multi-drug and extremely drug-resistant pseudomonas aeruginosa · extremely drug resistant (xdr) p....
TRANSCRIPT
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)
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
Summary
• Multidrug and Extremely resistant (MDR, XDR)
P. aeruginosa
• Epidemiology: high risk clones
• Current therapeutic options
• Future options
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.
Magiorakos et al., 2012, Peña et al., 2015; Sader et al., 2014;
Zhanel et al., 2010; Zilberberg and Shorr, 2013
72%
15%
13%
Ventas Non-MDR
XDR
MDR 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
Aminoglycoside Resistence
•Permeability alteration
• (ANT 2”Ia - ANT 4”-IIb) enzimes inactivation
• Efflux pumps Mex XY
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
Carbapenem resistance
• Porin OprM loss (imipenem)
• Efflux pumps Mex XY (affects aztreonam, meropenem and
cefepime)
Segura C et al Journal Microbiology Research 2012
XDR P. aeruginosa
Hospital del Mar,
Barcelona, Spain Extremely-resistance mechanisms
Montero M. PhD Thesis, 2012
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
P. aeruginosa high risk clones distribution
Oliver et al Diagn Resist Updates 2015; 21-22:41-59
P. aeruginosa high risk clones distribution
Oliver et al Diagn Resist Updates 2015; 21-22:41-59
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. 2017 Sep 5
Mechanisms of betalactam resistance
Multidrug resistant P. aeruginosa is
associated with higher mortality (2-fold)
Nathwani et al. Antimicrobial Resistance and Infection Control 2014, 3:32
Morales et al. BMC Health Services Research 2012,12:122
x2
Mortality risk factors XDR P. aeruginosa bacteremia
Risk factors for crude 14-day mortality
RR IC 95 % P
High risk source 2,42 1,17-5 0.02
PITT score ≥2
4,99 2,08-11,96 0,0001
McCabe score ≥2
2,02 1,03-3,98 0,041
Inadequate directed
therapy 2,88 1,14-7,32 0.02
402 PA bacteremia:123 (30.6%) XDR PA.
Propensity score: 116 BACPA VS 116 BACPA-XDR.
Montero et al. (unpublished data)
Morales et al. BMC Health Services Research 2012,12:122
Current therapeutic options for XDR
Pseudomonas aeruginosa
• Amikacin
• Colistin
• Ceftolozane tazobactam
• Ceftazidime avibactam
• Upcoming drugs
Amikacin for XDR P aeruginosa Sepsis
Britt et al. Antimicrob Agents Chemother 2018
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 0 1 (100)
Montero M, et al Infection 2009;37:461-5.
10 (8,3%) casos desarrollaron nefrotoxicidad
Yavah et al. Clin Microbiol Infect 2012; 18: 18–29
Favours colistin Favours comparator
MDR P. aeruginosa infections
treated with COLISTIN: comparative studies
Favours colistin
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
Sorlí et al. BMC Infectious Diseases (2017) 17:11
Independent risk factors for 30-day mortality:
Risk factor Odds Ratio 95% CI p
APACHE II score 1.98 1–1.20 0.046
McCabe score 2.49 1.145.43 0.021
Renal failure at EOT 3.8 1.26–11.47 0.018
Sorlí et al. BMC Infectious Diseases (2017) 17:11
No AKI (day 7) (n=76)
AKI (day 7) (n=26)
Age, years** 62.64 (24-91) 70.85 (41-84) 0.036 Male sex 61 (80.3) 18 (69.2) 0.281 Charlson Index** 4.12 (0-9) 5.5 (1-10) 0.031 APACHE II** 12.36 (2-28) 12.62 (5-24) 0.88 Clinical status: -Severe sepsis -Shock
39 (51.3)
7 (9.2)
9 (34.6) 1 (3.8)
0.175 0.457
BMI (Kg/m2)** 25.66 (14.69-54.6) 24.37 (15.24-39) 0.26
CMS total dose (MU)** 102.95 (5-465) 93.5 (20-442) 0.77 Cmin, mg/L* 1.01 (0.11-3.2) 3.13 (0.45-5.99) 0.000
Aminoglycoside use 24 (31.6) 8 (30.8) 1
Vancomycin use 8 (10.5) 1 (3.8) 0.442
NSAID use 11 (14.5) 22 (84.6) 0.005 Loop diuretic use 31 (40.8) 15 (57.7) 0.172
Other nephrotoxic drugs 17 (22.4) 4 (14.4) 0.579
Though colistin concentration is associated wih nephrotoxicity
Sorlí L, et al. BMC Infect Dis 2013;13:380
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, et al. BMC Infect Dis 2013;13:380
Though colistin concentration is associated wih nephrotoxicity
Sorlí L, et al. BMC Infect Dis 2013;13:380
Cminss ≤ 2.42 mg/L
N = 57
Cminss >2.42 mg/L
N= 7
p
Nephrotoxicity at day 7 of treatment, n (%) 11 (19.3%) 5 (71.4%) 0.001
Nephrotoxicity at the end of treatment, n (%) 18 (31,6%) 6 (85.7%) 0.009
Days until nephrotoxicity onset*, mean (SD) 9.2 (1,1) 6.2 (0.8)
0.091*
Cumulative CMS dose until nephrotoxicity
onset (millions IU), mean (SD)
47.8 (24.8) 43.2 (12.8) 0.880
Validation of Css = 2,42 mg/L and nephrotoxicity
* Mantel-Cox test
A Cminss> 2.42 mg/L was the only predictive factor of nephrotoxicity
in the multivariate analysis
(n = 64)
Horcajada JP et al. Int J Antimicrob Ther 2016;48:725
Current dosing of Colistin for severe infections
Nation et al. CID 2017;64(5):565–71
Urinary CMS and colistin concentrations in
XDR P. aeruginosa cUTI
Luque S et al. Antimicrobial Agents Chemother 2017;61(8).
