Avances en el tratamiento de las infecciones por bacterias multirresistentes.

Málaga, 14 de noviembre de 2017

Belén Gutiérrez-GutiérrezHospital Virgen Macarena REIPI/ESGBIS/IBIS

OMS febrero 2017

FEP AZT AMC PTZ MER COL TIG FOS AG

Rojo: >75%RNaranja: >25% o aumentando

Enterobacterias

Antibióticos de segunda línea

Incluso peor para XDR P. aeruginosa y A. baumannii!!

Qué podemos hacer…

• Programas de control de infecciones y de optimización de antibióticos.

• Mejorar el diagnóstico

• Mejorar el manejo clinico (optimizando el uso de antibioticos disponibles)

• Nuevos antibióticos…

ENTEROBACTERIAS

1. Productoras de BLEE

2. Resistentes a los carbapenemas

Enterobacterias productoras de BLEE

1. Avances en el uso de los fármacos habitualespara el tratamiento de las infecciones porestos microorganismos.

2. Nuevos fármacos

CARBAPENEMAS

• Son los antimicrobianos de elección porque no se afectan por estos mecanismos de resistencia

• Metaanálisis (Vardakas 2012): Tratamiento empírico o definitivo con carbapenemas < tasas de mortalidad que cefalosporinas, fluoroquinolonas o aminoglucósidos

• Antibióticos de referencia -> incrementa su consumo y (en parte) contribuye al desarrollo de las resistencias a carbapenemas.

CARBAPENEMAS. Consumo antibiótico porclase en 2000 y 2010

Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, Laxminarayan R.2014. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 14:742-750.

ERTAPENEM • Ertapenem no activo contra Pseudomonas aeruginosa ni

Acinetobacter baumannii

• Uso ->evitar presión selectiva.

• 5 estudios observacionales -> ertapenem vs otroscarbapenemas. No diferencias

• En uno de ellos (INCREMENT) tendencia a mayor mortalidad enel grupo de ertapenem en los pacientes con sepsis severa yshock

1. Lee NY, Huang WH, Tsui KC, et al. 2011. Carbapenem therapy for bacteremia due to extended-spectrum beta-lactamase-producing Escherichia colior Klebsiella pneumoniae. Diagn Microbiol Infect Dis 70:150–153.2. Wu UI, Chen WC, Yang CS, et al. 2012. Ertapenem in the treatment of bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli: a propensity score analysis. Int J Infect Dis 16: e47–e52.3. Collins VL, Marchaim D, Pogue JM, et al. 2012. Efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother 56:2173–2177.4. Lee NY, Lee CC, Huang WH, et al. 2012. Carbapenem therapy for bacteremia due to extended-spectrum-beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae: implications of ertapenem susceptibility. Antimicrob Agents Chemother 56:2888–2893.5. Gutiérrez-Gutiérrez B, Bonomo RA, Carmeli Y, et al. 2016. Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: a multinational pre-registered cohort study. J Antimicrob Chemother 71:1672-1680.

ERTAPENEM

Gutiérrez-Gutiérrez B, Bonomo RA,Carmeli Y, et al. 2016. Ertapenem forthe treatment of bloodstreaminfections due to ESBL-producingEnterobacteriaceae: a multinationalpre-registered cohort study. JAntimicrob Chemother 71:1672-1680.

Análisis de sensibilidad

Gutiérrez-Gutiérrez B, Bonomo RA, Carmeli Y, et al. 2016. Ertapenem for thetreatment of bloodstream infections due to ESBL-producingEnterobacteriaceae: a multinational pre-registered cohort study. J AntimicrobChemother 71:1672-1680.

Análisis con CART de la subcohorte de pacientes con tratamiento definitive con ertapenem: Modelo predictivo

asociado con la mortalidad en el día 30.

