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Evaluation of Polymyxin B-Based and Dual- Carbapenem Combinations Against Carbapenem-Resistant Enterobacteriaceae Co- Harbouring Mcr-1 and KPC-2

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Evaluation of Polymyxin B-based and Dual- Carbapenem Combinations against Carbapenem-Resistant Enterobacteriaceae co- harbouring mcr-1 and KPC-2 Jocelyn Teo1, Tze-Peng Lim1, Si-Xuan Tan1, Yiying Cai1, Winnie Lee1, Tse-Hsien Koh1, Thuan-Tong Tan1, Maciej Piotr Chlebicki1, Andrea Kwa1,2,3 1 Singapore General Hospital 2 National University of Singapore 3 Duke-NUS Medical School Disclosures › This study was funded in part by the National Medical Research Council (Singapore) Centre Grant A serious public health threat CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf Increasing carbapenem resistance in Singapore 15.0 - 13.0 11.0 9.0 7.0 5.0 3.0 susceptibility (%) susceptibility % carbapenem non % carbapenem 1.0 -1.0 2011 2012 2013 2014 2015* Klebsiella spp. E. coli Enterobacter spp. JQ Teo et al. Microorganisms 4 (1). 2016 Feb 16. Last resort antibiotic Polymyxin, an old antibiotic, is increasingly being used for multi-drug resistant infections POLYMYXIN RESISTANCE ANOTHER NAIL IN THE ANTIBIOTIC COFFIN… http://www.nbcnews.com/health/health-news/nevada-woman- died-near-ultimate-superbug-n706641 S. Baron et al. International Journal of Antimicrobial Agents 48 (2016) 583–591 13% OF CRE ISOLATES WERE PB-RESISTANT 140 120 9% 100 17% 19% 80 11% 60 40 7% No of CRE isolates, n isolates, CRE of No 20 0 2010 2011 2012 2013 2014 2015 2016 PB susceptible PB resistant J. Teo et al. 27th ECCMID (23rd Apr 2017) Poster P0711 Study objective › To evaluate the in vitro activity of multiple antibiotics in combination with polymyxin B against mcr-1 -harbouring CRE through time-kill studies METHODS Study Isolates › CRE prospective surveillance in Singapore General Hospital › Retrospective screening for mcr-1 via WGS and/or PCR for the period 2013 - 2015 Susceptibility Testing (MIC) › Microbroth dilution panels (Trek Diagnostics, West Sussex, UK) Study Antibiotics Antibiotic Simulated Dosing Regimens Concentration (mg/L) Polymyxin B 30,000IU/kg/day 2 Ertapenem 1g every 24h 15 Aztreonam 8g every 24h (infused over 24h) 24 Cefepime 2g every 8h (infused over 4h) 50 Piperacillin/ tazobactam 4.5g every 6h (infused over 4h) 35/7 Meropenem 2g every 8h (infused over 3h) 20 Doripenem 2g every 8h (infused over 4h) 26 Imipenem 1g every 6h (infused over 1h) 12.5 Levofloxacin 750mg every 24h 8 Rifampicin 600mg every 12h 4 Tigecycline 100mg every 12h 2 Polymyxin B Combinations Time-kill Studies Antibiotic Simulated Dosing Regimens Concentration (mg/L) Polymyxin B 30,000IU/kg/day 2 Ertapenem 1g every 24h 15 Aztreonam 8g every 24h (infused over 24h) 24 Cefepime 2g every 8h (infused over 4h) 50 Piperacillin/ tazobactam 4.5g every 6h (infused over 4h) 35/7 Meropenem 2g every 8h (infused over 3h) 20 Doripenem 2g every 8h (infused over 4h) 26 Imipenem 1g every 6h (infused over 1h) 12.5 Levofloxacin 750mg every 24h 8 Rifampicin 600mg every 12h 4 Tigecycline 100mg every 12h 2 Dual Carbapenems Time-kill Studies Antibiotic Simulated Dosing Regimens Concentration (mg/L) Polymyxin B 30,000IU/kg/day 2 Ertapenem 1g every 24h 15 Aztreonam 8g every 24h (infused over 24h) 24 Cefepime 2g every 8h (infused over 4h) 50 Piperacillin/ tazobactam 4.5g every 6h (infused over 4h) 35/7 Meropenem 2g every 8h (infused