Outline. Antimicrobial resistance. Antimicrobial resistance in gram negative bacilli. % susceptibility 7/11/2010

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1 Multi-Drug Resistant Organisms Is Combination Therapy the Way to Go? Sutthiporn Pattharachayakul, PharmD Prince of Songkhla University, Thailand Outline Prevalence of anti-microbial resistance in Acinetobacter baumannii Anti-bacterial agents commonly used for A. baumannii infections Combination therapy for multi-drug resistant (MDR) A. baumanni In vitro and animal studies Clinical studies Antimicrobial resistance Prevalence of antimicrobial resistance among GNB is increasing especially Pseudomonas aeruginosa and Acinetobacter baumannii Pharmaceutical pipeline against MDR GNB is limited Antimicrobial resistance in gram negative bacilli MDR A. baumannii is the rapidly emerging pathogen in the health care setting worldwide MDR A. baumannii is the most difficult to treat antimicrobial resistant GNB Prevalence of antimicrobial resistance in A. baumannii US National Nosocomial Infection Surveillance System ( ) CID 2009;49:s4-10 In vitro susceptibility of A. baumannii in Thailand % susceptibility Drugs Ceftazidime Cefoperazone Imipenem Ciprofloxacin Amikacin

2 In vitro susceptibility of A. baumannii at Songklanagarind HHospital Drugs % Susceptibility Ceftazidime Cefoperazone Imipenem Merpenem Ciprofloxacin Amikacin Colistin Multi drug resistant Acinetobacter baumannii Definition Carbapenem resistance A.baumannii R to other ATB e.g. other beta-lactam, AMG, FQ R to >3 classes of traditional drugs: anti- pseudomonas penicillin, cephalosporin, carbapenem, aminoglycosides qinolones **Non-traditional drugs:, colistin, tigecyline Antibacterial Therapy for MDR-A.baumannii New anti-baterial agents: tigecycline, doripenem Anti-bacterial agents that A. baumanii may be susceptible to: colistin, fosfomycin, Combination therapy Optimized PK/PD : cont. infusion of beta- lactams Alter route of administration: nebulizer, intra- thecal, intra-ventricle Carbapenem-R Acinetobacter baumannii Class D beta-lactamase: OXA Class B beta-lactamase: VIM, IMP Loss of Porin Efflux pump: AdeABC Anti-bacterial agents commonly used for MDR A. baumannii infections Sulbactam Intrinsic activity against A. baumannii Cefoperazone -, ampicillin - Most efficacious and most studied agent Max dose : 24 gm/days Clinical studies 67% cure rate in carbapenem R A. baumanii infections Successful use in 14 pts with MDR A. baumanni VAP CID 2008;46: , Drug 2008;68:

3 Colistin Bactericidal against A. baumannii A. baumanni infection treatment outcome 57-67% cure rate in MDR A. baumannii infections 25-61% success rate for MDR A. baumanni VAP Tigecycline Bacteriostatic activity against MDR A. baumanii Emerging R during therapy reported efflux pump CID 2008;46: CID 2008;46: , Drug 2008;68: Rational for combination therapy Combination Therapy for MDR A. baumanni Improving treatment outcome (relatively to mono therapy) via synergistic effect Prevention of emerging resistance during therapy CID 2008;46: , Drug 2008;68: Novel Combinations Carbapenem combination Sulbactam combination Colistin combination Tigecycline combination Fosfomycin combination Other combinations Combination Therapy In vitro and animal studies 3