Drug Positive aspects Negative aspects Dosing (adults, normal renal function) and comments

Meropenem, imipenem, (doripenem)

Reference drugs Ecological impact.Less experience with doripenem

Standard dosing is recommended

Ertapenem Not active against P. aeruginosaConvenient for outpatienttherapy and de-escalationfrom other carbapenems

Ecological impact if CPE endemicity/outbreakDoubts in septic shock (insufficientdosing?)Anecdotal failures described withdevelopment of resistance (porin loss)

1 g/day in most situations. Forseptic shock or high-inoculuminfections with borderline MIC isolates, use other alternativesor increase dose to 2 g/day

Piperacillin-tazobactam Areas with high proportion of susceptible isolatesProbably non-inferior to carbapenems in UTI and biliary tract infections

False susceptibility with some automated systemsInoculum effect (unrelated to ESBLs)Doubts in septic shock, pneumonia,Susceptibility breakpoint too high?

4.5 g every 8 hours (extended infusion) or every 6 hours

Amoxicillin-clavulanicacid

No inoculum effectProbably non-inferior to carbapenems in UTI and biliary tract infectionsNot active against P. aeruginosaConvenient for oral switch

Not available for IV use in many countries 2.2 g/8h

Ceftolozane-tazobactam Areas with high proportion of susceptible isolates

Reserve drug for MDR P. aeruginosaScarce experience so far

1.5 g/8h. Approved for cUTI and cIAI (with metronidazole)

Ceftazidime-avibactam Areas with a high proportion of susceptible isolates

Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae;Scant experience so far

2.5 g/8h. Approved for cUTI and cIAI (withmetronidazole) in Europe, also for HAP withlimited options

Cefotaxime, ceftriaxone, ceftazidime, cefepime

Some ESBL-E may be susceptible Most isolates are resistant. Inoculum effect. Ecological impact.Clinical data scarce and contradictory

If used, high doses are recommended(cefotaxime: 1 g/6h – 2 g/8h; ceftazidime orcefepime, 2 g/8h)

Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef

Not active against P. aeruginosaAreas with high proportion of susceptible isolatesProbably useful in UTI for stable patients

Inoculum effectObservational studies with contradictory resultsDevelopment of resistance during therapy anecdotally described

High dose, close follow-up needed

Temocillin Active against ESBL and AmpC producers. Not active against P. aeruginosa

Not available in many countries,Comparative studies lacking

Probably 2 g every 8 hours

Gentamicin, tobramycin, amikacin

Active against most ESBL producersUseful in UTI

Controversial toxicity data in short-term useLess efficacious in non-UTI infections

Standard dosing.Could be considered empirically as a way to sparecarbapenems until microbiological data are available

Tigecycline Active against most ESBL producers FDA and EMA warnings for use only if other options are unavailable/unsuitableProbably not a good option for UTI or HAP

100 mg loading dose, 50 mg/12h. Could be analternative in cIAI

Fosfomycin (IV) Non-inferior to piperacillin-tazobactam in cUTI (pending publication of data)

Not available in many countriesScant experienceRisk of emergence of resistant subpopulations as monotherapy

4g/6 hours to 6-8 g/8 hours

Ciprofloxacin, Potentially useful for fully susceptible Ecological impact. Most isolates are resistant. Failures for isolates Ciprofloxacin: 500 mg/12 hours

Table 1. Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of ESBL-producing Enterobacteriaceae

J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017

BLBLI clásicos

• AMC, AMS, PTZ, Ticarcilina-Sulbactam y cefoperazona-sulbactam son activos contra BLEE en ausencia de otrosmecanismos de resistencia.

• Tasas de resistencia a los BLBLI muy diferentes según áreasgeográficas y altas en algunas zonas. ¿Tratamiento empirico?

BLBLI clásicos

Rodríguez-Baño J, Navarro MD, Retamar P, et al. 2012. β-Lactam/β-Lactam Inhibitor Combinations for theTreatment of Bacteremia Due to Extended-Spectrum β-Lactamase–Producing Escherichia coli: A Post Hoc Analysis ofProspective Cohorts. Clin Infect Dis 54:167–174.

BLBLI clásicos

Shiber S, Yahav D, Avni T, et al. 2015. β-Lactam/β-lactamase inhibitorsversus carbapenems for the treatmentof sepsis: systematic review and meta-analysis of randomized controlledtrials. J Antimicrob Chemother. 70:41-47.

