Therapeutic challenge of MDR- Enterobacteriaceae infections · •Asymptomatic carrier, follow-up:...

Therapeutic challenge of MDR-Enterobacteriaceae infections

Jesús Rodríguez Baño, MD PhD FESCMID

Infectious Diseases Division, Hospital Universitario Virgen Macarena

Biomedicine Institute of Seville (IBiS), University of Seville

Spanish Network for Reearch in Infectious Diseases (REIPI)

Conflicts of interest

• Honoraria for accredited educational activities (Merck), 2016

• Honoraria for design and coordination of a research project, unrelated to products (AstraZeneca), 2015

• Funds for research from IMI, COMBACTE projects (EU+EFPIA)

Resistance in Enterobacteriaceae

• Fluoroquinolones

– 2+ chromosomal mutations

– Low level: 1 mutation or plasmid-mediated mechanisms

• Cephalosporins

– ESBLs (CTX-M most frequent)

– AmpC

• Carbapenems

– β-lactamases + permeability

– Carbapenemases (KPC, MBL, OXA-48)

Clinical epidemiology

• Reservoirs

– Bowel of persons, animals

– Environment

• Transmission

– Person-to-person (K. pneumoniae: HCA; E. coli: household)

– Contaminated food, water

– Facilitated by antibiotics (cephs, FQ, carbapenems, etc)

Molecular epidemiology

• Microorganisms

– E. coli: policlonal (but some succesful clones – ST131)

– K. pneumoniae: frequently clonal – eg, KPC “high-risk clones” (STs 258, 11, 512)

• Resistance genes – succesful mobile genetic elements

EARS-net 2016. E. coli

Fluoroquinolone-R Third gen. ceph-R

Third gen. ceph-R

EARS-net 2016. K. pneumoniae

Carbapenem-R

Penicillinases

Cephalosporinases (ESBLs, AmpCs)

Carbapenemases (MLBs, KPC, OXA)

Broad spectrum penicillinases (TEM-1, SHV-1)

The β-lactamases staircase

… and then colistin-resistance!

FEP AZT FOX AMC TZP MER

>75% R

Enterobacteriacae: susceptibilty to β-lactams according to β-lactamases

>25% R <25% R

Van Boeckel et al

Clin Infect Dis 2016 N=37. Mortality 24% 10 microbiological failure 3 resistance

Antimicrob Agents Chemother 2017

Ceftazidime-avibactam: development of R

Challenges

• When is it neccesary to empirically cover ESBL/AmpC and carbapenemase-producers?

• Are there carbapenem-spare options for empirical or targeted therapy of ESBL/AmpC?

• What is the best treatment for carbapenemase-producers?

• How can we preserve new drugs?

Challenges

• When is it neccesary to empirically cover ESBL/AmpC and carbapenemase-producers?

• Are there carbapenem-spare options for empirical or targeted therapy of ESBL/AmpC?

• What is the best treatment for carbapenemase-producers?

• How can we preserve new drugs?

Predictors for invasive infection due to ESBL producers

• A) Highly predictive

– Colonization/infection with ESBL1,2

– Recent antibiotics (mainly cephs, FQ)1,2,3

• B) Moderately predictive

– Healthcare-associated (LTCF, recent admission)1,3

– Recent procedure 1,2,3

• Proposal

– If severe sepsis/shock: 1 (A) or 2 (B)

– Non-severe: 2 (A) or 1 (A) + 2 (B)

1. Godman et al, Clin Infect Dis 2016

2. Augustine et al, Infect Control Hosp Epidemiol 2016

3. Lee et al, Medicine 2017

Challenges

• When is it neccesary to empirically cover ESBL/AmpC and carbapenemase-producers?

• Are there carbapenem-spare options for empirical or targeted therapy of ESBL/AmpC?

• What is the best treatment for carbapenemase-producers?

• How can we preserve new drugs?

