Management of Infections with Multi-drug Resistance Bacteria การร กษาการต ดเช อแบคท เร ยด อยา

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1 Management of Infections with Multi-drug Resistance Bacteria การร กษาการต ดเช อแบคท เร ยด อยา รองศาสตราจารย แพทย หญ งศศ โสภ ณ เก ยรต บ รณก ล คณะแพทยศาสตร โรงพยาบาลรามาธ บด Sasisopin Kiertiburanakul, MD, MHS Associate Professor Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University 2 nd IC on Stage, Nakornthon Hospital (November 29, 2012)

2 Outline Introduction Bacterial resistance Current guidelines Antibiotic options

3 Most Popular in Your Hospital A. A. baumannii B. P. aeruginosa C. ESBLs-producing Gram-negative bacteria

4 Superbug on IDSA hit list Enterococcus S. aureus K. pneumoniae A. baumannii P. aeruginosa E. cloacae Boucher HW et al. Clin Infect Dis 2009;48:1-12.

5 Bad Gram-negative Bugs Fermentative gram negative bacteria Enterobacteriaceae Klebsiella, Escherichia, Enterobacter, Salmonella, Shigella Proteus, Citrobacter, Serratia, Morganella, Yersinia, Edwardsiella, Providencia Non-fermentative gram negative bacteria P. aeruginosa Acinetobacter spp. Stenotrophomonas maltophilia

6 Bad Gram-Positive Bugs Methicillin-resistant Staphylococcus aureus (MRSA) 1 Methicillin-resistant coagulase-negative Staph (CoNS) 1 Vancomycin-resistant enterococci (VRE) 1 Penicillin-resistant Streptococcus pneumoniae 1 Clostridium difficile 2 1. Infectious Diseases Society of America. 2004: available on-line: 2. Peterson LP. Clin Infect Dis 2009;49:992-3.

7 Definitions Multidrug resistance (MDR) Non-susceptible to >1 agent in >3 antimicrobial categories* Extensive drug resistance (XDR) Non-susceptibility >1 agent in all but <2 antimicrobial categories* Pandrug resistance (PDR) Non-susceptibility to all agents in all antimicrobial categories* for each bacteria *List of antimicrobial agents used to treat the infections caused by this bacteria Falagas ME et al. Clin Infect Dis 2008;46: Magiorakos AP et al. Clin Microbiol Infect doi: /j x

8 Magiorakos AP et al. Clin Microbiol Infect 2012;18: X= non-susceptible

9 Susceptibility of E. coli Percentage (%) AMOX/CLAV CFR CRO CAZ NFX AMK GEN TMP/SMX National Antimicrobial Resistance Surveillance Center, Thailand

10 Susceptibility of A. baumannii 100 Percentage (%) CPZ/SUL IMP National Antimicrobial Resistance Surveillance Center, Thailand

11 Ramathibodi Antibiogram: June 2012 Organisms Ceftri Ceftaz Pip/tazo Imip Dori Cipro Amik A. baumannii E. cloacae E. coli K. pneumoniae P. aeruginosa S. maltophilia* *levofloxacin 85%, co-trimoxazole 82%

12 Nakornthon Antibiogram 2011 Organisms Ceftri Ceftaz Cef/sub Imip Cipro Amik A. baumannii Enterobacter spp E. coli K. pneumoniae P. aeruginosa S. maltophilia* *levofloxacin 92%, co-trimoxazole 71%

13 Mechanisms of Resistance of GNB Peleg AY, et al. N Engl J Med 2010;362:

14 Risk Factors for Resistance Health care associated infections Hospitalization for 2 days in preceding 90 days Residence in a nursing home or long-term care facility Home infusion therapy, including antimicrobial agents Long-term dialysis within 30 days Home wound care Family member with multidrugresistant pathogen Infection with drug-resistant bacteria Antimicrobial therapy in preceding 90 days Current hospitalization for 5 days High frequency of antibiotic resistance in the community or in the specific hospital unit Immunosuppression Guidelines for the management of adults with hospital-acquired, ventilator associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:

15 Clinical Outcome of Mortality Resistant organism KPN-ESBL+ Non-resistant organism KPN-ESBL- P-value Bacteremia 1* 52% (n=48) 29% (n=99) AB (IMP-R) AB (IMP-S) Bacteremia % (n=40) 27.5% (n=40) <0.05 MDR-Pae No-MDR-Pae Bacteremia 3 21% (n=82) 12% (n=82) 0.08 EB (IMP-R) EB (IMP-S) Multiple sources 4 11% (n=33) 3% (n=33) KPN=K. pneumoniae; ESBL=extended-spectrum β-lactamase; AB=A. baumannii; IMP=imipenem; R=resistant; S=susceptible; Pae=P. aeruginosa; EB=Enterobacter spp. *95% CI, Tumbarello M et al. Antimicrob Agents Chemother 2006;50: Kwon KT et al. J Antimicrob Chemother 2007;59: Aloush V et al. Antimicrob Agents Chemother 2006;50: Marchaim D et al. Antimicrob Agents Chemother 2008;52:

16 Mortality Associated with Initial Inadequate Therapy in Critically Ill ICU Patients Alvarez-Lerma, 1996 Luna, 1997 Initial adequate therapy Initial inadequate therapy Rello, 1997 Kollef, 1998 Ibrahim, 2000** Harbarth, 2003 Valles, 2003** Mortality* 0% 20% 40% 60% 80% *Mortality refers to crude or infection-relate mortality- ** Patients had blood stream infections rather than pneumonia as in the other studies Intensive Care Med 1996;22: Chest 1997;111: Am J Respir Crit Care Med 1997;156: Chest 1996;113: Chest 2000;118: Am J Med 2003:115: Chest 2003;123:

17 Current Guidelines

18 Current Guidelines Hospital-acquired pneumonia Diabetes foot infection Intra-abdominal infection Complicated urinary tract infection

19 Hospital-, Ventilator-, and Healthcare-associated Pneumonia HAP: pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission VAP: pneumonia that arises >48 72 hours after endotracheal intubation HCAP: hospitalized in acute care hospital >2 days within 90 days, resided in nursing home or longterm care facility, received recent IV antibiotic therapy, chemotherapy, or wound care within the past 30 days, or attended hospital or hemodialysis clinic ATS, IDSA. Am J Respir Crit Care Med 2005;171:

20 Hospital-, Ventilator-, and Healthcare-associated Pneumonia Aerobic gram-negative bacilli P. aeruginosa, E. coli, K. pneumoniae, and Acinetobacter spp. Gram-positive cocci S. aureus, MRSA Polymicrobial infection Multidrug-resistance pathogens Antimicrobial therapy in preceding 90 days Current hospitalization >5 days High frequency of resistance in community or specific hospital unit Presence of risk factors for HCAP Immunosuppressive disease and/or therapy ATS, IDSA. Am J Respir Crit Care Med 2005;171:

21 ATS/IDSA Guideline: Empiric Therapy HAP, VAP or HCAP suspected (all disease severity) Late onset (>5 days) or risk factors for MDR pathogens No Yes Limited spectrum antibiotic therapy Broad spectrum antibiotic therapy for MDR pathogens ATS, IDSA. Am J Respir Crit Care Med 2005;171:

22 Risk Factors for MDR Pathogens or Late Onset ATS, IDSA. Am J Respir Crit Care Med 2005;171:

23 Nosocomial Pneumonia Treatment Caused by MDR Pathogens Jean SS et al. Expert Opin Pharmacother 2011;12:

24 Solomkin JS et al. Clin Infect Dis 2010;50:

25 Complicated Intra-abdominal Infections Perforated intestines, intra-abdominal abscesses, appendicitis, diverticulitis, or cholecysitis with perforation and/or abscess with fecal contamination, or perforated gastric/duodenal ulcers, and complicated peritonitis Healthcare-associated infections generally require broader antibacterial coverage P. aeruginosa, Enterobacter spp. and MRSA Objectives for the treatment: to minimize time to clinical improvement, prevent recurrence, and eradicate causative microorganisms

26 Complicated Intra-abdominal Infections Solomkin JS et al. Clin Infect Dis 2010;50:

27 Recommendations for Empirical Therapy Solomkin JS et al. Clin Infect Dis 2010;50:

28 Urinary Tract Infections Hsueh PR et al. J Infect 2011;63:

29 Empirical Antimicrobial Therapy e: for multidrug-resistant Enterobacteriaceae and A. baumannii and vancomycin-resistant enterococci. f: for multidrug-resistant Enterobacteriaceae, P. aeruginosa, and A. baumannii. Hsueh PR et al. J Infect 2011;63:

30 Antibiotic Selection

31 Consensus Prescribing Principles Appropriate and effective prescribing guidelines TREAT OPTIMIZE MAXIMIZE RECOGNIZE UTILIZE INTEGRATE bacterial infection only diagnosis/severity assessment bacterial eradication (local) resistance prevalence pharmacodynamics - for effective agents and dosage local resistance, efficacy and cost-effectiveness Ball et al. J Antimicrob Chemother 2002;49:31 40.

