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Strategie terapeutiche innovative nelle infezioni
da Gram-negativi multiantibiotico resistenti:
studio in vitro dell’attività sinergica e battericida
di differenti combinazioni antibiotiche
Oliva Alessandra, MD, PhD
Infectious Diseases Consultant,
Sapienza University Rome
[email protected]
Baveno, 17 Ottobre 2016
MULTIDRUG RESISTANCE (MDR)
Klebsiella pneumoniae MDR
Acinetobacter baumannii MDR
Aim of the study
To evaluate the in-vitro activity and clinical
effectiveness of innovative antimicrobial
combinations
Carbapenem-resistant
Klebsiella pneumoniae
(CR-Kp)
ERTAPENEM (ERT)
+
MEROPENEM (MEM
Carbapenem-resistant
Acinetobacter baumannii
(CR-Ab)
COLISTIN (COL)
+
VANCOMYCIN (VAN)
Study Design
62 patients with MDR Gramnegative infections
Group A
51 subjects with CR-Kp
infections at Department of
Infectious Diseases, Sapienza
University of Rome, (20122016)
19 treated
with double
carbapenem
32 treated
with other
regimens
ERT 1g die
plus
MEM 2g td
COL+MEM
COL+TIG
COL+AG
Group B
11 subjects with CR-Ab
infections at Pediatric
Intensive Care Unit (PICU),
Sapienza University of Rome
(2015-2016)
5 treated
with
COL+VAN
6 treated
with other
regimens
COL+MEM
COL+TIG
COL+RIF
Pagina 4
Microbiological analyses
• MIC determination throughout macrobroth dilution for
ERT, MEM, VAN and COL
ERT
+
MEM
COL
+
VAN
• CHECKERBOARD ASSAY for qualitative synergy
evaluation
• TIME-KILL ASSAY for quantitative evaluation of
bactericidal and synergistic activity
Results: CR-Kp
Overall
n (%)
Double carbapenem regimen
(n=19), n (%)
Other regimens
(n=32), n (%)
p value
Classification of
infection (%)
HA
HCA
31 (60.8)
14 (27.5)
11 (58)
5 (42.1)
20 (62.5)
6 (18.8)
0.77
0.10
Risk factors for infection
Hospitalization
CVC
Catheter
Previous surgery
ICU
46 (90.2)
9 (17.6)
25 (49)
32 (62.7)
22 (43)
17 (89.5)
3 (15.8)
8 (42)
14 (73.7)
8 (42)
29 (90.6)
6 (18.8)
17 (53)
18 (56.3)
14 (43)
1.00
1.00
0.56
0.24
1.00
9; 0-90
2; 0-70
14;0-90
0.24
36 (72)
15 (83.3)
21 (65.6)
0.21
11 (21.6)
34 (66.7)
4 (21.1)
10 (52.6)
7 (21.9)
24 (75)
1.00
0.13
6 (11.7)
5 (26.3)
1 (3.1)
12 (23.5)
11 (21.6)
2 (3)
5 (26.3)
6 (31.6)
1 (5)
7 (21,9)
5 (15,6)
1 (3)
Duration of
hospitalization before
infection onset, days
(median, range)
Previous antimicrobials
Type of infection
Pneumonia
Urinary tract infections
(UTI)
Other
Clinic
Sepsis
Severe sepsis
Septic shock
0.74
0.29
1.00
Overall
n (%)
Double carbapenem
regimen
(n=19), n (%)
Other regimens
(n=32), n (%)
p value
Early response
(5th day)
27 (53)
12 (44)
15 (46)
0.38
60-days outcome
39 (79)
14 (77)
25 (80)
1.00
Double-carbapenem regimen
Other regimens
p value= 0.88
MICs 50/90 (µg/ml)
ERTAPENEM
256/256
MEROPENEM
256/512
Synergism
No interaction
(FIC ≤ 0.5)
(FIC> 0.5)
4/19
15/19
(21.1%)
(78.9%)
MEROPENEM + ERTAPENEM
Results: CR-Ab
Overall,
n (%)
COL+VAN, (n=5)
n (%)
Other regimens, (n=6)
n (%)
p value
Classification of infection (%)
HA
HCA
10 (90.9)
1 (9.1)
5 (100)
0
5 (83-3)
1 (16.7)
1.00
1.00
Risk factors for infection
Hospitalization
CVC
Catheter
7 (63)
9 (81.8)
9 (81.8)
2 (40)
3 (60)
3 (60)
5 (83)
6 (100)
6 (100)
0.24
0.18
0.18
Comorbidities
Malformative diseases
Haematological neoplasia
5 (45.5)
3 (27.3)
2 (40)
0
3 (50)
3 (50)
1.00
0.10
Previous antimicrobials
Carbapenems
Cefalosporins
Others
11 (100)
4 (36.4)
6 (54.5)
1 (9.1)
5 (100)
2 (40)
3 (60)
0 (0)
6 (100)
2 (33.3)
3 (50)
1 (16.7)
1.00
1.00
Type of infection
Pneumonia
8 (72.7)
4 (80)
4 (66.7)
0.46
Presence of bacteremia
3 (27.2)
3 (60)
0
0.03
Early response
(5th day)
4 (66.7)
1 (50)
3 (75)
1.00
60-days outcome
10 (91)
5 (100)
5 (83.3)
0.88
MIC MER
(µg/ml)
MIC VAN
(µg/ml)
MIC COL
(µg/ml)
SYN
COL+VAN
(FIC)
Pt 1
128
256
1
0.5
Pt 2
128
32
0.25
0.625
Pt 3
256
64
<0.06
0.75
Conclusions
• Clinical effectiveness and safety of studied unconventional combinations
• In-vitro synergistic and bactericidal activity of ERT+MEM and COL+VAN
•In-vitro synergy studies should be performed whenever a MDR Gram
negative causing infection is detected
Double carbapenem
regimen
Colistin plus vancomycin
Valid therapeutic option
in case of CR-Kp
infections
Encouraging therapeutic
option in case of CR-Ab
infections
Personal data
Thanks to….
Department of Public Health and Infectious Diseases
Sapienza University of Rome
Prof. V. Vullo
Prof. C.M. Mastroianni
Dott.ssa G. d’Ettorre
Microbiology Reasearch Lab
(Department of Public Health and Infectious Diseases)
Sapienza University of Rome
Dott.ssa A. Cipolla
Dott. M. De Angelis
Dott.ssa L. Cannella
Department of Pediatry, Pediatric Intensive Care Unit
Sapienza University of Rome
Prof.ssa P. Papoff