Candidates as carbapenems-spare regimens

• Beta-lactams – BLBLI – Cephamycins – Cephalosporins – Temocillin – Pivmecillinam

• Aminoglycosides • Fluroquinolones • TMP/SMX • Fosfomycin

Clin Infect Dis 2017

Clin Microbiol Rev 2018

PS-adjusted HR for mortality (reference= carbapenem): 0.65 (0.23-1.65) PS-matched pairs: mortality carbapenem 16.4% vs BLBLI 7,3%

Antimicrob Agents Chemthr 2016

Meta-analyses for BLBLI in ESBLs

• Muhammed et al, OFID 2017

– Empirical: RR=1.05 (95% CI: 0.83–1.37)

– Definite: RR=0.62 (95% CI: 0.25–1.52)

• Son et al, J Antimicrob Chemother 2018

– Empirical: RR=1.01 (95% CI: 0.74, 1.38)

– Definite: RR=0.67 (95% CI: 0.37, 1.20)

• Meropenem vs piptazo for targeted treatment of bloodstream infection due to ceph-R Enterobacteriaceae

• Trial stopped because of non-inferiority of piptaz – Mortality 3.7% v 12.3%

• Limitations – Piptaz susceptibility by E-test (EUCAST warning)

– Potental disbalance between groups

– Mortality unrelated to infection

– Higher mortality wit piptazo in low-middle income countries

JAMA 2018

Empirical therapy No. deaths/ treated (%)

High-risk score (%)

Low-risk score (%)

Carbapenems 51/249 (20.4) 41/81 (50.6) 11/168 (6.5)

Other active drugs 16/87 (18.3) 14/28 (50) 2/59 (3.3)

Cephalosporin as only active drug 2/7 (28.6) 1/2 (50) 1/5 (20)

Aminoglycoside as only active drug 9/41 (21.9) 8/16 (50) 1/25 (4)

Fluoroquinolone as only active drug 2/19 (10.5) 2/2 (100) 0/17 (0)

TMP-SMX as only active drug 0/4 (0) 0/1 (0) 0/3 (0)

Tigecycline as only active drug 1/2 (50) 1/2 (50) 0

Others used as only active drug 2/10 (20) 2/4 (50) 0/6 (0)

Other combinations 0/4 (0) 0/1 (0) 0/3 (0)

Adjusted HR (mortality) = 0.75 (95% CI: 0.38-1.48) p=0.42 HR in propensity-score matched pairs: 0.68 (95% CI 0.31–1.48; P = 0.33).

BMJ Open 2015

Challenges

• When is it neccesary to empirically cover ESBL/AmpC and carbapenemase-producers?

• Are there carbapenem-spare options for empirical or targeted therapy of ESBL/AmpC?

• What is the best treatment for carbapenemase-producers?

• How can we preserve new drugs?

Clin Microbiol Infect 2011

Clin Microbiol Rev 2012

Clin Microbiol Rev 2012

AG Carb

TIG

COL Inactive

Comb (-carba)

Comb (+carba)

BSI due to CPE Combination vs monotherapy - Cohort studies

• Not associated with mortality

– Capone, CMI 2013

– De Oliveira, CMI 2015

– Satlin, AAC 2015

– Gomez-Simmonds, AAC 2016

• Associated with lower mortality

– Qureshi, AAC 2012

– Tumbarello, CID 2012

– Daikos, AAC 2014

– Tofas, IJAA 2016

– Trecarichi, Am J Hematol 2016

– Machuca, AAC 2017

– Papadimitrou, EJCMID 2017

Reviewed at Clin Microbiol Rev 2018

aHR=

aOR=1.21 (0.56-2.56) p=0.62 aHR=0.56 (0.34-0.91) p=0.02 Absolute difference 14% Absolute difference -4%

COL COL+MER RR comb (95% CI) P Absolute difference

RCT (Paul et al, TLID 2018)

COL COL+MER RR comb (95% CI) P Absolute difference

Observational, high-risk (Gutierrez-Gutierrez et al, Lancet Infect Dis 2017) Enterobacteriaceae 64 (62%) n=103 30 (48%) n=63 0.56 (0.34-0.91) 0.002 14%

14%

RCT (Paul et al, TLID 2018)

Some problems

• Inclusion allowed until 6 days after susceptibility was available

• Only 3% of isolates with meropenem MIC <16 mg/L

• Colistin MIC performed at each site – method??