Age, years** 65.1 + 13.1
Male sex, n (%)
Charlson score**
26 (78.8)
2.21 + 1.25
Upper Urinary Tract Infections 3 (9.1)
2CMS daily dose (millions IU)**
2CMS total cumulative dose (millions IU)*
2CMS treatment duration, days**
Colistin base activity (mg/kg/day)**
3GFR at baseline (ml/min/1.73 m2)**
4.8 + 2.4
24 (14.2-39.7)
8.3 + 6.4
2.21 + 1.25
100.3 + 65.2
Patients with 4CKD at baseline, n (%) 8 (24.2)
5Css (mg/L)** 1.2 + 1.1
7AUC/MIC** 61.6 + 56.8
7AUC/MIC ≥ 60 mg*h/L,n (%)
5CSS > 2.5 mg/L
8AKI at the end of treatment, n (%):
Clinical cure, n (%)
11 (33.3)
4 (12.1)
10 (30.3)
30 (90.9)
XDR P. aeruginosa cUTI treated with colistin (n=33)
Sorli L et al. ECCMID 2018 P2126
Isolate ST
Acquired
β-lactamases
AmpC hyperp
OprD
MIC (EUCAST category)
TOL/TZ MER CAZ AZT AMI COL
06-042 235 VIM-47 NO NO ˃64/4(R) ˃32 (R) 64 (R) 32 (R) 64 (R) 2 (S)
10-009 111 VIM-2 YES YES ˃64/4 (R) ˃32 (R) ˃64 (R) ˃128 (R)
32 (R) 4 (R)
04-025 175 YES YES 2/4 (S) 16 (R) 32 (R) 16 (I) 4 (S) 1 (S) 12-012 175 VIM-20, OXA-2 NO YES ˃64/4 (R) ˃32 (R) 16 (R) 8 (I) 16 (I) 2 (S)
07-004 235 GES-19, OXA-2 NO YES ˃64/4 (R) ˃32 (R) ˃64 (R) 128 (R) 128 (R)
2 (S)
04-017 111 OXA-46 YES NO 8/4 (R) 32 (R) 64 (R) 64 (R) 4 (S) 2 (S)
In vitro synergistic effects of colistin plus meropenem combination on
extensively drug-resistant (XDR) Pseudomonas aeruginosa high-risk clones María M Montero1, Sandra Domene Ochoa1, Carla López Causapé2, Núria Campillo1, Sonia Luque1, Luisa Sorlí1, Eduardo Padilla3,
Núria Prim3, Concepción Segura3, Virginia Pomar4, Alba Rivera4, Santiago Grau1, Antonio Oliver2, Juan P Horcajada1
Montero M. et al. ECCMID 2018, Madrid. Oral Presentation O0128
0
2
4
6
8
10
12
0 4 8 12 16 20 24
Log10CFU/ML
TimeHours
PAST175(04-025)ACONTROL
BAMIKACIN1gq24h
CMEROPENEM2gq8h
DCEFTAZIDIME2gq8h
EAZTREONAM2gq8h
FCOLISTIN4.5MUIq12h
GCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h
HAMIKACIN1gq24h+MEROPENEM2gq8h
IAMIKACIN1gq24h+CEFTAZIDIME2gq8h
JAMIKACIN1gq24h+AZTREONAM2gq8h
KAMIKACIN1gq24h+CEFTOLOZANE2gq24h/TAZOBACTAM1gq8hLCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h+MEROPENEM2gq8hMCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h+CEFTAZIDIME2gq8hNCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h+AZTREONAM2gq8hOCEFTAZIDIME2gq8h+COLISTIN4.5MUlq12h
PCEFTAZIDIME2gq8h+AZTREONAM2gq8h
QMEROPENEM2gq8h+COLISTIN4.5MUIq12h
P. aeruginosa high risk clone ST175
Time kill curves
Montero M. et al. ECCMID 2018, Madrid. Oral Presentation O0128
COLISTIN+MEROPENEM
COLISTIN+CEFTAZIDIME
0
2
4
6
8
10
12
0 4 8 12 16 20 24
Log10CFU/ML
TimeHours
PAST111(10-009)
ACONTROL
BAMIKACIN1gq24h
CMEROPENEM2gq8h
DCEFTAZIDIME2gq8h
EAZTREONAM2gq8h
FCOLISTIN4.5MUIq12h
GCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h
HAMIKACIN1gq2h4+MEROPENEM2gq8h
IAMIKACIN1gq24h+CEFTAZIDIME2gq8h
JAMIKACIN1gq24h+AZTREONAM2gq8h
KAMIKACIN1gq24h+CEFTOLOZANE2gq24h/TAZOBACTAM1gq8hLCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h+MEROPENEM2gq8hMCEFTOLOZANE2gq24h/TAZOBACTAM1gq8h+CEFTAZIDIME2gq8hNCEFTAZIDIME2gq8h+COLISTIN4.5MUlq12h
OAZTREONAM2gq8h+COLISTIN4.5MUIq12h
PMEROPENEM2gq8h+COLISTIN4.5MUIq12h
0
2
4
6
8
10
12
0 4 8 12 16 20 24
Log10CFU/ML
