The Challenge of MDR and XDR infections Friday 14th September, Barcelona Multi-drug and Extremely drug-resistant Pseudomonas aeruginosa

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1 The Challenge of MDR and XDR infections Friday 14th September, Barcelona Multi-drug and Extremely drug-resistant Pseudomonas aeruginosa Juan P. Horcajada Service of Infectious Diseases Hospital del Mar, Barcelona, Spain Hospital del Mar Research Institute (IMIM)

2 Disclosures Advisory boards: Pfizer, MSD, Astellas, Angelini, Novartis, Astra Zeneca, Zambon Presentations: Pfizer, MSD, Astellas, Angelini, Novartis, Astra Zeneca Grants: MSD Supported by Insituto de Salud Carlos III FIS, REIPI

3 Summary Multidrug and Extremely resistant (MDR, XDR) P. aeruginosa Epidemiology: high risk clones Current therapeutic options Future options

4 Extremely drug resistant (XDR) P. aeruginosa MDR: resistance to at least three of eight antibiotic classes Prevalence has increased to 15 to 30% in many areas. XDR: resistance to all but one or two of the eight classes. In a multicentre spanish study on P. aeruginosa bloodstream infections 28% of the isolates were MDR and 52% of them (15% of all isolates) met the XDR criteria, most being only susceptible to polymixins ± amikacin Ventas Non-MDR XDR MDR 13% 15% 72% Magiorakos et al., 2012, Peña et al., 2015; Sader et al., 2014; Zhanel et al., 2010; Zilberberg and Shorr, 2013

5 XDR P. aeruginosa Hospital del Mar, Barcelona, Spain Extremely-resistance mechanisms Betalactamic resistance Chromosomal AmpC hyperproduction Efflux pumps Mex XY Porin OprM mutation Type OXA 1 & 2 enzymes Quinolone Resistence Girase (gyra) - Topoisomerase (parc) mutations Permeability alteration Aminoglycoside Resistence Permeability alteration (ANT 2 Ia - ANT 4 -IIb) enzimes inactivation Efflux pumps Mex XY Carbapenem resistance Porin OprM loss (imipenem) Efflux pumps Mex XY (affects aztreonam, meropenem and cefepime) Montero M. PhD Thesis, 2012 Segura C et al Journal Microbiology Research 2012

6 P. aeruginosa high risk clones MDR/XDR global clones disseminated worldwide They play a major role in the spread of resistance, Risk = tenacity and a flexible ability to accumulate and switch resistance Association with transferable and mutational resistance mechanisms Highly infrequent among susceptible isolates Woodford N, et al. FEMS Microbiol Rev. 2011;35:736 Oliver A, et al. Diagn Resist Updates 2015;21-22:41-59

7 P. aeruginosa high risk clones distribution Oliver et al Diagn Resist Updates 2015; 21-22:41-59

8 P. aeruginosa high risk clones distribution Oliver et al Diagn Resist Updates 2015; 21-22:41-59

9 XDR Pseudomonas. COLIMERO study 150 XDR clinical isolates from 9 Spanish hospitals in 2015 ST175: the most frequent high-risk clone (67.3%) and disseminated Mechanisms of betalactam resistance Barrio-Tofiño E et al. Antimicrob Agents Chemother Sep 5

10 Multidrug resistant P. aeruginosa is associated with higher mortality (2-fold) Nathwani et al. Antimicrobial Resistance and Infection Control 2014, 3:32

11 x2 Morales et al. BMC Health Services Research 2012,12:122

12 Mortality risk factors XDR P. aeruginosa bacteremia 402 PA bacteremia:123 (30.6%) XDR PA. Propensity score: 116 BACPA VS 116 BACPA-XDR. Risk factors for crude 14-day mortality RR IC 95 % P High risk source 2,42 1, PITT score 2 4,99 2,08-11,96 0,0001 McCabe score 2 Inadequate directed therapy 2,02 1,03-3,98 0,041 2,88 1,14-7, Montero et al. (unpublished data)

13 Morales et al. BMC Health Services Research 2012,12:122

14 Current therapeutic options for XDR Pseudomonas aeruginosa Amikacin Colistin Ceftolozane tazobactam Ceftazidime avibactam Upcoming drugs