BLBLI clásicos

Tamma PD, Han JH, Rock C, et al. 2015. Carbapenemtherapy is associated with improved survival compared withpiperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia. Clin Infect Dis 60:1319-1325.

BLBLI clásicos

Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, et al. 2016. A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae. Antimicrob Agents Chemother 60:4159-4169.

BLBLI clásicos

Gutiérrez-Gutiérrez B, Pérez-Galera S, Salamanca E, et al. 2016. A Multinational, PreregisteredCohort Study of β-Lactam/β-Lactamase Inhibitor Combinationsfor Treatment of BloodstreamInfections Due to Extended-Spectrum-β-Lactamase-ProducingEnterobacteriaceae. AntimicrobAgents Chemother 60:4159-4169.

170 BLBLI vs 195 carbapenemas c. empírica92 BLBLI vs 509 carbapenemas c. definitiva

INCREMENT en bacteriemias BLEE de distintos orígenes

Gudiol C, Royo-Cebrecos C, Abdala E, et al. 2017. Efficacy of β-Lactam/β-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-β-bactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia. Antimicrob Agents Chemother. 61. pii: e00164-17. doi: 10.1128/AAC.00164-17.

BLBLI clásicos

• MERINO TRIAL (PTZ vs Meropenem): Ayudará aaclarar discrepancias

BLBLI clásicos

Drug Positive aspects Negative aspects Dosing (adults, normal renal function) and comments

Meropenem, imipenem, (doripenem)

Reference drugs Ecological impact.Less experience with doripenem

Standard dosing is recommended

Ertapenem Not active against P. aeruginosaConvenient for outpatient therapy and de-escalation from other carbapenems

Ecological impact if CPE endemicity/outbreakDoubts in septic shock (insufficient dosing?)Anecdotal failures described with development of resistance(porin loss)

1 g/day in most situations. For septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase dose to 2 g/day

Piperacillin-tazobactam

Areas with highproportion of susceptible isolatesProbably non-inferior tocarbapenems in UTI and biliary tract infections

False susceptibility with someautomated systemsInoculum effect (unrelated to ESBLs)Doubts in septic shock, pneumonia,Susceptibility breakpoint too high?

4.5 g every 8 hours (extended infusion) or every 6 hours

Amoxicillin-clavulanicacid

No inoculum effectProbably non-inferior tocarbapenems in UTI and biliary tract infectionsNot active against P. aeruginosaConvenient for oral switch

Not available for IV use in manycountries

2.2 g/8h

Ceftolozane-tazobactam Areas with high proportion of susceptible isolates

Reserve drug for MDR P. aeruginosaScarce experience so far

1.5 g/8h. Approved for cUTI and cIAI (with metronidazole)

Ceftazidime-avibactam Areas with a high proportion of susceptible isolates

Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae;Scant experience so far

2.5 g/8h. Approved for cUTI and cIAI (withmetronidazole) in Europe, also for HAP withlimited options

Cefotaxime, ceftriaxone, ceftazidime, cefepime

Some ESBL-E may be susceptible Most isolates are resistant. Inoculum effect. Ecological impact.Clinical data scarce and contradictory

If used, high doses are recommended(cefotaxime: 1 g/6h – 2 g/8h; ceftazidime orcefepime, 2 g/8h)

Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef

Not active against P. aeruginosaAreas with high proportion of susceptible isolatesProbably useful in UTI for stable patients

Inoculum effectObservational studies with contradictory resultsDevelopment of resistance during therapy anecdotally described

High dose, close follow-up needed

Temocillin Active against ESBL and AmpC producers. Not active against P. aeruginosa

Not available in many countries,Comparative studies lacking

Probably 2 g every 8 hours

Gentamicin, tobramycin, Active against most ESBL producers Controversial toxicity data in short-term use Standard dosing.

Table 1. Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of ESBL-producing Enterobacteriaceae

J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017

Fosfomicina• Es un viejo antibiótico que permanece activo contra

la mayoría de los E. coli y K. pneumoniaeproductores BLEE y AmpC.

