possible P

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29 A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter- Cohort Study Using Risk Factors for MDR Pathogens To Select Initial Empiric Therapy. Maruyama T et al, Clin Infect Dis 2013; 57: multicenter cohort study of 445 pneumonia patients, including both CAP (n=124) and HCAP (n=321).

30 A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter- Cohort Study Using Risk Factors for MDR Pathogens To Select Initial Empiric Therapy. Maruyama T et al, Clin Infect Dis 2013; 57: microorganism CAUSATIVE MICROORGANISMS HCAP with 0-1 RF (n=151) HCAP with >2 RF (n=170) % % S. pneumoniae S. aureus <.001 MRSA Enterobacteriaceae P. aeruginosa MDR gram negatives <.001 In total, 93.1% of HCAP patients were treated according to the therapy algorithm, with only 53% receiving broad spectrum empiric therapy. P

31 A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter- Cohort Study Using Risk Factors for MDR Pathogens To Select Initial Empiric Therapy. Maruyama T et al, Clin Infect Dis 2013; 57: DAY MORTALITY In the subgroup with less than 2 RF the incidence of difficult to treat pathogens is low, justifying a conservative therapeutic approach

32 HCAP = HAP? Aggressive largest spectrum therapy Decisional Criteria RISK FACTORS FOR MDR MICROORGANISMS HCAP = hospitalized CAP? Standard conservative approach

33 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURANCY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS 3. THE VALUE OF COMBINATION THERAPIES IN THE MANAGEMENT OF MDR GRAM NEGATIVE SEVERE INFECTION

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35 OUTCOMES A multicenter, parallel, randomized, open-label clinical trial enrolling 210 patients with lifethreatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infectionrelated death, microbiologic eradication, and LOS.

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37 Effect of Adequate Single-Drug vs Combination Antimicrobial Therapy on Mortality in Pseudomonas aeruginosa Bloodstream Infections: A Post Hoc Analysis of a Prospective Cohort Peña C et al. Clin Infect Dis 2013;57: Cumulative risk of death for patients receiving adequate empirical antimicrobial therapy

38 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURANCY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS 3. THE VALUE OF COMBINATION THERAPIES IN THE MANAGEMENT OF MDR GRAM NEGATIVE SEVERE INFECTION 4. THE CLINICAL VALUE OF A CORRECT ANTIMICROBIALS EXPOSURE

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40 Continuous Infusion of Beta-Lactam Antibiotics in Severe Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial Dulhunty JM et al, Clin Infect Dis 2013;56: A prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary PK outcome was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7 14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups Study endpoints by treatment group Endopoint CI Control P Plasma antibiotic concentration >MIC 81.8% 28.6%.001 Clinical cure (TOC date) 76.7% 50.1%.032 ICU LOS 7.5 d 9 d.50 ICU free days (all) 19.5 d 17 d.14 Hospital survival 90.0% 80.0%.47

41 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURANCY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS 3. THE VALUE OF COMBINATION THERAPIES IN THE MANAGEMENT OF MDR GRAM NEGATIVE SEVERE INFECTION 4. THE CLINICAL VALUE OF A CORRECT ANTIMICROBIALS EXPOSURE 5. THE VARIABILITY OF THE PROSTHETIC JOINT INFECTIONS MANAGEMENT

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43 MAJOR UNMET NEEDS in BACTERIAL and FUNGAL INFECTIONS AND THEIR FEASIBLE ANSWERS IN 2013 LITERATURE 1. THE MANAGEMENT OF CDI RECURRENCES 2. THE HEALTHCARE-ASSOCIATED PNEUMONIA DEFINITION AND THE ACCURANCY IN IDENTIFYING POTENTIALLY RESISTANT PATHOGENS 3. THE VALUE OF COMBINATION THERAPIES IN THE MANAGEMENT OF MDR GRAM NEGATIVE SEVERE INFECTION 4. THE CLINICAL VALUE OF A CORRECT ANTIMICROBIALS EXPOSURE 5. THE VARIABILITY OF THE PROSTHETIC JOINT INFECTIONS MANAGEMENT 6. THE DIAGNOSIS and MANAGEMENT OF INVASIVE CANDIDIASIS WITHOUT CANDIDEMIA

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45 Finding the "missing 50%" of invasive candidiasis: How non-culture diagnostics will improve understanding of disease spectrum and transform patient care. Clancy CJ & Nguyen MH Clin Infect Dis 2013 ; 56: What does it mean invasive candidasis?

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47 b-glucan Antigenemia Anticipates Diagnosis of Blood Culture Negative Intraabdominal Candidiasis Tissot F et al, Am J Respir Crit Care Med 2013;188:

48 b-glucan Antigenemia Anticipates Diagnosis of Blood Culture Negative Intraabdominal Candidiasis Tissot F et al, Am J Respir Crit Care Med 2013;188: NC COL SuIAC PrIAC Median BDG COLONIZED 99 pg/ml (8-440) IAC 254 pg/ml ( )

49 b-glucan Antigenemia Anticipates Diagnosis of Blood Culture Negative Intraabdominal Candidiasis Tissot F et al, Am J Respir Crit Care Med 2013;188: BDG Candida SCORE BDG in HR pts ROC curves for differentiating IAC from colonization Colonization INDEX

50 b-glucan Antigenemia Anticipates Diagnosis of Blood Culture Negative Intraabdominal Candidiasis Tissot F et al, Am J Respir Crit Care Med 2013;188: Time intervals between reaching values above the cut-off for 1,3-b-D-glucan (BG), Candida score (CS), Candida colonization index (CI), and corrected Candida colonization index (CCI), or start of antifungal therapy (AF) and microbiological diagnosis of intraabdominal candidiasis

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