15 Amikacin for XDR P aeruginosa Sepsis Britt et al. Antimicrob Agents Chemother 2018

16 Colistin for invasive XDR P. aeruginosa infections Total n = 121 Favourable Clinical response N (%) Crude Mortality N (%) Microbiological outcome N (%) Eradication Indeterminate Bacteremia (n=16) 10 (62.5) 6 (37.5) 7 (43.8) 3 (18.8) Pneumonia (n=20) 13 (65) 7 (35) 6 (30) 7 (35) Bronchial infection (n=59) 43 (72.9) 6 (10.2) 9 (15.3) 14 (23.7) Urinary (n=13) 11 (84.6) 1 (7.7) 3 (23.1) 4 (30.8) Skin and soft tissues (n=11) 8 (72.7) 0 5 (45.5) 3 (27.3) Otitis, (n=1) 1 (100) 0 1 (100) 0 Arthritis, (n=1) 1 (100) 0 10 (8,3%) casos desarrollaron nefrotoxicidad 0 1 (100) Montero M, et al Infection 2009;37:461-5.

17 MDR P. aeruginosa infections treated with COLISTIN: comparative studies Favours colistin Favours comparator Yavah et al. Clin Microbiol Infect 2012; 18: 18 29

18 Colistin dose and clinical response CR GNB bacteremia (n=127) High-dose colistin (>4.4 mg/kg/day) is independently associated with day 7 clinical cure, microbiologic success, and mortality Gibson et al. AAC 2016; 60:431-6

19 Sorlí et al. BMC Infectious Diseases (2017) 17:11

20 Independent risk factors for 30-day mortality: Risk factor Odds Ratio 95% CI p APACHE II score McCabe score Renal failure at EOT Sorlí et al. BMC Infectious Diseases (2017) 17:11

21 Though colistin concentration is associated wih nephrotoxicity No AKI (day 7) (n=76) AKI (day 7) (n=26) Age, years** (24-91) (41-84) Male sex 61 (80.3) 18 (69.2) Charlson Index** 4.12 (0-9) 5.5 (1-10) APACHE II** (2-28) (5-24) 0.88 Clinical status: -Severe sepsis -Shock 39 (51.3) 7 (9.2) 9 (34.6) 1 (3.8) BMI (Kg/m 2 )** ( ) ( ) 0.26 CMS total dose (MU)** (5-465) 93.5 (20-442) 0.77 C min, mg/l* 1.01 ( ) 3.13 ( ) Aminoglycoside use 24 (31.6) 8 (30.8) 1 Vancomycin use 8 (10.5) 1 (3.8) NSAID use 11 (14.5) 22 (84.6) Loop diuretic use 31 (40.8) 15 (57.7) Other nephrotoxic drugs 17 (22.4) 4 (14.4) Sorlí L, et al. BMC Infect Dis 2013;13:380

22 Though colistin concentration is associated wih nephrotoxicity The breakpoints that better predict nephrotoxicity at day 7 and EOT were 3.33 mg/l (p 0.001) and 2.42 mg/l (p 0.001) respectively. Sorlí L, L, et et al. al. BMC Infect Dis Dis 2013;13:380

23 Validation of Css = 2,42 mg/l and nephrotoxicity (n = 64) Cminss 2.42 mg/l N = 57 Cminss >2.42 mg/l Nephrotoxicity at day 7 of treatment, n (%) 11 (19.3%) 5 (71.4%) Nephrotoxicity at the end of treatment, n (%) 18 (31,6%) 6 (85.7%) N= 7 Days until nephrotoxicity onset*, mean (SD) 9.2 (1,1) 6.2 (0.8) Cumulative CMS dose until nephrotoxicity onset (millions IU), mean (SD) p 0.091* 47.8 (24.8) 43.2 (12.8) * Mantel-Cox test A Cmin ss > 2.42 mg/l was the only predictive factor of nephrotoxicity in the multivariate analysis Horcajada JP et al. Int J Antimicrob Ther 2016;48:725

24 Current dosing of Colistin for severe infections Nation et al. CID 2017;64(5):565 71

25 Urinary CMS and colistin concentrations in XDR P. aeruginosa cuti Luque S et al. Antimicrobial Agents Chemother 2017;61(8).