• Formulación oral-> ITU Blee?

• La formulación intravenosa está disponible enEspaña, Francia, Alemania y Austria.

• Dosis oscila entre 4g/6-8h hasta 8g/8h

• Como tratamiento empírico en ensayo clínico vspiperacilina-tazobactam (www.zavante.com) en ITUscomplicadas.

• FOREST, tratamiento dirigido bacteriemias ITU por E.coli multiresistente vs ceftriaxona y meropenem(estudio FOREST, protocolo: Rosso-Fernández C,Sojo-Dorado J BMJ Open 2015) .

Fosfomicina

Otras consideraciones en BLEE

Drug Positive aspects Negative aspects Dosing (adults, normal renal function) and comments

Meropenem, imipenem, (doripenem)

Reference drugs Ecological impact.Less experience with doripenem

Standard dosing is recommended

Ertapenem Not active against P. aeruginosaConvenient for outpatient therapy and de-escalation from other carbapenems

Ecological impact if CPE endemicity/outbreakDoubts in septic shock (insufficient dosing?)Anecdotal failures described with development of resistance(porin loss)

1 g/day in most situations. For septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase dose to 2 g/day

Piperacillin-tazobactam Areas with high proportion of susceptible isolatesProbably non-inferior to carbapenems in UTI and biliary tract infections

False susceptibility with some automated systemsInoculum effect (unrelated to ESBLs)Doubts in septic shock, pneumonia,Susceptibility breakpoint too high?

4.5 g every 8 hours (extended infusion) or every 6 hours

Amoxicillin-clavulanicacid

No inoculum effectProbably non-inferior to carbapenems in UTI and biliary tract infectionsNot active against P. aeruginosaConvenient for oral switch

Not available for IV use in many countries 2.2 g/8h

Ceftolozane-tazobactam Areas with high proportion of susceptible isolates

Reserve drug for MDR P. aeruginosaScarce experience so far

1.5 g/8h. Approved for cUTI and cIAI (with metronidazole)

Ceftazidime-avibactam Areas with a high proportion of susceptible isolates

Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae;Scant experience so far

2.5 g/8h. Approved for cUTI and cIAI (withmetronidazole) in Europe, also for HAP withlimited options

Cefotaxime, ceftriaxone, ceftazidime, cefepime

Some ESBL-E may be susceptible Most isolates are resistant. Inoculum effect. Ecological impact.Clinical data scarce and contradictory

If used, high doses are recommended(cefotaxime: 1 g/6h – 2 g/8h; ceftazidime orcefepime, 2 g/8h)

Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef

Not active against P. aeruginosaAreas with high proportion of susceptible isolatesProbably useful in UTI for stable patients

Inoculum effectObservational studies with contradictory resultsDevelopment of resistance during therapy anecdotally described

High dose, close follow-up needed

Temocillin Active against ESBL and AmpC producers. Not active against P. aeruginosa

Not available in many countries,Comparative studies lacking

Probably 2 g every 8 hours

Gentamicin, tobramycin, amikacin

Active against most ESBL producersUseful in UTI

Controversial toxicity data in short-term useLess efficacious in non-UTI infections

Standard dosing.Could be consideredempirically as a way tospare carbapenems untilmicrobiological data are available

Tigecycline Active against most ESBL producers FDA and EMA warnings for use only if other options are unavailable/unsuitableProbably not a good option for UTI or HAP

100 mg loading dose, 50 mg/12h. Could be analternative in cIAI

Fosfomycin (IV) Non-inferior to piperacillin-tazobactam in cUTI (pending publication of data)

Not available in many countriesScant experience

4g/6 hours to 6-8 g/8 hours

Table 1. Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of ESBL-producing Enterobacteriaceae

J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017

Enterobacterias productoras de BLEE

1. Avances en el uso de los fármacoshabituales para el tratamiento de lasinfecciones por estos microorganismos.

2. Nuevos fármacos

Ceftolozane-tazobactam

Ceftazidima-avibactam

Nuevos BLBLI: ceftolozane-tazobactam

• Combinación de una nueva cefalosporina (ceftolozane) conactividad anti-pseudomonas con un inhibidor de beta-lactamasasclásico (tazobactam).

