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In Vitro Efficacy of Meropenem-Cefmetazole Combination Therapy Against NDM-Producing Escherichia Coli

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In Vitro Efficacy of Meropenem-Cefmetazole Combination Therapy Against NDM-Producing Escherichia Coli In vitro efficacy of Meropenem-Cefmetazole combination therapy against NDM-producing Escherichia coli Meropenem Cefmetazole (MEPM) (CMZ) Hideharu Hagiya, M.D., Ph.D. Yo Sugawara, Rathina Kumar, Naohiro Hara, Norihisa Yamamoto, Noriko Sakamoto, Dan Takeuchi, Geoffrey Peterkins Kumwenda, Hisao Yoshida, Yukihiro Akeda, Kazunori Tomono Department of Infection Control and Prevention, Osaka University Graduate School of Medicine, and Research Institute for Microbial Diseases, Osaka University, Osaka, Japan Conflict of Interest None to Declare Introduction 1 ~CPE, an emerging crisis~ Deaths attributable to AMR every year Antimicrobial resistance is an global problem by 2050 Especially, we are facing a renewed threat of carbapenemase-producing Enterobacteriaceae (CPE) Mortality of severe CPE infection is very high Clin Microbiol Infect. 2014;20:862–72. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations, chaired by Jim O’Neill (2014) Introduction 2 ~Only limited treatment options available for CPE~ Development of NEW antibiotics Revival use of “old” antibiotics Plazomicin Colistin Eravacycline Tigecycline Ceftazidi me/aviba Fosfomycin ctam Facilitated but delayed Effectiveness depends on situations Introduction 3 ~No “Carbapenem salvaging therapy” for NDM~ Classification of Carbapenemases Serine Metallo Carbapenemase Carbapenemase - Class A (KPC) - Class B (NDM, VIM, IMP) - Class D (OXA-48) “Carbapenem salvaging therapy” by inhibitors - Double-carbapenem therapy using ertapenem (ERT) No clinically-applicable inhibitors - Ceftazidime-avibactam (AVI) - Meropenem-vaborbactam - Imipenem-relebactam etc Introduction 4 ~Cefmetazole (CMZ) as a NEW Carbapenemase-inhibitor~ One day, we noticed…. NDM-producers show very high MICs especially to CMZ…. Higher MIC ⇒ Higher Affinity of CMZ to NDM ?? … Can it be a good inhibitor ?? Double-Carbapenem Therapy CMZ-Combination Therapy Method 1 Materials: Microbiological organisms 1) Clinical isolates derived from Myanmar (n=12) - showing resistance to MEPM and harboring blaNDM-type gene - screened for blaNDM, blaKPC, blaIMP, blaVIM, and blaOXA-48 by PCR - sequenced for blaNDM-type 2) NDM-1-positive standard strain (E. coli ATCC25922) RESULT 1 Antimicrobial susceptibility profiles of the clinical isolates Antimicrobial susceptibilities No Organism Carbapenemase ABPC P/T CEZ CTX CAZ CMZ AZT IPM MEPM GM AMK MINO FOM ST CPFX 1 E. coli NDM-5 R R R R R R R R R R R S S R R 2 E. coli NDM-5 R R R R R R R R R R R R S R R 3 E. coli NDM-5 R R R R R R R R R R R R S R R 4 E. coli NDM-4 R R R R R R R R R R R R S R R 5 E. coli NDM-7 R R R R R R R R R R S R I S R 6 E. coli NDM-4 R R R R R R R R R R R R S R R 7 E. coli NDM-1, 5 R R R R R R R R R R R R S R R 8 E. coli NDM-4 R R R R R R R R R R R R S R R 9 E. coli NDM-5 R R R R R R R R R R R S S R R 10 E. coli NDM-5 R R R R R I R R R R R S S R S 11 E. coli NDM-4 R R R R R R R R R R R R S R R 12 E. coli NDM-5 R R R R R R R R R R R S S R R MicroScan WalkAway 96 Plus (BECKMAN COULTER, Brea, CA) Method 2 (A) MIC measurement MICs of MEPM, CMZ, and ERT were determined by a broth microdilution method based on CLSI document M07-A10. An example image on 96 well plate CMZ (B) Checkerboard method 1 2 3 4 5 6 7 8 or ERT Set up by 2-fold-decreasing concentrations A 512 5 B 256 Bacterial inoculation; 5.0 x 10 CFU/mL C 128 Evaluation; 18-20 h of shaking incubation at 35°C. D 64 E 32 Performed in triplicate. F 16 Evaluation - Synergistic; FIC index, ≦0.5 G 8 - Indifferent ; FIC index, > 0.5 H 0 MEPM 64 32 16 8 4 2 1 0 FIC (fractional inhibitory concentration) index =(MIC drug A in combination / MIC drug A alone ) + (MIC drug B in combination / MIC drug B alone ) RESULT 2 Synergistic effects between MEPM and ERT/CMZ in checkerboard assay Checkerboard assay No. NDM-type MIC MEPM & ERT MEPM & CMZ FIC index FIC index MEPM ERT CMZ Evaluation Evaluation (triplicate) (triplicate) 1 NDM-5 32 64 256 