26 XDR P. aeruginosa cuti treated with colistin (n=33) Age, years** Male sex, n (%) 26 (78.8) Charlson score** Upper Urinary Tract Infections 3 (9.1) 2 CMS daily dose (millions IU)** CMS total cumulative dose (millions IU)* 24 ( ) 2 CMS treatment duration, days** Colistin base activity (mg/kg/day)** GFR at baseline (ml/min/1.73 m 2 )** Patients with 4 CKD at baseline, n (%) 8 (24.2) 5 C ss (mg/l)** AUC/MIC** AUC/MIC 60 mg*h/l,n (%) 5 C SS > 2.5 mg/l 8 AKI at the end of treatment, n (%): Clinical cure, n (%) 11 (33.3) 4 (12.1) 10 (30.3) 30 (90.9) Sorli L et al. ECCMID 2018 P2126

27 In vitro synergistic effects of colistin plus meropenem combination on extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clones María M Montero 1, Sandra Domene Ochoa 1, Carla López Causapé 2, Núria Campillo 1, Sonia Luque 1, Luisa Sorlí 1, Eduardo Padilla 3, Núria Prim 3, Concepción Segura 3, Virginia Pomar 4, Alba Rivera 4, Santiago Grau 1, Antonio Oliver 2, Juan P Horcajada 1 Isolate ST Acquired β-lactamases AmpC hyperp OprD MIC (EUCAST category) TOL/TZ MER CAZ AZT AMI COL VIM-47 NO NO 64/4(R) 32 (R) 64 (R) 32 (R) 64 (R) 2 (S) VIM-2 YES YES 64/4 (R) 32 (R) 64 (R) 32 (R) 4 (R) (R) YES YES 2/4 (S) 16 (R) 32 (R) 16 (I) 4 (S) 1 (S) VIM-20, OXA-2 NO YES 64/4 (R) 32 (R) 16 (R) 8 (I) 16 (I) 2 (S) GES-19, OXA-2 NO YES 64/4 (R) 32 (R) 64 (R) 128 (R) 2 (S) (R) OXA-46 YES NO 8/4 (R) 32 (R) 64 (R) 64 (R) 4 (S) 2 (S) Montero M. et al. ECCMID 2018, Madrid. Oral Presentation O0128

28 Log 10 CFU/ML P. aeruginosa high risk clone ST175 Time kill curves PA ST175 (04-025) A CONTROL B AMIKACIN 1g q24h C MEROPENEM 2g q8h D CEFTAZIDIME 2g q8h E AZTREONAM 2g q8h F COLISTIN 4.5 MUI q12h G CEFTOLOZANE 2g q24h/tazobactam 1g q8h H AMIKACIN 1g q24h + MEROPENEM 2g q8h I AMIKACIN 1g q24h + CEFTAZIDIME 2g q8h J AMIKACIN 1g q24h + AZTREONAM 2g q8h COLISTIN+CEFTAZIDIME Time Hours COLISTIN+MEROPENEM K AMIKACIN 1g q24h + CEFTOLOZANE 2g q24h/ TAZOBACTAM 1g q8h L CEFTOLOZANE 2g q24h/tazobactam 1g q8h + MEROPENEM 2g q8h M CEFTOLOZANE 2g q24h/tazobactam 1g q8h + CEFTAZIDIME 2g q8h N CEFTOLOZANE 2g q24h/tazobactam 1g q8h + AZTREONAM 2g q8h O CEFTAZIDIME 2g q8h + COLISTIN 4.5MUl q12h P CEFTAZIDIME 2g q8h + AZTREONAM 2g q8h Q MEROPENEM 2g q8h + COLISTIN 4.5 MUI q12h Montero M. et al. ECCMID 2018, Madrid. Oral Presentation O0128