• Aprobado por FDA y EMA para infección intraabdominalescomplicadas (en combinación con metronidazole) y para ITUincluyendo pielonefritis.

Ceftolozane-tazobactam: Actividad in vitro

• Puntos de corte (EUCAST)– Enterobacterias ≤1 mg/L– P. aeruginosa ≤4 mg/L

• Activo contra– Enterobacterias: productores de BLEE/AmpC– P. aeruginosa

• No activo contra– Productores de carbapenemasas– MDR A. baumannii– S. maltophilia

Livermore, IJAA 2009; Castanheira AAC 2014; Van Duin CID 2016

• Combinación de una cefalosporina de tercerageneración conocida con un nuevo inhibidor debetalactamasas no betalactámico.

• Recientemente aprobado por FDA y EMA para eltratamiento de ITUs e infecciones abdominalescomplicadas (en combinación con metronidazol).

Nuevos BLBLI: ceftazidima-avibactam

Ceftazidime-avibactam: actividad in vitro

• Puntos de corte (EUCAST)– Enterobacterias ≤8 mg/L

– P. aeruginosa ≤8 mg/L

• Activo contra – Enterobacterias: productores de BLEE /AmpC, KPC, OXA-48

– P. aeruginosa: (No MBL)

• No activo contra– MBL (pero 2 estudios en animales mostraron una inesperada actividad

contra productores NDM [MacVane, AAC 2014; Monogue, AAC 2017])

– MDR A. baumannii

– S. maltophilia

Livermore, IJAA 2009; Castanheira, AAC 2014; Van Duin, CID 2016

• Al igual que cefto-tazo, eficaces en ITU BLEE ypara intraabdominales, ojo!-> prudentereservarlos (p.ej. KPC, OXA…) si hayalternativas.

Nuevos BLBLI: ceftazidima-avibactam

Drug Positive aspects Negative aspects Dosing (adults, normal renal function) and comments

Meropenem, imipenem, (doripenem)

Reference drugs Ecological impact.Less experience with doripenem

Standard dosing is recommended

Ertapenem Not active against P. aeruginosaConvenient for outpatient therapy and de-escalation from other carbapenems

Ecological impact if CPE endemicity/outbreakDoubts in septic shock (insufficient dosing?)Anecdotal failures described with development of resistance(porin loss)

1 g/day in most situations. For septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase dose to 2 g/day

Piperacillin-tazobactam Areas with high proportion of susceptible isolatesProbably non-inferior to carbapenems in UTI and biliary tract infections

False susceptibility with some automated systemsInoculum effect (unrelated to ESBLs)Doubts in septic shock, pneumonia,Susceptibility breakpoint too high?

4.5 g every 8 hours (extended infusion) or every 6 hours

Amoxicillin-clavulanicacid

No inoculum effectProbably non-inferior to carbapenems in UTI and biliary tract infectionsNot active against P. aeruginosaConvenient for oral switch

Not available for IV use in many countries 2.2 g/8h

Ceftolozane-tazobactam

Areas with high proportionof susceptible isolates

Reserve drug for MDR P. aeruginosaScarce experience so far

1.5 g/8h. Approved for cUTI and cIAI (with metronidazole)

Ceftazidime-avibactam

Areas with a high proportionof susceptible isolates

Reserve drug for KPC- or OXA-48-producing Enterobacteriaceae;Scant experience so far

2.5 g/8h. Approved for cUTIand cIAI (with metronidazole) in Europe, also for HAP withlimited options

Cefotaxime, ceftriaxone, ceftazidime, cefepime

Some ESBL-E may be susceptible Most isolates are resistant. Inoculum effect. Ecological impact.Clinical data scarce and contradictory

If used, high doses are recommended(cefotaxime: 1 g/6h – 2 g/8h; ceftazidime orcefepime, 2 g/8h)