0.63_0.75_0.75 Indifferent 0.25_0.38_0.38 Synergistic 2 NDM-5 16 128 256 0.50_0.53_0.75 Indifferent 0.38_0.56_0.56 Indifferent 3 NDM-5 16 64 512 0.50_0.63_0.63 Indifferent 0.25_0.38_0.38 Synergistic 4 NDM-4 16 32 128 0.53_0.53_0.75 Indifferent 0.38_0.50_0.56 Synergistic 5 NDM-7 8 64 512 0.63_0.63_0.75 Indifferent 0.28_0.38_0.52 Synergistic 6 NDM-4 32 128 512 0.75_0.75_1.00 Indifferent 0.31_0.38_0.38 Synergistic 7 NDM-1, 5 16 64 256 0.56_0.56_1.00 Indifferent 0.38_0.50_0.50 Synergistic 8 NDM-4 32 128 512 0.50_0.75_0.75 Indifferent 0.31_0.38_0.38 Synergistic 9 NDM-5 32 64 512 0.50_1.00_1.00 Indifferent 0.25_0.25_0.31 Synergistic 10 NDM-5 16 32 32 0.63_0.75_0.75 Indifferent 0.50_0.50_0.50 Synergistic 11 NDM-4 16 64 256 0.75_1.00_1.00 Indifferent 0.38_0.50_0.63 Synergistic 12 NDM-5 16 64 512 0.75_0.75_0.75 Indifferent 0.28_0.38_0.50 Synergistic 13* NDM-1 32 16 128 0.63_0.75_0.75 Indifferent 0.25_0.38_0.38 Synergistic Strain No. 13* is NDM-1-positive standard strain (E. coli BAA-2469). Defined synergistic, when more than two of three times of FIC index were 0.5 or less. (C) Time–killing assay - Concentrations of antimicrobials Method 3 0.5xMIC MEPM, 0.5xMIC CMZ, and 0.5xMIC MEPM plus 0.5xMIC CMZ - Under 37oC shaking condition in ambient air, aliquots were obtained at 0, 4, 8, 12 and 24 hours. Evaluations - Bactericidal as a decrease in more than 3 log10 CFU/mL at each tested point compared to the initial inoculum - Synergistic as combination showing bactericidal effect until 24 hour 1.E+10 1.E+10 1.E+10 CTRLGrowth CTRL 1.E+08 1.E+08 1.E+08 0.5xMIC CMZ0.5xMIC CMZ 1.E+06 1.E+06 1.E+06 0.5xMIC0.5xMIC MEPM MEPM 1.E+04 1.E+04 1.E+04 1.E+02 0.5xMIC MEPM + 0.5xMIC CMZ1.E+02 1.E+02 Cut-off level of bactericidal effect 1.E+00 1.E+00 1.E+00 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Synergistic Bactericidal Not bactericidal at all (Bactericidal at 24 hour) RESULT 3 Time-Killing assays with MEPM & CMZ 1.E+10 Standard strain (BAA-2469) MEPM & CMZ Growth CTRL No. NDM type 1.E+08 Checkerboard Time-Killing 0.5xMIC CMZ 1.E+06 1 NDM-5 Synergistic Synergistic 0.5xMIC MEPM 1.E+04 2 NDM-5 Indifferent Bactericidal 1.E+02 0.5xMIC MEPM + 0.5xMIC CMZ 3 NDM-5 Synergistic Indifferent 1.E+00 4 NDM-4 Synergistic Bactericidal 0 4 8 12 16 20 24 5 NDM-7 Synergistic Synergistic 6 NDM-4 Synergistic Bactericidal % Bactericidal 4 h 8 h 12 h 24 h 7 NDM-1, 5 Synergistic Indifferent 0.5xMIC MEPM 7.7% 7.7% 0 0 8 NDM-4 Synergistic Bactericidal 9 NDM-5 Synergistic Bactericidal 0.5xMIC CMZ 0 0 0 0 10 NDM-5 Synergistic Synergistic 0.5xMIC MEPM 11 NDM-4 Synergistic Indifferent 61.5% 38.5% 38.5% 30.8% plus 12 NDM-5 Synergistic Bactericidal (8/13) (5/13) (5/13) (4/13) 0.5xMIC CMZ 13* NDM-1 Synergistic Synergistic Strain No. 13* is NDM-1-positive standard strain (E. coli BAA-2469). Bactericidal in 10/13 isolates (76.9%) Synergistic in 4/13 isolates (30.8%) Discussion ~Possible mechanism of action~ porin Cefmetazole (CMZ)◆ Outer membrane - cephamycin-class beta-lactam - Stable for ESBLs ①CMZ combines with the NDM - Clinical effectiveness of CMZ preferentially, acting as a NDM inhibitor monotherapy against ESBLs in Japan ②Salvaged MEPM binds efficiently with PBP Int J Infect Dis 2013; 17:e159-e163. MEPM BMC Infect Dis 2016; 16:427. CMZ AAC 2015; 59:5107-5113. NDM - Widely used in Japanese clinical settings - Cost-effective PBP PBP PBP Inner - Availability membrane - Safety Limitations Serum antibiotic concentration needed for combination effect - may be above the serum levels achieved in patients. Inoculum effect - should be noted when clinically applied AmpC beta-lactamase - may disturb the CMZ combination effect Other resistant mechanism - efflux pump, porin loss may influence Conclusions “Revival use” of existing antimicrobial Carbapenem agents may alleviate the global threat of antimicrobial resistance. Salvaging Therapy With CMZ As a NEW carbapenem-salvaging therapy, CMZ combination therapy Double- Colistin may provide a breakthrough therapeutic Carbapenem strategy. Treatment for CPE Further investigations on pK/pD profiles and in vivo examinations are warranted for clinical application of our Tigecycline Fosfomycin combination therapy..
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