Update on Resistance and Epidemiology of Nosocomial Respiratory Pathogens in Asia Po-Ren Hsueh National Taiwan University Hospital
Ventilator-associated Pneumonia
Microbiological Report Sputum from a ICU Patient
Asian HAP Working Group. Am J Infect Control 2008;36:S83-92. Masterton RG et al. J Antimicrob Chemother 2008;62:5-34.
Selection of Antimicrobials in the Management of HAP (UK) Empirical antibiotic therapy of patients in an individual unit should be based on Knowledge of the nature and susceptibility patterns of the pathogens Duration of hospital stay (i.e. early- or late-onset infection) Recent administration of antibiotic therapy and co-morbidities Definitive therapy should be determined by culture and susceptibility test results Masterton RG et al. J Antimicrob Chemother 2008;62:5-34.
Etiology of HAP in Asia 50 40 K. pneumoniae P. aeruginosa A. baumannii MRSA 42.1 30 20 10 14 18 16 16 11 23 9 23 5.8 17.6 23 11.8 26.3 13.1 9 21 20 18 7.7 17.8 28.2 7.6 0 China Korea Malaysia Philippines Taiwan Thailand Chawla R. Am J Infect Control 2008;36:S93-100.
Susceptibility to P. aeruginosa and A. baumannii SENTRY, 2001-4, Asia-Pacific Region 100 80 60 % P. aeruginosa (n=898) A. baumannii (n=411) 81.6 82.3 92.7 86.1 81.2 82.2 73.7 64 58.4 58.4 59.2 55 40 20 0 Ceftazidime Cefepime Pip/Taz Ciprofloxacin Amikacin Imipenem Gales AC et al. Clin Microbiol Infect 2006; 12: 315 21.
Percentage of Isolates Susceptibility of Pseudomonas species TEST, Asia/Pacific Rim, 2006-9 (n=1370) 100 a 80 60 82.8 67.2 64.7 82.1 73.9 61.8 80.2 40 20 0 8.5 AN CPE CAZ CRO IPM MEM LVX TZP
Percentage of Isolates Susceptibility of Acinetobacter species TEST, Asia/Pacific Rim, 2006-9 (n=985) 100 80 66.2 a 83.8 60 40 55.8 44 41 53.8 48.6 43.7 20 22.7 0 AN CPE CAZ CRO IPM MEM LVX MNO TZP
Healthcare-associated Respiratory Infections in ICUs Taiwan Nosocomial Infection Surveillance Systems, TNIS, 2008 30 Medical centers (n=901) Regional hospitals (n=1,571) 20 21 21.4 18.8 22 % 10 12.9 9.9 9.8 12 4.5 3.6 3.9 2.3 7.8 0 P. aeruginosa A. baumannii S. aureus K. pneumoniae E. coli E. cloacae S. maltophilia
Major Resistant Pathogens in ICUs Taiwan Nosocomial Infection Surveillance Systems, TNIS, 2008 100 Medical centers Regional hospitals % 80 60 80.1 79.7 56.3 62.1 40 20 0 16.4 15.6 6.2 3.3 MRSA CRKP CRAB CRPA Lee CM, et al. Infect Control J 2010.
Healthcare-associated Respiratory Tract Infections 365 Pathogens, NTUH, 2009 Klebsiella spp. 18.9 P. aeruginosa S. aureus Acinetobacter spp. 12.5 13.7 15.1 MRSA, 51.9% S. maltophilia E. coli Enterobacter 8.2 7.1 5.8 0 5 10 15 20 %
% 70 Resistance in Major HAP Pathogens NTUH, 2009 K. pneumoniae P. aeruginosa A. baumannii 60 50 54.3 52.2 52.3 48.4 46.4 40 30 20 10 26.6 13.5 13.2 18.4 19.7 17.2 21.4 6.4 10.5 9.3 2.6 8.7 0 Ceftazidime Cefepime Pip/Taz Ciprofloxacin Imipenem Amikacin (ertapenem)
Antibiotic Treatment of Infections due to MDR or XDR Superbugs P. aeruginosa Combination with two susceptible agents Colistin alone or in combination (XDR) Fosfomycin in combination A. baumannii A carbapenem plus sulbactam Colistin alone or in combination Tigecycline alone or in combination Bonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.
Susceptibility to A. baumannii SMART, 2005, 10 ICUs (N=167), Taiwan; SENTRY (AP) 100 94 94 98.1 80 60 40 20 33 57 Intermediate, 82.5% 7.5 0 AMP/SUL CFP/SUL Fosfomycin Colistin Tigecycline Polymyxin B Jean SS, Hsueh PR et al. Int J Antimicrob Agents 2009;33:266-71. Gales AC et al. Clin Microbiol Infect 2006; 12: 315 21.
Risk Factors for Multidrug-Resistant Pathogens (MDRP) HAP, VAP, HCAP Antimicrobial therapy in preceding 90 days Current hospitalization of 5 days or more High frequency of antibiotic resistance in the community or in the specific hospital unit Presence of risk factor for HCAP Hospitalization for 2 days or more in preceding 90 days Residence in a nursing home or extended care fascility Home infusion therapy (including antibiotics) Chronic dialysis within 30 days Home wound care Family member with MDRP Immunosuppressive disease and/or therapy Bonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.