over 3h) 20 Doripenem 2g every 8h (infused over 4h) 26 Imipenem 1g every 6h (infused over 1h) 12.5 Levofloxacin 750mg every 24h 8 Rifampicin 600mg every 12h 4 Tigecycline 100mg every 12h 2 Study Endpoint 9 Growth control Drug A 8 Drug B 7 Drug A + B 6 Baseline incoculum 5 /mL Bactericidal activity cfu 4 10 ≥ 3 log decrease in cfu/mL 3 Log from original inoculum 2 1 0 0 2 4 8 12 24 Time (Hours) RESULTS EC249 EC250 ENT702 Species E. coli E. coli E. aerogenes MLST ST2006 ST2006 N.A. Isolation site Rectal swab Rectal swab Urine Carbapenemase KPC-2 KPC-2 KPC-2 Other beta- TEM-1B, TEM-1A TEM-1A, AmpC1 lactamases CTX-M-15 strA, strB, aadA1, aadA2, aadA2, mph(A), aac(6')Ib-cr, Test Isolates Other resistance mph(A), cmlA1, cmlA1, sul3, aac(3)-IIa, qnrB66, determinants sul3, dfrA12 dfrA12 mph(A), catB3, sul2, tet(A), dfrA14 Porin loss No No Yes EC249 EC250 ENT702 Species E. coli E. coli E. aerogenes MLST ST2006 ST2006 N.A. Isolation site Rectal swab Rectal swab Urine Carbapenemase KPC-2 KPC-2 KPC-2 Other beta- TEM-1B, TEM-1A TEM-1A, AmpC1 lactamases CTX-M-15 strA, strB, aadA1, aadA2, aadA2, mph(A), aac(6')Ib-cr, Test Isolates Other resistance mph(A), cmlA1, cmlA1, sul3, aac(3)-IIa, qnrB66, determinants sul3, dfrA12 dfrA12 mph(A), catB3, sul2, tet(A), dfrA14 Porin loss No No Yes Highly similar → possibly clonal MIC, mg/L EC249 EC250 ENT702 Polymyxin B 4 4 8 Aztreonam ≥128 ≥128 ≥128 Cefepime ≥128 64 ≥128 Piperacillin/Tazobactam ≥256/4 ≥256/4 ≥256/4 Doripenem 8 8 8 Imipenem ≥32 ≥32 ≥32 Meropenem ≥32 ≥32 ≥32 Ertapenem ≥32 ≥32 ≥32 Susceptibilities Levofloxacin ≥64 ≥64 1 Tigecycline ≤0.25 ≤0.25 1 Rifampicin ≥64 ≥64 ≥64 MIC, mg/L EC249 EC250 ENT702 Polymyxin B 4 4 8 Aztreonam ≥128 ≥128 ≥128 Cefepime ≥128 64 ≥128 Piperacillin/Tazobactam ≥256/4 ≥256/4 ≥256/4 Doripenem 8 8 8 Imipenem ≥32 ≥32 ≥32 Meropenem ≥32 ≥32 ≥32 Ertapenem ≥32 ≥32 ≥32 Susceptibilities Levofloxacin ≥64 ≥64 1 Tigecycline ≤0.25 ≤0.25 1 Rifampicin ≥64 ≥64 ≥64 MIC, mg/L EC249 EC250 ENT702 Polymyxin B 4 4 8 Aztreonam ≥128 ≥128 ≥128 Cefepime ≥128 64 ≥128 Piperacillin/Tazobactam ≥256/4 ≥256/4 ≥256/4 Doripenem 8 8 8 Imipenem ≥32 ≥32 ≥32 Meropenem ≥32 ≥32 ≥32 Ertapenem ≥32 ≥32 ≥32 Susceptibilities Levofloxacin ≥64 ≥64 1 Tigecycline ≤0.25 ≤0.25 1 Rifampicin ≥64 ≥64 ≥64 Polymyxin Time-kill Curves 10 8 Control 6 EC249 (PB MIC 4 mg/L) cfu/mL 10 4 EC250 (PB MIC 4 mg/L) Log 2 EC702 (PB MIC 8 mg/L) 0 0 4 8 12 16 20 24 Time/hr Doripenem Time-kill Curves 10 Control 8 EC249 6 cfu/m EC250 10 4 Log EC702 2 0 Doripenem MIC 0 4 8 12 16 20 24 = 8 mg/L Time/hr Levofloxacin Time-kill Curves 10 8 Control 6 ≥ cfu/mL EC249 (MIC 64 mg/L) 10 4 ≥ Log EC250 (MIC 64 mg/L) 2 EC702 (MIC 1 mg/L) 0 0 4 8 12 16 20 24 Time/hr Tigecycline time-kill curves 10 8 Control 6 ≤ cfu/mL EC249 (MIC 0.25 mg/L) 10 4 ≤ Log EC250 (MIC 0.25 mg/L) 2 EC702 (MIC 1 mg/L) 0 0 4 8 12 16 20 24 Time/hr EC249 kill Antibiotic - Log CFU/mL at 24h Aztreonam 0.00 10 Control Cefepime 4.13 9 PT4 9.00 8 Polymyxin B 7 Doripenem 4.32 Polymyxin B + 6 Aztreonam Imipenem 4.05 5 Polymyxin B + Tigecycline Polymyxin Meropenem 2.89 4 LogCFU/ml Ertapenem + Imipenem Rifampicin 2.78 3 Ertapenem + Tigecycline 2.34 2 Meropenem Levofloxacin 5.04 1 Ertapenem + Doripenem 0 Doripenem 0.00 0 4 8 12 16 20 24 Imipenem 0.00 Time (h) EC249 Combination Time Combination EC249 Ertapenem Meropenem 0.00 EC250 kill Antibiotic - Log CFU/mL at 24h Control Aztreonam 4.81 10 Polymyxin B 9 Cefepime 0.65 Polymyxin B + 8 Cefepime PT4 9.00 Polymyxin B + 7 Doripenem