• Not applicable to P. aeruginosa or Enterobacteriaceae

• Asymptomatic carrier, follow-up: GR score (risk of infection due to KPC)

– <7 (low risk of infection): no intervention

– 7-11 (moderate risk): consider decolonization with gentamicin*

– ≥12 (high risk): decolonization with gentamicin*

• Infection, empirical therapy: GR and INCREMENT (risk of mortality)

– GR <7, INCREMENT <7: standard treatment (no KPC coverage)

– GR ≥7 , INCREMENT<7: monotherapy with KPC coverage

– INCREMENT ≥7: combination with KPC coverage

Clin Infect Dis 2018

*Machuca et al, JAC 2016

Inhibition of beta-lactamases: new compounds

Ambler class

Enzime Ceftolozane/ tazobactam

Ceftazidime/ avibactam1

Meropenem/ vaborvactam2

A ESBL Yes Yes Yes

KPC No Yes Yes

B MBL No No No

C AmpC Variable Yes Yes

D OXA-48 No Yes No

Ceftazidime-avibactam N=38

Colistin N=99

BSI 15 (39.4) 48 (48.4)

Combination therapy 24 (63.1) 93 (93.3)

In-hospital mortality 3 (7.8) 33 (33.3)

DOOR:IPTW-adjusted probability (95% CI)

Efficacy 0.64 (0.57-0.71)

Safety 0.62 (0.52-0.72)

Benefit:risk 0.64 (0.53-0.75)

Van Duin et al, Clin Infect Dis 2017

IDWeek 2017

Isolate susceptibility High risk: COMBINATION therapy

Susceptible to a β-lactam (use according to susceptibility)

Backbone: CAZ-AVI, MER-VAB Alternatives: MER (MIC ≤8 mg/L) or CAZ or ATM

Accompanying drug: COL or TIG or AG or FOS (CAZ-AVI or MER-VAB might not need combination)

Resistant to all β-lactams (MER >8 mg/L), susceptible to at least 2 drugs including colistin

Backbone: COL

Accompanying drug: TIG, AG (high risk of nephrotoxicity), FOS

Resistant to all β-lactams and colistin, susceptible to at least 2 drugs

Backbone: TIG or AG

Accompanying drug: TIG, AG, FOS

Pandrug-resistant or susceptible only to one drug

(MER + ERT) or (CAZ-AVI + ATM) Consider: any active drug (CLO, RMP…), investigational drugs, in vitro testing for synergy

Low risk: MONOTHERAPY

According to susceptibility CAZ-AVI, MER-VAB, MER, CAZ, ATM, COL, TIG, AG

TIG: mostly for cIAI; for HAP/VAP, consider double dose AG: mostly for cUTI; for HAP/VAP, consider high dose. TDM recommended. FOS: mostly for cUTI

Rodríguez-Baño J, Gutiérrez B, Machuca I, Pascual A. Clin Microbiol Rev 2018

Drug Usual/standard doses Dosing for CRE and comments

Meropenem 1 gr/8 hours 2 g/8 hours in EI (isolates with MIC 2-8 mg/L) Ertapenem 1 g/24 hours Consider 2 g/day for double-carbapenem regimens

Colistin1 EMA: Loading dose, 6-9 MU; 9 MU/day in 2-3 doses FDA: 2.5-5 mg of colistin-base activity/kg/day

EMA dose is recommended for severe CRE infections. Need for loading dose and high continuation dose in patients without severe infection/shock is controversial

Polymyxin B2 FDA: 1.5-2.5 mg/Kg/day in 2 doses.

Mild infections and isolates with MIC ≤1 mg/L: FDA dose is probably appropriate. Severe infections and MIC up to 4 mg/L: loading dose 2-2.5 mg/kg followed by 3 mg/kg/day in 2 doses recommended (controversial).