TimeHours
ST235(06-042)ACONTROL
BAMIKACIN1gq24h
CMEROPENEM2gq8h
DCEFTAZIDIME2gq8h
EAZTREONAM2gq8h
FCOLISTIN4.5MUIq12h
GCEFTOLOZANE/TAZOBACTAM2gq8h
HAMIKACIN1gq24h+MEROPENEM2gq8h
IAMIKACIN1gq24h+CEFTAZIDIME2gq8h
JAMIKACIN1gq24h+AZTREONAM2gq8h
KAMIKACIN1gq24h+CEFTOLOZANE/TAZOBACTAM2gq8hLCEFTOLOZANE/TAZOBACTAM2gq8h+MEROPENEM2gq8hMCEFTOLOZANE/TAZOBACTAM2gq8h+CEFTAZIDIME2gq8hNCEFTAZIDIME2gq8h+COLISTIN4.5MUIq12h
PA high risk clones ST111, ST 235
Montero M. et al. ECCMID 2018,
Madrid Oral Pres. O0128
ST111
Pan-drug resistant
ST 235
High virulence clone
Time kill curves
Time kill curves
COLISTIN+MEROPENEM
COLISTIN+CEFTAZIDIME
COLISTIN+MEROPENEM
New and upcoming antipseudomonal drugs
• Cetolozane-tazobactam
• Ceftazidime-avibactam
• Imipenem-relebactam
• Cefepime-zidebactam
• Cefiderocol
• Murepavadine
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):1046–56
Cho JC, Pharmacotherapy.2015;35(7):701–15.
Castanheira M. et al. Antimicrob Agents Chemother 2014;58:6844–6850.
In vitro activity of Ceftolozano-tazobactam
Farrell DJ,. Antimicrob Agents Chemother 2013;57:6305–10.
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. 2017 Sep 5
Clinical experience with TOL-TAZ in
MDR P. aeruginosa infections
N = 21
• 30-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
Clinical experience with TOL-TAZ in
MDR P. aeruginosa infections
Escolà-Vergè et al. Infection 2018
Montero M, et al. Antimicrobial Agents Chemother (under review) Montero M, et al. Antimicrob Agents Chemother 2018; Mar 12. pii: AAC.00026-18.
Emergence of resistance during drug
administration in P. aeruginosa ST175
Montero M, et al. Antimicrob Agents Chemother 2018; Mar 12. pii: AAC.00026-18.
CAZ and CAZ-AVI MIC distributions in
bacteremic MDR P. aeruginosa isolates in Spain
Torrens G et al. Antimicrob Agents Chemother 2016; 60:6407-10
Ceftazidime-avibactam
CAZ and CAZ-AVI MIC distributions in
bacteremic MDR P. aeruginosa isolates in Spain
Torrens G et al. Antimicrob Agents Chemother 2016; 60:6407-10
Clinical activity of ceftazidime/avibactam against MDR
Enterobacteriaceae and P. aeruginosa: from
5 Phase III clinical trials
Stone et al. JAC 2018 Sep
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;68:2286–2290
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 MBL-
producing 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:e02529-16.
• 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.
Cefepime-zidebactam
Moya et al. Antimicrob Agents Chemother 2016; 61:e02529-16.
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
Murepavadine: a specific
antipseudomonal peptidomimetic
Inhibition of LPS transport to the cell surface
Inhibition of Outer membrane LPS synthesis
Werneburg M, et al. Chembiochem 2012;13:1767–1775
Andolina G, et al. ACS Chem Biol. 2018 Mar 16;13:666
Murepavadin (POL7080) [Internet]. Polyphor Ltd. [cited 2017 Nov 7]. https://www.polyphor.com/pol7080/.
.
Strong activity against
P. aeruginosa
among over 1500 worldwide
isolates (MIC90 ≤0.25 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
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, cefepime-zidebactam, cefiderocol, murepavadine