Doripenem 0.00 6 Polymyxin B + Imipenem 5.50 Meropenem 5 Polymyxin B + Levofloxacin Polymyxin Meropenem 2.03 LogCFU/ml 4 Polymyxin B + Rifampicin 0.00 3 Rifampicin Polymyxin B + Tigecycline 2.44 2 Tigecycline Ertapenem + Levofloxacin 0.00 1 Imipenem Ertapenem + 0.65 0 Doripenem 0 4 8 12 16 20 24 Meropenem Ertapenem + Imipenem 1.80 Time (h) Doripenem EC250 Combination Time Combination EC250 Ertapenem Meropenem 0.65 EC720 kill Antibiotic - Log CFU/mL at 24h Aztreonam 9.00 10 Control Cefepime 3.12 9 Polymyxin B PT4 9.00 8 7 Doripenem 9.00 Polymyxin B + Meropenem 6 Imipenem 9.00 Polymyxin B + 5 Levofloxacin Polymyxin Meropenem 0.00 Polymyxin B + LogCFU/ml 4 Rifampicin Rifampicin 0.00 3 Ertapenem + Tigecycline 4.76 Imipenem 2 Ertapenem + Levofloxacin 0.65 Meropenem 1 Ertapenem + Doripenem 0.00 0 Doripenem Imipenem 1.65 0 4 8 12 16 20 24 Time (h) EC720 Combination Time Combination EC720 Ertapenem Meropenem 0.00 Log CFU/mL at 24h Antibiotic EC249 EC250 ENT702 Polymyxin B + Aztreonam 0.00 4.81 9.00 kill - Polymyxin B + Cefepime 4.13 0.65 3.12 Polymyxin B + Piperacillin/Tazobactam 9.00 9.00 9.00 ime Polymyxin B + Doripenem 4.32 0.00 9.00 T Polymyxin B + Imipenem 4.05 5.50 9.00 Polymyxin B + Meropenem 2.89 2.03 0.00 Polymyxin B + Rifampicin 2.78 0.00 0.00 Polymyxin B + Tigecycline 2.34 2.44 4.76 Polymyxin B + Levofloxacin 5.04 0.00 0.65 Ertapenem + Doripenem 0.00 0.65 0.00 Combination Combination Ertapenem + Imipenem 0.00 1.80 1.65 Ertapenem + Meropenem 0.00 0.65 0.00 Log CFU/mL at 24h Antibiotic EC249 EC250 ENT702 Polymyxin B + Aztreonam 0.00 4.81 9.00 kill - Polymyxin B + Cefepime 4.13 0.65 3.12 Polymyxin B + Piperacillin/Tazobactam 9.00 9.00 9.00 ime Polymyxin B + Doripenem 4.32 0.00 9.00 T Polymyxin B + Imipenem 4.05Different isolates5.50 → different9.00 Polymyxin B + Meropenem 2.89bactericidal2.03 combinations0.00 Polymyxin B + Rifampicin 2.78 0.00 0.00 Polymyxin B + Tigecycline 2.34 2.44 4.76 Polymyxin B + Levofloxacin 5.04 0.00 0.65 Ertapenem + Doripenem 0.00 0.65 0.00 Combination Combination Ertapenem + Imipenem 0.00 1.80 1.65 Ertapenem + Meropenem 0.00 0.65 0.00 Log CFU/mL at 24h Antibiotic EC249 EC250 ENT702 Polymyxin B + Aztreonam 0.00 4.81 9.00 kill - Polymyxin B + Cefepime 4.13 0.65 3.12 Polymyxin B + Piperacillin/Tazobactam 9.00 9.00 9.00 ime Polymyxin B + Doripenem 4.32 0.00 9.00EC249 & T Polymyxin B + Imipenem 4.05 5.50 EC2509.00 similar Polymyxin B + Meropenem 2.89 2.03 but0.00 different Polymyxin B + Rifampicin 2.78 0.00 bactericidal0.00 Polymyxin B + Tigecycline 2.34 2.44 combinations4.76 Polymyxin B + Levofloxacin 5.04 0.00 0.65 Ertapenem + Doripenem 0.00 0.65 0.00 Combination Combination Ertapenem + Imipenem 0.00 1.80 1.65 Ertapenem + Meropenem 0.00 0.65 0.00 Log CFU/mL at 24h Antibiotic EC249 EC250 ENT702 Polymyxin B + Aztreonam 0.00 4.81 9.00 kill - Polymyxin B + Cefepime 4.13 0.65 3.12 Polymyxin
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  • Occurrence of PER-1 Producing Clinical Isolates of Pseudomonas Aeruginosa in Japan and Their Susceptibility to Doripenem