Initial Empiric Antibiotic Therapy for HAP, VAP, HCAP Risk Factors for MDRP, Late Onset, Any Disease Severity Potential pathogen Combination antibiotic therapy Pathogens (early-onset) + Cefepime, ceftazidime MDRP or P. aeruginosa Imipenem or meropenem K. pneumoniae (ESBL) or Acinetobacter spp. Piperacillin-tazobactam PLUS Ciprofloxacin or levofloxacin or Amikacin, gentamicin, or tobramicin L. pneumophila + a macrolide (azithromycin) or a fluoroquinolone (CIP, LVX) MRSA PLUS Linezolid or vancomycin Bonten MJ et al. Am J Respir Crit Care Med 2005;171:388-416.
Validation of the ATS/IDSA Guidelines for HAP in the ICU 276 patients Group 1 (early onset without risk factors for MDRO, n=38) Group 2 (late onset or risk factors for MDRO, n=238) Adherence to guidelines Group 2: more guideline adherence, more adequate treatment and a trend to a better clinical response in Did not influence mortality Ferrer M et al. Clin Infect Dis 2010;50:945-52.
Initial Empirical Antibiotic Treatment for Late onset VAP- HAP in Asia Potential pathogen MDR pathogens P. aeruginosa Acinetobacter ESBL (+) K. pneumoniae MRSA Recommended antibiotic regimen Antipseudomonal carbepenem (imipenem or meropenem) or beta-lactam/beta-lactamase inhibitor (piperacillintazobactam) Fluoroquinolone (ciprofloxacin or levofloxacin) or aminoglycoside (amikacin, gentamicin, or tobramycin) linezolid or vancomycin cefoperazone/sulbactam fluoroquinolones or aminoglycosides ampicillin/sulbactam (if sulbactam is not available) linezolid or vancomycin or fluoroquinolone (ciprofloxacin) plus an aminoglycoside linezolid or vancomycin Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.
Antibiotic Regimens against Specific Antibiotic-resistant Pathogens- HAP in Asia Pathogen Rank Antibiotic regimen MRSA 1 Vancomycin or teicoplanin 2 Linezolid or tigecycline MDR P. aeruginosa 1 Piperacillin/tazobactam or carbapenems aminoglycosides or fluoroquinolones (ciprofloxacin) 2 Polymyxin B or colistin ciprofloxacin MDR Acinetobacter 1 Cefoperazone/sulbactam and/or tigecycline ESBL (+) K. pneumoniae or E. coli 2 Polymyxin B or colistin 1 Carbapenems or tigecycline 2 Piperacillin/tazobactam Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.
Fluoroquinolones in HAP and VAP Advantages High concentrations in lung tissue and respiratory secretions Synergistic activity in combined treatment against P. aeruginosa Substitution for aminoglycosides Impaired renal function or at risk for renal dysfunction Need to extend antibiotic coverage to intracellular pathogens No need to monitor plasma drug concentration to ensure effectiveness and to avoid toxicity Possibility of sequential therapy in patients with satisfactory clinical response Synergistic interaction with antifungals (improve outcomes) Patients with suspected or confirmed allergy to -lactams Lower capacity to induce P. aeruginosa resistance Lvarez-Lerma F et al. Clin Microbiol Infect Dis 2006;12 (Suppl 3):81-92. Stergiopoulou T et al. J Antimicrob Chemother 2009;63:343-8.
% 60 50 40 Emergence of Resistance among P. aeruginosa The emergence of resistance occurred less often with quinolones than with imipenem 30 20 10 0 Imipenem Ciprofloxacin Cirpofloxacin Levofloxacin Fink et al Torres et al West et al Shorr AF et al. Clin Infect Dis 2005;40:S115-22.
% 100 80 60 40 20 0 Treatment of Severe HAP Ciprofloxacin vs. Imipenem 79 71 71 67 50 49 50 Success rate P. aeruginosa Success P. aeruginosa Resistance (PA) Clinical success Ciprofloxacin (0.8-1.2 g/d) (n=41) Imipenem 2-4 g/d (n=34) 25 Microbiological success 7 33 1/14 4/12 Torres A et al. Thorax 2000;55: 1033-9.
Ciprofloxacin and Levofloxacin Equal in P. aeruginosa??? Resistance Selection
Nonsusceptibility to Fluoroquinolone in P. aeruginosa Nosocomial Infections, NTUH, 2009 SMART, ICUs, 2005 % 20 10 Ciprofloxacin Levofloxacin 6.4 10.5 % 30 20 10 Ciprofloxacin Levofloxacin 19 23 0 0 Resistant Resistant Jean SS, Hsueh PR et al. Int J Antimicrob Agents 2008
Ciprofloxacin and Levofloxacin Not Equal in P. aeruginosa Antimicrobial (steady state) MIC 50 (μg/ml) 1 C max (μg/ml) AUC 0-24 (μg.h/ml) C max /MIC AUC 0-24 / MIC Ciprofloxacin (IV 400 mg q8h) Levofloxacin (IV 750 mg q24) Free drug, 70% for both 0.25 4.1 32.9 16.4 131.6 1 7.9 82.2 7.9 82.2 AUC/MIC >157:1, the threshold to suppress emergence of resistance Jean SS, Hsueh PR et al. Int J Antimicrob Agents 2008 Jumbe N et al. J Clin Invest 2003;112:275-85.
