Mario Tumbarello

Terapia delle infezioni da carbapenemasi-produttori

Istituto di Clinica delle Malattie Infettive

7° Congresso Nazionale SITA

Genova, 23 settembre 2016

37 °C

38 °C

39 °C

40 °C

08/03 09/03 10/03 11/03 12/03 13/03 14/03 - 15/03

Klebsiella pneumoniae

Prospective cohort study on KP BSI in 13 Italian

hematological units.

161/278 (57.9%) of KP BSI were CR.

Mortality was significantly higher for patients

with CRKP BSI (84/161, 52.2%) than for those

with BSI caused by CSKP (17/117, 14.5%;

P<0.001)

CRKp infections were

documented in 25 auto-SCTs

and 87 allo-SCTs

2009 2014

Klebsiella pneumoniae: percentage of invasive isolates with resistance to carbapenems

http://www.eurosurveillance.org/images/dynamic/ES/V18N04/V18N04.pdf

02

55

07

51

00

Su

rviv

al, %

0 10 20 30Days

Combination therapy Monotherapy

Kaplan-Meier survival estimates of 125 patients who received adequate therapy

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)

2013

Observational study in two

hospitals located in a high-

prevalence area (Athens,

Greece) including 205 patients

with CP-Kp BSIs.

For definitive treatment, 103

patients received combination

therapy and 72 monotherapy.

A significantly higher mortality

rate was observed in patients

treated with monotherapy than

in those treated with

combination therapy (44.4%

versus 27.2%; P=0.018).

2014

In the multivariate analysis, definitive therapy with a

combination regimen was independently associated with

survival (OR, 0.07 [95% CI 0.009-0.71], P = 0.02).

The 28-day mortality was 13.3% in the combination therapy

group compared with 57.8% in the monotherapy group (P =

0.01)

The most commonly used combinations were colistin/polymyxin

B or tigecycline combined with a carbapenem.

AAC 2012

The fundamental question is whether

carbapenems can still be used in the treatment

of infections caused by CRKP isolates…

Daikos CMI 2011

Concentration–time profiles of three

different dosing regimens of meropenem

Daikos CMI 2011

meropenem should be administered by extended infusion (lasting > 3 h) at a

dose of 2 g every 8 hrs to obtain the best concentration-time profile.

«in vitro» models…

In vitro models simulating human

pharmacokinetics suggest that

carbapenems in optimized dosing

regimens, either alone or in

combination with tigecycline, may

cause a significant reduction in the

viable counts of KPC-producing K.

pneumoniae, including isolates

resistant to carbapenems Wiskirchen et al AAC 2011

In vitro evaluation of antibiotic

synergy

time-kill studies have indicated

synergistic effects of colistin with

various antibiotics, including

tigecycline, carbapenems,

rifampin, and doxycycline, against

CPKP Elemam et al. JCM 2010

Pournaras et al. IJAA 2011

Shock - - 0.008 7.17 (1.65-31.03)

Inadequate initial treatment - - 0.003 4.17 (1.61-10.76)

APACHE III score (mean ± SD) - - <0.001 1.04 (1.02-1.07)

Tigecycline & Colistin & Meropenem - - 0.01 0.11 (0.02-0.69)

Multivariate analysis of factors associated with death among

patients with bloodstream infection due to KPC producing K.

pneumoniae.

http://cid.oxfordjournals.org/content/current

2014

2015

90% of isolates had

meropenem MICs ≥16

μg/mL.

30-day mortality was 33%

overall and did not

significantly differ across

the 4 treatment groups

Of 141 CRKP BSI episodes, 23%

were treated with a single active

agent (SAA), 26% with SAA plus

BL, 28% with multiple active

agents (MAA), and 23% with MAA

plus BL.

ESCs included cefepime and

ceftazidime.

A carbapenem-sparing regimen of tigecycline

plus gentamicin or colistin was effective for

treating 24 of 26 (92%) KPC-producing Klebsiella

infectious episodes in polytrauma intensive care

unit patients without other substantial

comorbidities or immunosuppression.

Years 2009-2010

60.7% monotherapy

39.3% combination therapy

The most frequent combination was colistin plus

aminoglycoside and tigecycline plus aminoglycoside

Forty-eight (45.2%) of the cases that received active

treatment were considered clinical failures, with

23.5% mortality at 14 days CMI 2013

2015

72% of ColR KPC-Kp

without a history of

previous colistin

administration

Multivariate analysis adjusted for appropriate

treatment, combination therapy and infectious-

source removal, showed that Charlson

comorbidity score, intensive-care unit onset of

infection, bacteraemia and infection due to a

colistin-resistant CR-KP strain were

independent risk factors for mortality.

CMI 2013

Combination therapy including

Gentamicin

Fosfomycin

The use of targeted gentamicin

was associated with reduced

mortality (20.7% versus 61.9%).

In all multivariate regression

models, the use of gentamicin

was independently associated

with lower mortality after

controlling for other potential

confounding variables such as

age, optimal treatment, renal

function, severity of infection,

underlying disease, use of

tigecycline and previous

hospitalization

2015

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

Colistin plus rifampin is the most consistently

synergistic combination against KPC-producing

K. pneumoniae isolates, including colistin-

resistant strains.

Colistin-rifampin combinations may have a role

in the treatment of multidrug-resistant K.

pneumoniae and may possibly slow the

selection of heteroresistant subpopulations

during colistin therapy

2013

2014

The efficacy of a combination of ertapenem and

doripenem was evaluated in both an in vitro chemostat

and an in vivo murine thigh infection model.

The combination of doripenem plus ertapenem

demonstrated enhanced efficacy over either agent

alone.

The efficacy of this dual-carbapenem therapy against

KPC-producing K. pneumoniae may be related to the

KPC enzyme’s preferential affinity for ertapenem.

Bactericidal activity and degree of killing by single drugs

and 2- and 3-drug combinations against KPC K. pneumoniae

isolates

Hong AAC 2013

Doxycycline alone or in combination with an aminoglycoside

possesses potential antibacterial activity and can be

considered an alternative for CRE infections..

http://maneypublishing.com/journals/cover/joc/

The antimicrobial spectrum of activity of these antibiotics includes multi-drug resistant Gram-negative bacteria, including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem resistant Enterobacteriaceae that produce KPC.

However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases.

Research towards development of novel antibiotics with targeted anti-MDR Gram negative activity should be a top priority for the pharmaceutical industry, and governments.