Cefoxitin, cefotetan, cefmetazole, moxalactam, flomoxef

Not active against P. aeruginosaAreas with high proportion of susceptible isolatesProbably useful in UTI for stable patients

Inoculum effectObservational studies with contradictory resultsDevelopment of resistance during therapy anecdotally described

High dose, close follow-up needed

Temocillin Active against ESBL and AmpC producers. Not active against P. aeruginosa

Not available in many countries,Comparative studies lacking

Probably 2 g every 8 hours

Gentamicin, tobramycin, amikacin

Active against most ESBL producersUseful in UTI

Controversial toxicity data in short-term useLess efficacious in non-UTI infections

Standard dosing.Could be considered empirically as a way to sparecarbapenems until microbiological data are available

Tigecycline Active against most ESBL producers FDA and EMA warnings for use only if other options are unavailable/unsuitableProbably not a good option for UTI or HAP

100 mg loading dose, 50 mg/12h. Could be analternative in cIAI

Fosfomycin (IV) Non-inferior to piperacillin-tazobactam in cUTI (pending publication of data)

Not available in many countriesScant experienceRisk of emergence of resistant subpopulations as monotherapy

4g/6 hours to 6-8 g/8 hours

Ciprofloxacin, levofloxacin

Potentially useful for fully susceptible isolates

Ecological impact. Most isolates are resistant. Failures for isolateswith MIC 0.5-1 mg/L described

Ciprofloxacin: 500 mg/12 hoursLevofloxacin: 750 mg/24 hours

Table 1. Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of ESBL-producing Enterobacteriaceae

J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017

Enterobacterias resistentes a los carbapenemas

1. Avances en el uso de los fármacos habitualespara el tratamiento de las infecciones porestos microorganismos.

2. Nuevos fármacos

3. Pipeline (en desarrollo)

MONO VS COMBI

Enterobacterias resistentes a los carbapenemas

1. Avances en el uso de los fármacos habitualespara el tratamiento de las infecciones porestos microorganismos.

2. Nuevos fármacos

3. Pipeline (en desarrollo)

Nuevos antimicrobianos para CRE

• Recientemente aprobados

– Ceftazidime-avibactam

– Meropenem-vaborbactam

• Pipeline (en desarrollo)

Ceftazidime-avibactam: actividad in vitro

• Puntos de corte (EUCAST)– Enterobacterias ≤8 mg/L

– P. aeruginosa ≤8 mg/L

• Activo contra – Enterobacterias: productores de BLEE /AmpC, KPC, OXA-48

– P. aeruginosa

• No activo contra– MBL (pero 2 estudios en animales mostraron una inesperada actividad

contra productores NDM [MacVane, AAC 2014; Monogue, AAC 2017])

– MDR A. baumannii

– S. maltophilia

Livermore, IJAA 2009; Castanheira, AAC 2014; Van Duin, CID 2016

N=8 and 23, mortality 25% vs 52% (p=0.19)Int J Infect Dis. 2017 Jun; 59:118-123.

King et al, Antimicrob Agents Chemother. 2017 Jun 27;61(7).N=60, mortality 32%

N=38, mortality 39%

KPC: 6/23 (26.0%) p=0.07OXA-48: 8/13 (61.5%)

Antimicrob Agents Chemother. 2017 Jan 24;61(2)

Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-

Resistant Enterobacteriaceae Infections.

Clin Infect Dis 2016

N=37. Mortality 24%10 microbiological failure 3 resistance

Antimicrob Agents Chemother 2017

CAZ-AVI vs COLISTIN in CRE infections (KPC)CRACKLE cohort

Outcome Proportionwith CAZ-AVI

vs COL

DOOR (adjusted probability

estimate)

Mortality 8% vs 33% 0.64 (0.57-0.71)

Death or renal failure 12% vs 39% 0.62 (0.52-0.72)

CAZ-AVI (n=39) vs colistin (n=99), Infections: BSI (39%), pneumonia (24%), UTI (16%), others (21%)

Van Duin et al, Clin Infect Dis 2017

Meropenem-vaborbactam

• Non-inferior to pip-taz in cUTI includingpyelonephritis (TANGO-1)