Clin Infect Dis 2004; 39:497 503. Kaye KS et al. Antimicrob Agents Chemother 2006; 50:2192-8.
Trend of Hospital Fluoroquinolone Use 1999 (n=24), 2000-2001 (n=35), USA p=0.01 p=0.0006 p >0.05 Clinical Infectious Diseases 2004; 39:497 503 Polk RE et al. Clin Infect Dis 2004; 39:497 503.
Individual Hospital Levofloxacin Use and FQ Resistance in P. aeruginosa 2000, USA N=27, p=0.0006 Clinical Infectious Diseases 2004; 39:497 503 Polk RE et al. Clin Infect Dis 2004; 39:497 503.
Risk Factors for FQ-Resistant P. aeruginosa Multivariate Analysis Variable Adjusted OR (95% CI) for: FQ-resistant FQ-susceptible (n=147) (n=255) Levofloxacin 1.7 (1.0 2.9) 0.6 (0.4 0.9) Ciprofloxacin 1.2 (0.6 2.5) 1.0 (0.6 1.8) Other antibiotics 2.2 (1.3 3.8) 2.1 (1.5 3.0) ICU stay 3.3 (2.1 5.1) 3.7 (2.7 5.1) Presence of 2 comorbid conditions 1.7 (1.1 2.8) 1.6 (1.1 2.3) TAR of >6 days 1.8 (1.1 2.8) Age of 64 yrs 1.4 (1.0 2.0) Kaye KS et al. Antimicrob Agents Chemother 2006; 50:2192-8.
Lee YJ, Hsueh PR et al. Int J Antimicrob Agents 2010;35:261-4.
Ciprofloxacin-resistant P. aeruginosa Ciprofloxacin and Levofloxacin Usages Lee YJ, Hsueh PR et al. Int J Antimicrob Agents 2010;35:261-4.
Ciprofloxacin-resistant P. aeruginosa Parenteral Ciprofloxacin and Levofloxacin Usages Lee YJ, Hsueh PR et al. Int J Antimicrob Agents 2010;35:261-4.
Ciprofloxacin-resistant P. aeruginosa IV+PO Ciprofloxacin and Levofloxacin Usages Lee YJ, Hsueh PR et al. Int J Antimicrob Agents 2010;35:261-4.
Reasons for the Differences Better activity of ciprofloxacin Fluoroquinolone-resistant P. aeruginosa are most likely to originate in the gastrointestinal tract Higher bioavailability of levofloxacin (100%) than ciprofloxacin (60% 70%) Higher GI concentrations of ciprofloxacin may eliminate more borderline fluoroquinolones-susceptible organisms and levofloxacin may select more fluoroquinolone-resistant strains In vitro serial passage studies Rate of accumulation of P. aeruginosa mutants with a drug MIC of 4 g/ml was fastest for levofloxacin and slowest for ciprofloxacin Polk RE et al. Clin Infect Dis 2004; 39:497 503. Gilbert DN et al. Antimicrob Agents Chemother 2001;45:883-92.
Dynamic Selection of Quinolone Resistance Rate for Emergence of Resistance Phenotypes K. pneumoniae, E. cloacae, S. marcescens Trovafloxacin > levofloxacin > ciprofloxacin P. aeruginosa Levofloxacin > trovafloxacin > ciprofloxacin In vitro behavior can predict clinical resistance??? Gilbert DN et al. Antimicrob Agents Chemother 2001;45:883-92.
Risks for Acquisition of FQ-Resistant P. aeruginosa Ciprofloxacin and Levofloxacin Individual patient Exposure to levofloxacin, but not to ciprofloxacin, was associated with increased risk For hospitals Different FQs prescribing should be examined Hospital s formulary: which FQ should be included? Ciprofloxacin is more appropriate than levofloxacin for empirical therapy for suspected pseudomonal infections Kaye KS et al. Antimicrob Agents Chemother 2006; 50:2192-8.
Fluoroquinolone Use Different Resistance Selection for P. aeruginosa? Need adequate dosage Ciprofloxacin: 400 mg q8h Levofloxacin: 750 mg qd Combination therapy vs. monotherapy Clonal spreads? Appropriate Use
Ciprofloxacin nonsusceptibility (%) DDD/1000 patient-days Fluoroquinolone Consumption and Ciprofloxacin Nonsusceptibility NTUH, 2000-2009 20 18 16 9.5 6.4 11.6 16.1 170.6 14.1 170 10.9 171.5 13 187.3 7.9 159.4 7.4 155.5 6.4 157.4 200 180 160 14 140 12 10 106.7 115.7 120 100 8 76.4 80 6 60 4 40 2 20 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Lai CC, Hsueh PR et al. Data submitted