32 Factors to Consider When Selecting Antibiotics Spectrum Prove clinical efficacy PK/PD Convenience/compliance Cost Adverse effects Antibiotic factors Disease specific factors Patients factors Previous ATB Age Concomitant diseases Pregnancy Drug allergy Possible pathogens Likelihood of resistance Severity of infection

33 Comparison of Antimicrobial Spectra Organism 3rd/4th Cephalosporins BL/BI Carbapenems Ceftazidime Cefepime Pip/tazo Doripenem Imipenem Meropenem Ertapenem Gram-Positive: S. pneumoniae MSSA +/ E. faecalis /- + +/- 0 E. faecium +/- 0 +/- 0 0 Gram-Negative: E. coli Klebsiella spp E.coli /Kleb spp. ESBL / Enterobacter spp Proteus spp Acinetobacter spp. +/- +/- +/- +/- +/- +/- 0 P. aeruginosa Anaerobes: B. fragilis Clostridium (not difficile) Peptostreptococcus spp The Sanford Guide to Antimicrobial Therapy = usually effective clinically or >60% susceptible; +/- = clinical trail lacking or 30-60% susceptible 0= not effective clinically or <30% susceptible; blank = data not available

34 Local Antibiogram: iphone Application

35 What to Treat? ESBLs Imipenem Meropenem Doripenem Ertapenem Peleg AY et al. N Engl J Med 2010;362:

36 Management Options: ESBLs Antimicrobial agent Pros Cons Carbapenems Fluoroquinolones Drug of choice for severe infections Option for non-serious UTIs, if sensitive Ertapenem-less susceptible; overuse? Empirical use-not recommended Aminoglycosides Effective if sensitive Avoided monotherapy Fosfomycin Tigecycline β-lactamase inhibitor combinations Option for UTIs, oral form (cystitis) Excellent in vitro activity against ESBL producers May be active against ESBL producers, UTIs Conjunction with other antibiotics for other infections, less clinical data FDA warned against its use for serious HAP/VAP, less clinical data Should not used for serious infections Polymixins Excellent efficacy Nephrotoxicity Modified from Dhillon RH et al. Crit Care Res Pract 2012;2012:

37 What to Treat? ESBLs Imipenem Meropenem Doripenem Ertapenem Carbapenemase-producing Enterobacteriaceae Colistin Tigecycline Combination with others Carbapenem-resistant P. aeruginosa Carbapenem-resistant A. baumannii Colistin Extended infusion of carbapenem Combination with others Colistin Tigecycline Sulbactam combination Extended infusion of carbapenem Combination with others Peleg AY et al. N Engl J Med 2010;362:

38 Other Options

39 Combat to Antibiotic-resistant Pathogens New drugs Increased dose Increased frequency Prolonged or continuous infusion Combination anitibiotics

40 Problems!!! Bad_Bugs_No_Drugs/Press_Releases/Antibiotic%20Resistance%20Fact%20Sheet.pdf

41 Dosage of Antibiotics: HAP, VAP, HCAP Doripenem 500 mg every 8 h Dosages are based on normal renal and hepatic function Trough levels for gentamicin and tobramycin should be less than 1 g/ml, and for amikacin they should be less than 4 5 g/ml Trough levels for vancomycin should be g/ml ATS, IDSA. Am J Respir Crit Care Med 2005;171:

42 β-lactams Antibiotics T >MIC (% of dosing interval) C max (Peak) Serum level Serum Concentration Time above MIC MIC = 4 C min (Trough) MIC = 2 Time 6 hours

43 Time-dependent Killing %T>MIC <50% %T>MIC >50% MIC 90 MIC 90 More frequent infusion %T>MIC = 100% %T>MIC >50% 32 MIC MIC 90 Continuous infusion Prolonged infusion Modified from and Courtesy of Koomanachai P.