29 Log 10 CFU/ML Log 10 CFU/ML PA high risk clones ST111, ST 235 Time kill curves PA ST111 (10-009) A CONTROL B AMIKACIN 1g q24h C MEROPENEM 2g q8h D CEFTAZIDIME 2g q8h 8 E AZTREONAM 2g q8h F COLISTIN 4.5 MUI q12h ST111 6 G CEFTOLOZANE 2g q24h/tazobactam 1g q8h H AMIKACIN 1g q2h4 + MEROPENEM 2g q8h Pan-drug resistant I AMIKACIN 1g q24h + CEFTAZIDIME 2g q8h 4 J AMIKACIN 1g q24h + AZTREONAM 2g q8h COLISTIN+CEFTAZIDIME 2 COLISTIN+MEROPENEM Time Hours K AMIKACIN 1g q24h + CEFTOLOZANE 2g q24h/ TAZOBACTAM 1g q8h L CEFTOLOZANE 2g q24h/tazobactam 1g q8h + MEROPENEM 2g q8h M CEFTOLOZANE 2g q24h/tazobactam 1g q8h + CEFTAZIDIME 2g q8h N CEFTAZIDIME 2g q8h + COLISTIN 4.5 MUl q12h O AZTREONAM 2g q8h + COLISTIN 4.5 MUI q12h P MEROPENEM 2g q8h + COLISTIN 4.5 MUI q12h Time kill curves 12 ST235 (06-042) A CONTROL B AMIKACIN 1g q24h 10 C MEROPENEM 2g q8h 8 D CEFTAZIDIME 2g q8h E AZTREONAM 2g q8h F COLISTIN 4.5 MUI q12h ST G CEFTOLOZANE/TAZOBACTAM 2g q8h H AMIKACIN 1g q24h + MEROPENEM 2g q8h High virulence clone I AMIKACIN 1g q24h + CEFTAZIDIME 2g q8h 4 J AMIKACIN 1g q24h + AZTREONAM 2g q8h 2 0 COLISTIN+MEROPENEM Time Hours K AMIKACIN 1g q24h + CEFTOLOZANE/TAZOBACTAM 2g q8h L CEFTOLOZANE/TAZOBACTAM 2g q8h + MEROPENEM 2g q8h M CEFTOLOZANE/TAZOBACTAM 2g q8h + CEFTAZIDIME 2g q8h N CEFTAZIDIME 2g q8h + COLISTIN 4.5 MUI q12h Montero M. et al. ECCMID 2018, Madrid Oral Pres. O0128

30 New and upcoming antipseudomonal drugs Cetolozane-tazobactam Ceftazidime-avibactam Imipenem-relebactam Cefepime-zidebactam Cefiderocol Murepavadine

31 Ceftolozane-tazobactam High affinity for PBPs: P. aeruginosa: PBP1b, PBP1c, PBP3 E. coli: PBP3 Higher stability against AmpC type enzyms GNB External membrane higher permeability Lack of efflux pumps and porine mutations effect Higher activity against P. aeruginosa, incl. XDR Tazobactam inhibits betalactamases and ESBLs Sucher AJ, et al. Ann Pharmacother. 2015;49(9): Cho JC, Pharmacotherapy.2015;35(7): Castanheira M. et al. Antimicrob Agents Chemother 2014;58:

32 In vitro activity of Ceftolozano-tazobactam Farrell DJ,. Antimicrob Agents Chemother 2013;57:

33 XDR Pseudomonas. COLIMERO study 150 XDR clinical isolates from 9 Spanish hospitals in 2015 ST175: the most frequent high-risk clone (67.3%) and disseminated Barrio-Tofiño E et al. Antimicrob Agents Chemother Sep 5

34 Clinical experience with TOL-TAZ in MDR P. aeruginosa infections N = day mortality: 10% Clinical failure 29% (6/21). SAPS-II score was the sole predictor of failure. Ceftolozane-tazobactam resistance emerged in 3 (14%) patients. ampc over-expresson and mutations within the AmpC Ω-loop or H2 helix Haidar G, et al Clin Infect Dis 2017;65:110

35 Clinical experience with TOL-TAZ in MDR P. aeruginosa infections Escolà-Vergè et al. Infection 2018

36 Montero M, et al. Antimicrobial Agents Chemother (under review) Montero M, et al. Antimicrob Agents Chemother 2018; Mar 12. pii: AAC

37 Emergence of resistance during drug administration in P. aeruginosa ST175 Montero M, et al. Antimicrob Agents Chemother 2018; Mar 12. pii: AAC

