Matteo Bassetti, MD, PhD Infectious Diseases Division

1. New specific therapeutic approach for ESBL producers Enterobacteriaceae and carbapenems resistant Matteo Bassetti, MD, PhD Infectious Diseases Division University of Udine and Santa Maria Misericordia University Hospital Udine, Italy

2. Disclosures • Research grants • Astellas, Pfizer, MSD, Gilead • Advisor/consultant • Angelini, Astellas, AstraZeneca, Bayer, Basilea, Gilead, Menarini, MSD, Pfizer, Novartis, Shionogi, Vifor, The Medicines company, Tetraphase, Achaogen, Paratek • Speaker/chairman • Angelini, Astellas, AstraZeneca, Bayer, Pfizer, MSD, Gilead, Vifor, Novartis, Bayer,Tetraphase

3. Last week’s experience Blood isolate in a transplant patient in ICU Klebsiella pneumoniae

4. Distribution of carbapenemases globally South Africa Vasso etal. Mayo Clin Proc 2015;90(3):395-403.

5. CPE: enzyme distribution in Europe: 2015 KPC VIM NDM OXA-48 Albiger et al. Carbapenemase-producing Enterobacteriaceae in Europe: assessment by national experts from 38 countries, May 2015 (EUSCAPE Project)

6. Proportion of CRKP in Europe 2006 2008 2015 2010 Europe: 7.3% Romania: 31.5% Italy: 32.9% Greece: 62.3%

7. Worldwide distribution of carbapenem and colistin resistant Enterobacteriaceae Bassetti M et al. Semin Respir Crit Care Med 2017:38(3)

8. How to manage CRE in the daily practice • Role of combination therapy • Role of carbapenems • Role of tigecycline, colistin, meropenem, fosfomycin and aminoglycosides • Role of ceftazidime/avibactam • Future options

9. Mortality: 25 of the 46 (54.3%) whose regimens were classified as monotherapy and 27 of the 79 (34.1%) who were on combination regimens (P = 0.02)

10. Bloodstream Infection Due to KPC-KP: Mortality KPC-KP: K. pneumoniae carbapenemase-producing K. pneumoniae; APACHE: Acute Physiology and Chronic Health Evaluation; CI: Confidence interval Tumbarello M, et al.Clin Infect Dis 2012;55(7):943–50

11. Combination therapy lowering mortality in KPC bacteremia 205 KPC bacteremia M C Daikos GL et al. Antimicrob Agents Chemother 2014;58: 2322

12. 437 patients with BSIs due to CPE enrolled in the INCREMENT cohort. • Among those receiving appropriate therapy, 135 (39%) received combination therapy and 208 (61%) received monotherapy. • Overall mortality was not different between those receiving combination therapy or monotherapy (35% vs 41%; • However, combination therapy was associated with lower mortality than was monotherapy in the high-mortality-score stratum

13. 100 Mortality (%) 50 Monotherapy 0 Combination therapy Two-drug combinations Septic shock APACHE III score ≥15 Inadequate initial therapy 100 Three-drug combinations Combinations with meropenem Combinations without meropenem Mortality (%) 50 0 Colistin resistant Meropenem MIC≤8 mg/L Meropenem MIC≤16 mg/L KPC-K. pneumoniae treatment : 661 adults with bloodstream infections (BSIs; n 447) or non-bacteraemic infections * * * * * * * * * * * * * * * * * * Tumbarello M et al. J Antimicrob Chemother. 2015;70:2133-2143.

14. 2014

15. accepted october 2016 • Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. • Average doses of continuous infusion meropenem ranged from 1.8 to 13.2 g/daily • High dose continuous infusion meropenem optimized by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with an MIC for meropenem of ≤ 64mg/L.

16. 595 patients • 77% of isolates with carba MIC ≥16 • 428 (71.9%) received a HD carba-based combination therapy. • 14 day mortality: 21.3%

17. High doses tigycicline in clinical practice in VAP De Pascale G et al. Crit Care. 2014;18(3):R90

18. High-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 clinical cure, microbiologic success, and mortality but not with the development of acute kidney injury.

19. Fosfomycin was administered intravenously at a median dose of 24 g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. Pontikis K et al IJAA 2016

20. New Agents being developed to treat resistant Gram-negative bacteria

21. Anti-Gram-negative activity of new antibiotics Bassetti M et al. Expert Review of Anti-infective Therapy 2017 Jan;15(1):55-65

22. Ceftazidime–avibactam in CRE Klebsiella pneumoniae bacteremia Rates of 30-day clinical success across treatment regimens Among patients with CRE Klebsiella pneumoniae bacteremia, rates of clinical success at 30-day were significantly higher among patients receiving ceftazidime-avibactam compared to those who received a carbapenem plus aminoglycoside (P=0.04) or colistin (P=0.009) and other regimens (P=0.004) C-A, ceftazidime–avibactam; CB+AG, carbapenem and aminoglycoside; CB+COL, carbapenem and colistin; CRE, carbapenem-resistant EnterobacteriaceaeShields RK, et al. Antimicrob Agents Chemother 2017. Jul 25;61(8) e00883-17

23. Ceftazidime–avibactam in CRE Klebsiella pneumoniae bacteremia Shields RK et al. Antimicrob Agents Chemother. 2017 Jul 25; 61(8) e00883-17

24. Colistin versus Ceftazidime-avibactam in the Treatment of Infections due to Carbapenem-Resistant Enterobacteriaceae • 38 patients were treated first with ceftazidime-avibactam and 99 with colistin • Bloodstream (n=63, 46%) and respiratory (n=30, 22%) infections • All-cause hospital mortality at 30-days • ceftazidime-avibactam 9% • colistin 32%, (p=0.0012) • Disposition at 30 days, patients treated with • ceftazidime-avibactam had 64% probability of a better outcome as compared to patients treated with colistin. • Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin Van Duin D et al. Antibacterial Resistance Leadership Group. Clin Infect Dis. 2017 Sep 4, DOI: 10.1093/cid/cix783

25. Italian experience with ceftazidime/avibactam Tumbarello M, Bassetti M et al. Submitted

27. Management of KPC-Producing Klebsiella pneumoniae Infections: expert review on behalf of ESCMID, HSC and SITA Bassetti M et al. Clin Microbiol Infect. (2017) , https://doi.org/10.1016/j.cmi.2017.08.030

28. Management of KPC-Producing Klebsiella pneumoniae Infections: expert review on behalf of ESCMID, HSC & SITA Adjusted from Bassetti M et al. Clin Microbiol Infect. (2017) https://doi.org/10.1016/j.cmi.2017.08.030 BSIs, bloodstream infection; IU, units; For all medicinal products mentioned, please refer to the approved Summaries of Product Characteristics *Tigecycline is indicated for the treatment of complicated intra-abdominal infections & complicated skin and soft tissue infections, excluding diabetic foot infections- should be used only in situations where other alternative antibiotics are not suitable, posology: initial dose of 100 mg followed by 50 mg every 12 hours daily iv

29. Expert opinion on MIC driven therapy for KPC-Kp. TREATMENT OPTIONS Meropenem: loading dose (2 g in 1 hour) followed by maintenance doses with continuous infusion (1.5 g every 6 hours in 6 hours infusion). Therapeutic drug monitoring suggested Bassetti M et al. Semin Respir Crit Care Med 2017:38(3)

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