44 Prolonged or Continuous Infusion Extending infusion time, antibiotic levels will be sustained above MIC of targeted organisms 1,2 May potentially result in improved drug efficacy Improve clinical outcomes for meropenem (cure rate 90.5% vs. 59.6%; P <0.001) 3 Prolonged infusion consistently achieved higher pharmacodynamic endpoints 4 Improved clinical outcomes in subgroup of P. aeruginosa infection and APACHE >17 Prospective randomized trial: doripenem 4-hour infusion vs imipenem 30/60-minutes infusion 5 Reduction in development of resistant P. aeruginosa 1. Lodise TP et al. Pharmacotherapy 2006;26: Kim A et al. Pharmacotherapy 2007;27: Lorente L et al. Ann Pharmacother 2006;40: Mah GT et al. Ann Pharmacother 2012;46: Chastre J et al. Crit Care Med 2008;36:

45 Prolonged Infusion for MDR Organisms Piperacillin/tazobactam g q 6-8 hr, drip 3-4 hr 1,2 Continuous infusion Cefepime: 2 g q 8 hr, drip 3 hr 3 Ceftazidime: 2 g q 8 hr, drip 3 hr 4 Meropenem: 2 g q 8 hr, drip 3 hr 4 Imipenem: 500 mg or 1 g q 8 hr, drip 2-3 hr 5 Doripenem: 500 mg q 8 hr, drip 4 hr 1.Kim A et al. Pharmacotherapy 2007;27: Lodise TP Jr et al. Clin Infect Dis 2007;44: Crandon JL et al. Ann Pharmacother 2009;43: Kiim A et al. Clin Ther 2009;31: Jaruratanasirikul S et al. J Antimicrob Chemother 2009;63:560-3.

46 Why Empiric Combination Therapy? A. Synergistic B. More coverage C. Prevent/minimize drug resistance

47 Combination Therapy: Why? Severe infection or critically-ill patient Optimize coverage Exact pathogen is unknown Immunoduratory effect? Prevent emergence of resistance? Synergistic effect? Overuse resistance

48 Optimize Spectrum Coverage Micek ST et al. Antimicrob Agents Chemother 2010;54:

49 Combination Therapy and MDR A. baumannii Yoon J et al. Antimicrob Agents Chemother 2004;48:

50 Combination vs. Monotherapy for Empiric Therapy PRO Synergistic effect in vitro Good outcome in severely ill Septic shock, neutropenia, infection with MDR organisms Higher rate of microbiological cure CON Higher rates of resistance isolates Higher rates of side effects Lack of the power to showed consistent of good outcome No top-level evidence to support or reject* *Kollef MH et al. Clin Infect Dis 2011;53:S33 S55.

51 Combination Therapy: Suggestion For patients who are critically ill and in institutions with high rates of antibiotic resistance Empiric combination therapy is justified If use, not delay! * Early de-escalation to targeted monotherapy when susceptibilities are known With active β-lactam *Kumar A et al. Crit Care Med 2010;38:

52 A Patient with VAP

53 VAP with MDR Pathogens

54 Your Choice A. Combination B. Extended infusion C. Both

55 Vancomycin and S. aureus MSSA Inferior to at least some β-lactams for the treatment of bacteremia and endocarditis MRSA MIC creep Poor therapeutic response Limitations of the clinical lab in detecting reduced susceptibility and resistance Poor penetration into tissue Increasing dose may not safely overcome its poor activity and limited tissue penetration Inferior to some comparators in randomized control trials Combination with a second anti-staphylococcal antibiotic does not improve its therapeutic efficacy Deresinski S. Clin Infect Dis 2007;44:154-8.

56 Monitoring of Vancomycin IV vancomycin mg/kg/dose (actual body weight) every 8-12 h, not to exceed 2 g per dose Trough serum vancomycin concentrations Just before the 4 th or 5 th dose Should always be maintained >10 µg/ml to avoid development of resistance µg/ml are recommended to improve penetration In seriously ill patients, a loading dose of mg/kg Recommended Patients receiving aggressive dosing High risk of nephrotoxicity or unstable renal function Receiving prolonged courses of therapy Raybak M et al. Am J Health-Syst Pharm 2009;66:82-98.

57 Summary 1 Resistance should be a concern issue in clinical practice Infection with bacterial resistance is a leading cause of inadequate treatment and mortality Prompt empiric antimicrobial agents

58 Summary 2 Appropriate and adequate uses of antimicrobial agents Choosing antimicrobial agent depends on clinical indications, patients condition, and drugs profiles Streamline therapy Prolonged infusion and combination when appropriate

59 The WHO SAVE LIVES: Clean Your Hands