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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