Tigecycline 100 mg loading dose, then 50 mg/12 hours

If HAP, cUTI, BSI or shock: consider 200 mg loading dose, then 100 mg/12 hours

Gentamicin, tobramycin 5-7 mg/kg/day If HAP or shock without other options, higher dose (10-15 mg/kg) might be considered, but risk of toxicity is high. TDM recommended

Amikacin 15-20 mg/kg/day If HAP or shock without other options, higher dose (25-30 mg/kg) might be considered but risk of toxicity is high. TDM recommended

Fosfomycin 4 g/6 hours to 8 g/8 hours Use in combination. High sodium concentration. Temocillin 2 g/8-12 hours KPC producers occasionally susceptible. Continuous

infusion improves PK-PD target attainment Aztreonam 1-2 g/8 hours MBL producers susceptible if not ESBL or AmpC

Ceftazidime 1-2 g/8 hours OXA-48-producers susceptible if not ESBL or AmpC Ceftazidime-avibactam 2.5 g/8 hours KPC- and OXA-48-producers frequently susceptible Meropenem-vavorbactam 2/2 g/8 hours KPC-producers frequently susceptible

Rodríguez-Baño J, Gutiérrez B, Machuca I, Pascual A. Clin Microbiol Rev 2018

Challenges

• When is it neccesary to empirically cover ESBL/AmpC and carbapenemase-producers?

• Are there carbapenem-spare options for empirical or targeted therapy of ESBL/AmpC?

• What is the best treatment for carbapenemase-producers?

• How can we preserve new drugs?

Newcomers looking for…

Already here… • Ceftolozane-tazobactam

• Ceftazidime-avibactam • Meropenem-vaborbactam Soon to come (?) • Imipenem-relebactam • Aztreonam-avibactam • Cefepime-zidebatam • Plazomycin • Eravacycline • Cefiderocol • Murepavadine

Retrospective cohort, KPC-Enteroacteraceae infections treated with CAZ-AVI (Shields et al, AAC 2018)

• Clinical failure

HAP (33) 64%

BSI (20) 25%

UTI (8) 12%

IAI (7) 57%

Others (9) 67%

• Microbiological failure: 25 (32%)

• Development of resistence: 8 (10%), 22% of KPC-3 Kp.

Predictors: HAP (OR=3.1) RRT (OR=4.7)

Predictor: HAP (OR=2.7)

Predictors: RRT (and KPC-3)

Can we avoid development of R to new drugs?

• It will happen… but may be delayed

• Avoid use if not absolutely needed

• Hypothetical – to be investigated for each drug

– Combination for high bacterial load infections?

– Higher dose in difficult patients?

– Avoid if R subpopulations?

Do we need a new paradigm?

• Individualised treatment

Clin Microbiol Rev 2018

Problems for individualised antimicrobial therapy

• Generating “evidence” is difficult/imposible

– RCT cannot be performed for individual conditions

– RCT for “individualised vs stantard” would need to include only problematic patients/infections/organisms challenging!!

• Who is deciding individualised therapy? Can we extrapolate?

Conclusions

• Empirical therapy is no longer simple

• Carbapenem-spare regimens are still possible for low risk patients (more research is needed)

• Therapy of CPE must be individualised (drug/s, dosing)

• Judicious use of new drugs

• Expertise needed (ID + CM + CC + Ph)

Ackowledgements

• HUVM/IBiS team working in this area

– Infectious Diseases staff: P Retamar, LE López-Cortés, B Gutiérrez, J Sojo, Z Palacios

– Microbiology staff: A Pascual, M de Cueto, L López-Cerero, JM Rodríguez, F. Docobo, I López, M Delgado

– Pharmacy staff: V Merino, M Camean

– ICU staff: J Garnacho-Montero, A Arenzana

– PhD students: J Bravo-Ferrer, M Paniagua, P Martínez, J Lanz, S Pérez-Galera, J Girón, I Morales, L Cantón

– Data managers: M Barrio, V Palomo, A Sánchez, MD Navarro

• Funding institutions

– Instituto de Salud Carlos III (Spanish Network for Research in Infectious Diseases)

– IMI (EU + EFPIA)

– JPI-AMR

• Investigators from international groups and consortia (ESGBIS, INCREMENT, COMBACTE…)

@jesusrbano

Sevilla 2018 ESCMID Course on Research Methodology (November 7-9)

Goodman et al, Clin Infect Dis 2016

ESBL-producers: 5.7% of 1,141 episodes

ESBL-producers: 4.6% of 910 episodes

http://www.eucast.org/ast_of_bacteria/warnings/

P=0.05

Cause of death with piptazo

• Terminal/palliative care 8

• Other comorbidity 8

• Other infection 1

• Unclear 2