38 Ceftazidime-avibactam CAZ and CAZ-AVI MIC distributions in bacteremic MDR P. aeruginosa isolates in Spain Torrens G et al. Antimicrob Agents Chemother 2016; 60:

39 CAZ and CAZ-AVI MIC distributions in bacteremic MDR P. aeruginosa isolates in Spain Torrens G et al. Antimicrob Agents Chemother 2016; 60:

40 Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and P. aeruginosa: from 5 Phase III clinical trials Stone et al. JAC 2018 Sep

41 Imipenem relebactam Relebactam potentiates the activity of imipenem against imipenem non-susceptible P. aeruginosa with AmpC production and OprD porin loss Imipenem is a particularly good choice to combine with relebactam as both agents are poor substrates for efflux pumps Against imipenem non-susceptible P. aeruginosa (n=251) isolated from patients in USA, IMI-REL MIC90/50 was 4/2 μg/ml, 8-fold lower than imipenem alone (32/16 μg/ml). Only 6.8% of strains were IMI-REL resistant Lob SH, Antimicrob. Agents Chemother. 2017;61:1 9. Livermore DM, J. Antimicrob. Chemother. 2013;68:

42 Cefepime-zidebactam Zidebactam, a diazabicyclooctane in the same class as avibactam, has a dual mechanism Inhibition of several β-lactamases Selective and high-affinity binding to PBP-2 Active against many Enterobacteriaceae and P. aeruginosa, including MBLproducing P. aeruginosa, lowering the MIC90/50 from 128/32 μg/ml with cefepime alone to 8/4 μg/ml Moya et al. Antimicrob Agents Chemother 2016; 61:e

43 Cefepime-zidebactam Zidebactam is a β-lactam enhancer reduces the level of cefepime exposure required for efficacy. Both together act against PBP-1, 2 & 3: High-affinity PBP2 engagement by zidebactam causes the cells to convert into spheroplasts Perturbation in the outer membrane, leading to modulation of membrane-bound resistance mechanisms such as efflux, porin, and expression of β lactamases Then cefepime engages to other essential PBPs, leading to pronounced bacterial lysis. Moya et al. Antimicrob Agents Chemother 2016; 61:e

44 Cefiderocol Siderophore cephalosporin that reaches PBP-3, by using the iron transport system to augment periplasmic penetration. Stable to most Class A, B, C, and D β-lactamases. In vitro 353 (100%) meropenem-nonsusceptible P. aeruginosa strains exhibited MICs 4 μg/ml. In vivo in the neutropenic murine thigh infection model, showed potent efficay among 17 (85%) P. aeruginosa isolates Phase 3 trial APEKS-cUTI non-inferior to imipenem for with 183 (72.6%) patients achieving the outcome in the group versus 65 (54.6%) in the imipenem group Hackel MA, Antimicrob. Agents Chemother. 2017;61:1 22. Monogue ML,. Antimicrob. Agents Chemother. 2017;61:1 10

45 Murepavadine: a specific antipseudomonal peptidomimetic Strong activity against P. aeruginosa among over 1500 worldwide isolates (MIC μg/ml) Proven efficacy in animal models with good penetration into lung epithelial lining fluid (ELF) Clinical cure rate at test-of-cure was 91% in 12 patients with VAP caused by P. aeruginosa Inhibition of LPS transport to the cell surface Inhibition of Outer membrane LPS synthesis Werneburg M, et al. Chembiochem 2012;13: Andolina G, et al. ACS Chem Biol Mar 16;13:666 Murepavadin (POL7080) [Internet]. Polyphor Ltd. [cited 2017 Nov 7].

46 Conclusions XDR P. aeruginosa as a great concern High risk clones are disseminating around the world Colistin is not the best option. Moderate effectiveness and high toxicity. Narrow therapeutic window. TDM. Polymixins combinations as a possible option Ceftolozane-tazobactam plus meropenem useful for ST175 clone Ceftazidime-avibactam useful for hyper amp-c production Promising new drugs: imipenem-relebactam, cefepimezidebactam, cefiderocol, murepavadine

47 Thank you and welcome to Barcelona!