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

Disclosures Research grants Advisor/consultant Speaker/chairman 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

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

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

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

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

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

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

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)

Bloodstream Infection Due to KPC-KP: Mortality Multivariate analysis of factors associated with death among patients with bloodstream infection due to KPC-KP P value Odds Ratio (95% CI) Shock 0.008 7.17 (1.65–31.03) Inadequate initial treatment 0.003 4.17 (1.61–10.76) High APACHE III score <0.001 1.04 (1.02–1.07) Post-antibiogram therapy with tigecycline + colistin + meropenem 0.01 0.11 (0.02–0.69) 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

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

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

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

2014

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.

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

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

High-dose colistin (>4 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.

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

New Agents being developed to treat resistant Gram-negative bacteria Related-class Developer Ceftolozane-tazobactam BLBLI Merck Ceftazidime-avibactam Pfizer Meropenem-vaborbactam Medicine Company Imipenem-relebactam Aztreonam-avibactam Cefiderocol Cephalosporin Shionogi Eravacycline Tetracycline Tetraphase Plazomicin Aminoglycoside Achaogen

Anti-Gram-negative activity of new antibiotics ESBL CRE MDR P.aeruginosa MDR Acinetobacter S-649266 YES KPC and NDM-1 Ceftolozane- Tazobactam NO Ceftazidime-avibactam   KPCs and OXA-48 (not active against MBLs)  NO Ceftaroline fosamil-avibactam Aztreonam-avibactam MBLs such as NDM  Meropenem/vaborbactam KPCs NO^ NO ° Imipenem/cilastatin-relebactam Plazomicin most KPCs (not active against many NDMs) Eravacycline Bassetti M et al. Expert Review of Anti-infective Therapy 2017 Jan;15(1):55-65

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 Enterobacteriaceae Shields RK, et al. Antimicrob Agents Chemother 2017. Jul 25;61(8) e00883-17

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

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

Italian experience with ceftazidime/avibactam   No. (%) of patients P value Variable All infections (n=138) Bloodstream infections (n=104) Nonbacteremic Infections (n=34) Male sex 94 (68.1) 68 (65.4) 26 (76.5) 0.23 Age, year (median[IQR]) 60 (25-79) 61 (27-79) 57 (25-79) 0.31 ICU 46 (33.3) 39 (37.5) 7 (20.6) 0.07 Healthcare interventions Surgery a 60 (43.5) 41 (39.4) 19 (55.9) 0.09 Dialysis a 15 (10.9) 14 (13.5) 1 (2.9) 0.08 Endoscopy b 21 (15.2) 17 (16.3) 4 (11.7) 0.52 Mechanical ventilation b 43 (31.2) 24 (32.7) 9 (26.5) 0.49 Indwelling invasive devices Epidemiology Healthcare-associated 16 (11.6) 10 (9.7) 6 (17.6) 0.20 Hospital-acquired 122 (88.4) 94 (90.4) 28 (82.3) Septic shockc 34 (32.7) Treatment variables CAZ-AVI Monotherapy 29 (21.1) 22 (21.2) 0.94 CAZ-AVI Combination therapy 109 (78.9) 82 (78.8) 27 (79.4) Combination without carbapenems 88/109 (80.7) 63/82 (76.8) 25/27 (92.6) Combination including carbapenemsd 21/109 (19.3) 19/82 (23.17) 2/27 (7.4) Days of CAV-AVI treatment (median[IQR]) 14 (4-41) 14 (3-28) 15 (6-55) 0.18 Days before CAZ-AVI treatment 7 (3-10) 7 (3-9) 7 (4-10) Mortality 47 (34.1) 38 (36.5) 0.28 Relapse of infection 12 10 2 Tumbarello M, Bassetti M et al. Submitted

Management of KPC-Producing Klebsiella pneumoniae Infections: expert review on behalf of ESCMID, HSC and SITA What is currently the best treatment for KPC-KP infections?   Combination treatment should be preferred to treat KPC-KP infections compared to monotherapy in the case of severe infections and for critically ill patients. For non-critically-ill patients without severe infections, results from randomized clinical trials are needed for ultimately weighing the related benefits and costs, also in terms of induction of resistance. What is the role of carbapenems in the treatment of KPC-KP infections? Administration of high-dose (e.g., 2 grams q 8 hours), prolonged infusion meropenem could be beneficial in KPC-KP infections if MIC is ≤ 8 mg/L. For MIC up to 32-64 mg/L, meropenem administration should be considered if TDM is available to monitor optimal drug exposure. What is the role of nebulized antibiotics in the treatment of ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT) by KPC-KP? The use of nebulised antibiotics could be useful in selected clinical scenario, especially when there is lung involvement (e.g., use of inhaled colistin in VAP due to carbapenem-resistant pathogens). What is the optimal duration of treatment for KPC-KP infections? Treatment duration for KPC-KP infections should vary according to the source of the infection. Factors such as achievement of microbiological eradication, use of biomarkers and optimization of antibiotic exposure could be used to reduce treatment duration  Bassetti M et al. Clin Microbiol Infect. (2017) , https://doi.org/10.1016/j.cmi.2017.08.030 27

Management of KPC-Producing Klebsiella pneumoniae Infections: expert review on behalf of ESCMID, HSC & SITA Drug Loading dose   Daily dose for normal renal function Comments Colistina  9 million IU  4.5 million IU IV q 12h. Intrathecal/intraventricular: 125.000-250.000 IU Inhaled: 1 to 3 million IU q 8h Gentamicin and Amikacin  Not required when administered in pulse dosing schemes  5 to 7 mg/kg infused over 1 h  15 to 20 mg/kg infused over 1 h Tigecycline* 100-200 mg 50-100 mg q 12 h IV For BSIs or pneumonia or when tigecycline MIC > 0.5 mg/L, higher doses are recommended Fosfomycin Not required 18 to 24 g IV in 3 to 4 doses In combination Ceftazidime/avibactam 2.5g q 8 h IV infused over 2 h Combination with other agents better Meropenem 1-2 g 2 g q 8 h IV infused over 3-6 h Salvage therapy with association of two carbapenems can be considered when other options are not suitable or available. 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

Expert opinion on MIC driven therapy for KPC-Kp. TREATMENT OPTIONS KPC-Kp meropenem MIC ≤ 64 mg/L Colistin-S KPC-Kp meropenem MIC > 64 mg/L Colistin-S KPC-Kp meropenem MIC > 64 mg/L Colistin-R   Meropenem 2 g every 8 hours iv + Tigecycline 100 mg every 12 hours iv + Colistin 4.5 MU every 12 hours iv or Gentamicin 3 -5 mg/Kg/d every 24 hours iv or Fosfomycin 4 g every 4 hours iv Ceftazidime/avibactam 2.5 g every 8 hours iv + Gentamicin 3 -5 mg/Kg/d every 24 hours or Colistin 4.5 MU every 12 hours iv + Tigecycline 100 mg every 12 hours iv or Gentamicin 3-5 mg/Kg/d every 24 hours iv +/- Rifampin 600-900 mg every 24 hours iv Ceftazidime/avibactam2.5 g every 8 hours iv + Gentamicin 3 -5 mg/Kg/d every 24 hours iv or Tigecyclin 100 mg every 12 hours iv (C) + Colistin 4.5 MU every 12 hours iv + Ertapenem 500 mg every 6 hours iv + Meropenem 2 g every 8 hours iv Doripenem 500 mg every 8 hours iv Gentamicin 3 -5 mg/Kg/d every 24 hours iv or 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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