Post on 07-Jun-2020
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
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.
2014
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
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..
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.