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    J. Antibiot. 59(12): 791–796, 2006 THE JOURNAL OF ORIGINAL ARTICLE ANTIBIOTICS Occurrence of PER-1 Producing Clinical Isolates of Pseudomonas aeruginosa in Japan and their Susceptibility to Doripenem Yoshinori Yamano, Toru Nishikawa, Takaji Fujimura, Takashi Yutsudou, Masakatsu Tsuji, Hideaki Miwa Received: July 13, 2006 / Accepted: November 20, 2006 © Japan Antibiotics Research Association Abstract The acquisition of resistance by extended- Keywords Pseudomonas aeruginosa, doripenem, ESBL, spectrum b-lactamases (ESBL) has been reported primarily PER-1, in vivo activity for Enterobacteriaceae, but there are few reports on the isolation of ESBL-producing Pseudomonas aeruginosa. PER-1-type ESBL producing P. aeruginosa has been found Introduction in various regions around the world but there are no reports of clinical isolates in Japan. During our susceptibility Pseudomonas aeruginosa is an opportunistic pathogen surveillance studies over a 10 year period, we found causing serious infection in immunocompromised hosts. P. four clinical isolates resistant to ceftazidime due to aeruginosa has intrinsic resistance to many antibiotics and production of PER-1. They were resistant to ceftazidime produces a variety of virulence factors. The intrinsic but susceptible in the presence of clavulanic acid, a class resistance of P. aeruginosa to various antibiotics is A b-lactamase inhibitor. The strains had the ability to generally due to its low outer membrane permeability and hydrolyze ceftazidime. They also had the gene for PER-1- the production of efflux pumps [1]. Although there are type ESBL. This is the first report of the isolation of various antipseudomonal agents such as b-lactams, PER-1 producing strains in Japan. These four strains were quinolones, and aminoglycosides, resistance to these resistant to ceftazidime, cefepime and aztreonam with antibiotics is acquired by P.
  • In-Vitro Activity of Doripenem Vs. Imipenem & Meropenem Against

    In-Vitro Activity of Doripenem Vs. Imipenem & Meropenem Against

    International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571 Original Research Article In-Vitro Activity of Doripenem vs. Imipenem & Meropenem against Clinical Isolates of Pseudomonas and Other Oxidase-Positive Gram- Negative Bacilli Priya Singh1, Richa Misra2 1Department of Microbiology, Swargiya Dadasaheb Kalmegh Smruti Dental College & Hospital, Nagpur, India 2Department of Microbiology, Division Bacteriology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, India Corresponding Author: Richa Misra ABSTRACT Background & objectives: Doripenem is approved by United States Food and Drug Administration(US FDA) for the treatment of complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and in Europe for ventilator-associated pneumonia (VAP).We attempted to compare the in vitro activity of doripenem with imipenem and meropenem using current CLSI guidelines among clinical isolates of Pseudomonas spp. and other oxidase positive Gram-negative bacilli from clinical samples. Methods: Eighty consecutive clinical isolates were included in the study. Samples included were pus (n=29), blood (n=7), urine (n=24) and 20 sputum (n=20). MIC values of the imipenem, meropenem and doripenem were determined by E tests. Out of 72 Polymyxin B sensitive isolates 34 were Pseudomonas aeruginosa, 30 Fluorescent group and 8 Alcaligenes group. Polymyxin B (n=8) resistant isolates were identified as Burkholderia group. Pseudomonas aeruginosa ATCC 29853 was used as quality control strain. Results: In the Polymyxin B sensitive group (n=72), 29.1%, 23.6% and 26.3% isolates were susceptible to imipenem, meropenem and doripenem respectively. In the Polymyxin B resistant group (n=8) only one isolate was sensitive to imipenem and meropenem while 5 were moderately sensitive to doripenem.