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 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

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): 4

5. 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)

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

7. 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)

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
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

11. Combination therapy lowering mortality in KPC bacteremia
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. 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:

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
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
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

21. Anti-Gram-negative activity of new antibiotics
ESBL
CRE
MDR P.aeruginosa
MDR Acinetobacter S
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

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 Enterobacteriaceae Shields RK, et al. Antimicrob Agents Chemother Jul 25;61(8) e

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

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 Sep 4, DOI: /cid/cix783

25. 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

27. 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 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) , 27

28. 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: 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* mg
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)
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
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 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)

30. Regis
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