– Press release, data not published

– Approved by FDA, 2+2 gr every 8h

• Recruitment for CRE infections vs best availabletherapy (TANGO-2) stopped because of worseoutcomes in comparator

– Press release, data not published

Isolate susceptibility High risk1: combination therapy CommentsSusceptible to a β-lactam (use according to susceptibility)

Backbone: ceftazidime-avibactam (preferred) or meropenem or ceftazidime or aztreonam

Close clinical and microbiological follow-up neededColistin: preferred for HAP.Tigecycline: preferred for cIAI; if used for HAP, BSI or cUTI, consider double dose.Aminoglycoside: preferred for cUTI; if needed for HAP, consider high dose. TDM recommended.Fosfomycin: preferred for cUTI, but can be considered as third drug for any source if needed. For cIAI, consider adding metronidazole except for meropenem and tigecycline

Accompanying drug: colistin or tigecycline or aminoglycoside or fosfomycin(If isolate is intermediate to backbone, consider using 2 of these)

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

Backbone: colistinAccompanying drug: tigecycline, aminoglycoside (high risk of nephrotoxicity), fosfomycin

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

Backbone: tigecycline or aminoglycosideTigecycline or aminoglycoside, fosfomycin

Pandrug-resistant or susceptible only to one drug Meropenem + ertapenem orCeftazidime-avibactam + aztreonamAdd any active drugConsider active investigational drug if availableLow risk2: monotherapy

According to susceptibility Ceftazidime-avibactam, meropenem, ceftazidime, aztreonam, colistin, tigecycline, aminoglycoside(if intermediate susceptibility, choose another option or use combination)

Summary of recommended regimens for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae

HAP: hospital-acquired pneumonia. cIAI: complicated intraabdominal infection. cUTI: complicated urinary tract infection. TDM: therapeutic drug monitoring.High-risk: defined as septic shock or, for bloodstream infections, an INCREMENT mortality score of ≥8 points (severe sepsis or shock at presentation: 5 points; Pitt score ≥6: 4; Charlson index ≥2: 3; source of infection other than urinary or biliary tract: 3).Low-risk: defined as INCREMENT mortality score <8 points.

J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017J Rodriguez-Baño, B Gutiérrez-Gutiérrez, I Machuca, A Pascual; CMR (in press) 2017

Enterobacterias resistentes a los carbapenemas

1. Avances en el uso de los fármacos habitualespara el tratamiento de las infecciones porestos microorganismos.

2. Nuevos fármacos

3. Pipeline

Cefiderocol

• Actividad in vitro contra CRE, CR A.baumannii, CR P. aeruginosa, S. maltophilia yB. cepacia– Falagas JAC 2017. Hackel, AAC 2017

• Actualmente en fase III para neumoníanosocomial e infecciones intrabdominalescomplicadas por Gram negativos resistentes acarbapenemas

Eravaciclina

• 2-4 veces mayor actividad in vitro contra CRE que la tigeciclina

• Mayores niveles en plasma que la tigeciclina

• Phase 2/3 en cIAI : no inferior a ertapenem

– Solomkin, JAMA Surg 2017

Thaden, Virulence 2017

Plazomicina

• Actividad in vitro mejorada contraEnterobacteriaceae

• Parece menos nefro y oto-tóxico que los AGclásicos (debe ser probado definitivamente!!)

• Fase II/III en ITU complicadas e ITU y en CREcompletados

Thaden, Virulence 2017

P. AERUGINOSA MDR

1. Nuevos fármacos (Ceftolozane-tazobactam)

2. Pipeline (Cefiderocol)

Ceftolozane-tazobactam: in vitro activity

• Puntos de corte (EUCAST)– Enterobacterias ≤1 mg/L

– P. aeruginosa ≤4 mg/L

• Activo contra– Enterobacterias: productores de BLEE/AmpC

– P. aeruginosa resistente a ceftazidima y a carbapenemas(si no es productor de carbapenemasas)

• No activo contra– carbapenemasas

– MDR A. baumannii

– S. maltophilia

Livermore, IJAA 2009; Castanheira AAC 2014; Van Duin CID 2016

• N=35 (35 HAP; 6 con bacteriemia)• 87% sensible a cefto-taz• 77% monoterapia• 9 pacientes recibieron 3 g/8h• Éxito clínico 74%• 4/9 fallos tuvieron un aislado no sensible.