4 Carbapenem Combinations In Vitro and Animal Data Sulbactam Combinations Carbapenem (MIC) Combined drugs Results IMP (MIC 16 mg/l) 1 + amikacin (MIC 4 mg/l) Indifferent (1/1 Inferior than monotherapy (p=0.0001) IMP(MIC 8,128 mg/l) 2 +azithromycin (MIC 32,64 mg/l) Indifferent (2/2 I/M (MIC mg/l) 3 + minocycline (MIC 90 2mg/L) + tobramycin (MIC 90 >64mg/L) Synergy Synergy IMP ( mg/l) 4 + rifampicin (MIC 2-4 mg/l) Syn (9/9 Sulbactam (MIC) Combined drugs Results SUL (MIC > 16 mg/l) I/MRPA 1 Partial syn (4/4 (MIC of IMI> 8 mg/l, + meropenem Partial syn (4/4 MER>16 mg/l) SUL(MIC mg/l) 2 +meropenem Syn (3/10 (MIC of MER> 4 mg/l) Partial (5/10 SUL (MIC mg/l) 3 +amikacin (MIC Syn (45/5252 (S of IMI/MER 6%/ %/4%)%) 2,048 mg/l) Partial (6/52 SUL (MIC mg/l) 3 +cefepime (MIC 90 Syn (8/24 (MIC of IMI or MER >8mg/L) 128 mg/l) Partial (14/24 1.Clin Microbiol Infect 2005;11: Chemother 2003;49: Korean J Lab Med 2007;27: Int J Antimicrob Agents 2007;30: Pharmacother 2007;27(11): Diag Microbiol Infect Dis 2005;52: Int J Antimicrob Agents 2002;20: Korean J Lab Med 2007;27: Int J Antimicrob Agents 2007;30: Sulbactam Combinations Sulbactam (MIC) Combined drugs Results SUL/CPZ (MIC mg/l) 4 + minocycline (MIC 90 2mg/L) Syn (MIC 90 of I/M 32 mg/l) + tobramycin (MIC 90 >64mg/L) Syn + amikacin (MIC mg/L) Syn SUL (MIC mg/l) 5 + rifampicin (MIC 2-4 mg/l) Syn (9/9 (MIC of IMP mg/l) OXA-58 Colistin Combinations Colistin (MIC) Combined drugs Results COL 1 + meropenem Syn (6/6 (but only 2/6 (MIC of MER >16 mg/l) = clinically achievable MICs) PB 2 Cidal (7/8, (MIC of IMI > 32 mg/l) + rifampicin Cidal (7/8 Not MBL producing strain + IMI + RIF Cidal (8/8 COL (MIC 2 mg/l) 3 + rifampicin Syn (7/9) (MIC of IMP mg/l) (MIC 4 mg/l) OXA Pharmacother 2007;27(11): Diag Microbiol Infect Dis 2005;52: Int J Antimicrob Agents 2002;20: Korean J Lab Med 2007;27: Int J Antimicrob Agents 2007;30: AAC 2008;52(1): AAC 2004;48(3): Int J Antimicrob Agents 2007;30: Int J Animicrob Agents 2006;27: JAC 2007;60: Colistin Combinations Colistin (MIC) Combined drugs Results COL (MIC 4 mg/l) 4 + rifampicin (MIC 64) Partial (1/1 (MIC of MER 64 mg/l) + meropenem (MIC 64) Partial (1/1 + doxycycline (MIC 64) Indifferent (1/1 + azithromycin (MIC 16) Syn (1/1 COL (MIC mg/l) 5 + minocycline (MIC Cidal (9/13), Syn (12/13) (MIC of IMP 8 mg/l) mg/l) PB (MIC 0.25 mg/l) 6 Syn (1/5 (MIC of IMP 12, >32 mg/l) + rifampicin (MIC 4) Syn (1/5 OXA-23 +azithromycin (MIC >24) Additive (5/5 Colistin Combinations Colistin (MIC) Combined drugs Results COL (MIC mg/l) 6 + rifampicin (R3/5 Syn (3/5 (MIC of MER 64 mg/l) + In different (5/5 1. AAC 2008;52(1): AAC 2004;48(3): Int J Antimicrob Agents 2007;30: Int J Animicrob Agents 2006;27: JAC 2007;60: AAC 2008;52(1): AAC 2004;48(3): Int J Antimicrob Agents 2007;30: Int J Animicrob Agents 2006;27: JAC 2007;60:

5 Tigecylcine Combinations Tigecycline (MIC) Combined drugs Results TIG (MIC 90 8 mg/l) 1 +amikacin Cidal (MIC 90 of IMP 16 mg/l) + colistin Cidal IMP-1, VIM-2, OXA-23 TIG (MIC 4, 8 mg/l) 2 + levofloxacin (MIC 8,16) Syn (2/4, No cidal (MIC of IMP 2, 16, 32 mg/l) + amikacin (MIC 2, >64) Syn (1/2, No cidal Syn (1/2, No cidal + colistin (MIC <0.5) Syn (1/2, No cidal TIG 3 +amikacin Syn (4/9 + SUL or COL or RIF Syn (1/9 + P/T, PB Syn (2/9 + azithro or cipro Syn (0/9 TIG (MIC 2 mg/l) 4 + polymixin B Indifference (19/19 Fosfomycin Combinations Fosfomycin (MIC) Combined drugs Results FOS (MIC >128 mg/l) 1 + amikacin Syn (15/34 + tobramycin Syn (11/34 FOS (MIC ) + Syn (6/8, cidal + colistin Syn (1/8 1. AAC 2008;52(8): Ann Clin Microbiol Animicrob 2009;8:, 3. JAC 2006;57: Eur J Clin Microbiol Infec tdis 2007;6: Int J Antimicrob Agents 2009;34: PSU study Other Combinations Strains Antibiotic Combination Results IRAB (MIC = 8, 128 mg/l) 1 Azithromycin (MIC 32,64 mg/l) Additive (2/2 + ceftazidime (MIC 32,512 mg/l) Azithromycin + amikacin (MIC Indifferent (2/2 128,32 mg/l) or ciprofloxacin (MIC 512,64 mg/l) I/MRAB 12 Cefepime + amikacin Syn Amikacin + levofloxacin Additive Cefepime + levofloxacin Syn Summary for in vitro and animal combination studies Carbapenem + AMG Carbapenem + Rifampicin Carbapenem + Sulbactam Carbpenem + Tigecycline Carbapenem + Colistin 1, Chemother 2003;49: AAC 2008;52(8): Summary for in vitro and animal combination studies Sulbactam + AMG Sulbatam + rifampicin Sulbactam + minocycline Sulbactam + tigycycline Sulbactam + cefepime Summary for in vitro and animal combination studies Colistin + rifampicin Colistin + minocycline Colistin + tigcycline Tigecycline + amikacin Fosfomycin + AMG Fosfomycin + Fosfomycin + colistin 5

6 Combination Therapy Human data Combination Therapy: Human studies Lack of Clinical Trial Most available data: uncontrolled case series CID 2008;46: Carbapenem + Sulbactam Combinations Case series of 4 patients: 2 pneumonia, 2 catheter related infections Sulbactam (MIC) Combined drugs Results SUL (1 g q 6 g) I/MRPA 1 (500 mg q 6h) Cure (4/4) (MIC of IMI> 8 mg/l, + meropenem (1g q 6h) MER>16 mg/l) 1. R -mero (MIC-16 imi mic-8 and -MIC R -mero (MIC-64 imi mic-32 and -MIC R -mero (MIC-164 imi mic-32 and -MIC R -mero (MIC-16 imi mic-8 and -MIC-16 Lee, Pharmacotherapy 2007;27(11): Lee, et al. Pharmacother 2007;27(11): Colistin-based Regimens Tigecylcine Combinations Colistin Colistin combo Demo. Results COL ( MIU/d) C+meropenem 71, Various infect Response rate: not different COL died < COL+M Tigecycline Tigecylcine combo Demo. Results + P/T (4 g q 6 h) + TMP/SMX 1,Septic shock Cure 50 mg q 12 h MD (800/400 mg q 12 h) + colistin 7, VAP Cure 57% 50 mg q 12 h MD 9, VAP/bactere bactere- Cure 100% 50 mg q 12 h MD mia + colistin 4, VAP/bactere bactere- Cure 75% 50 mg q 12 h MD mia + meropenem 2 g q 8h + colistin 1, septic shock Cure mg q 12 h MD 3 MIU q 8 h Clin Microbiol Infect Dis 2008;12: Int J Antimicrobial Agents 2009;34:8 e1-8.e9 6

7 Riampicin + Imipenem Good outcome in mouse model of MDR A. baumanni pneumonia 1 In clinical study: high failure rate, 70% developed RF resistant 2 Rifampicin + Colistin Microbiological Clearance 67% CMI, , Montero (JAC 2004;54: ): 2. Saballs (JAC 2006:;58: : Pan - Resistant A. Baumanni Definition: R to all 7 anti-pseudomonal agents Pen, Ceph, Carba, Mono, FQ, AMG, & colistin Include strain that decreased S to No in vitro test for tigecycline Pan-Resistant A. Baumanni Age/gender U/D Specimen Treatment Outcome 19 yo M Multiple injury 24 yo F Multiple injury CSF Colistin + meropenem Bronchial Colistin + secretion meropenem injury secretion meropenem deterioration improvment Falagas, International J of Antimicrobial Agents 32(2008) Falagas, International J of Antimicrobial Agents 32(2008) Summary of Antibiotic Combinations MDR-Acinetobacter baumannii Many in vitro and animal studies show synergy in various antibacterial agents combination Limited clinical studies: case series Thanks for Your Attention 7