Sólo son series de casos!!!

Clin Infect Dis 2017

PIPELINE: Cefiderocol

• Actividad in vitro contra CRE, CR A. baumannii,CR P. aeruginosa, S. maltophilia y B. cepacia

– Falagas JAC 2017. Hackel, AAC 2017

A. BAUMANNI resistente a carbapenemas (CRAB)

1. Avances en el uso de los fármacos habitualespara el tratamiento de las infecciones porestos microorganismos.

2. Empleo de viejos fármacos: Minociclina

3. Pipeline: Cefiderocol

Fármacos habituales

Las opciones terapéuticas contra los CRAB son muylimitadas• Drogas de “Segunda línea”: colistina1, tigeciclina and

algunas veces aminoglucósidos• Tratamiento combinado?2,3,4,5,6.• Carbapenemas, sulbactam, rifampicina y tigeciclina han

sido los fármacos más estudiados en el contexto del tratamiento combinado.

El mejor tratamiento disponible (BAT) es desconocido.

1. Álvarez-Marín R, López-Rojas R, Márquez JÁ, et al. PLoS One. 2016 Dec19;11(12):e0168468. doi: 10.137

2. López-Cortés LE, Cisneros JM. J Antimicrob Chemother. 2014;69(11):3119–26.

3. Liu X, Zhao M. Int J Antimicrob Agents. 2016 Nov;48(5):559–63.

4. Batirel A, Balkan II. Eur J Clin Microbiol Infect Dis 2014.

5. Balkan I, Agalar C. Indian J Pharmacol . 2015;47(1):95.

6. Amat T, Gutiérrez-Pizarraya A, Machuca I, et al. Clin Microbiol Infect. 2017, pii: S1198-743X(17)30529-3.

Otras opciones: Viejos fármacos y pipeline

• Minociclina:• supera muchos mecanismos de resistencia que afectan a

otras tetraciclinas en A. baumannii, incluida la tigeciclina.

• Excelente actividad in vitro contra A. baumanniiresistente

• facilidad de dosificación sin necesidad de ajustes de ladosis renal o hepática y una mayor seguridad la hanconvertido en una terapia atractiva.

• Pipeline: Cefiderocol. Actividad in vitro contra CR A.baumannii

CRE and CRAB prospective cohort

248 Matched CSE (1:1)

744 Admitted (3:1)

248 CRE withcontrols

804 CRE201 CRAB

Study 1: Prospective Cohort Study

Outcome predictors

Study 2: Nested

Cases- Control

Risk Factors

Study 3:

Matched cohort

Study

-Cost

-Mortality

-Lenght of Stay

Control 1

Control 2

Esquema

• Drogas recientemente aprobadas

– Ceftolozane-tazobactam

– Ceftazidime-avibactam

– Meropenem-vaborbactam

• Pipeline

• Alternativas no antibióticas

Pipeline (fase 2 y 3)

• Inhibidores de beta-lactamasa

– Aztreonam/avibactam (en marcha fase 2)

– Imipenem/relebactam (en marcha fase 3)

• Siderofores

– Cefiderocol (finalizado/en marcha fase 3)

• Aminoglucósidos

– Plazomicina (finalizado/en marcha fase 3)

• Fluorociclina

– Eravaciclina (finalizado/en marcha fase 3)

Inhibición de las beta-lactamasas por los nuevos compuestos

Amblerclass

Enzime Cefto/taz

CAZ/AVI

ATM/AVI

MER/VAB

IMI/ REL

A ESBLs Yes Yes Yes Yes Yes

KPC No Yes Yes Yes Yes

B MBL No No Yes No No

C AmpC Yes Yes Yes Yes Yes

D OXA-48 No Yes Yes No No