Antimicrobial Cycling. Donald E Low University of Toronto

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1 Antimicrobial Cycling Donald E Low University of Toronto

2

3 Bad Bugs, No Drugs 1 The Antimicrobial Availability Task Force of the IDSA 1 identified as particularly problematic pathogens A. baumannii and P. aeruginosa ESBL-producing Enterobacteriaceae MRSA Vancomycin-resistant enterococcus Declining research investments in antimicrobial development 2 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. July, Accessed March 17, Talbot GH, et al. Clin Infect Dis. 2006;42:

4 Number of agents approved A Changing Landscape for Numbers of Approved Antibacterial Agents Resistance Bars represent number of new antimicrobial agents approved by the FDA during the period listed. Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38: ; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912

5 Problem Pathogens in the Hospital Setting Gram negatives Resistant Enterobacteriaceae β-lactamases Pseudomonas/Acinetobacter Gram positives MRSA

6 The Gram Negatives

7 Enterobacteriaceae The rapid and disturbing spread of: extended-spectrum ß-lactamases AmpC enzymes carbapenem resistance metallo-β-lactamases KPC and OXA-48 β-lactamases quinolone resistance

8 Prevalence of Isolates of Multidrug-Resistant Gram Negative Rods Recovered Within The First 48h After Admission to the Hospital Pop-Vicas and D'Agata CID 2005;40:

9 Frequency (%) E. coli and Klebsiella ESBL Phenotype Rates by Country (SENTRY Program) Switzer Sweden Spain Ireland Germany UK France Italy Israel Turkey Greece Poland Country Klebsiella E. coli

10 CTX-M-type ESBLs Now, the dominant ESBLs across most of Europe and Asia are CTX-M enzymes 80% of ESBL-positive E. coli from bacteraemias in the UK and Ireland are resistant to fluoroquinolones 40% are resistant to gentamicin Livermore, DM J. Antimicrob. Chemother 2009

11 Carbapenemases Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems KPC

12 K. pneumoniae carbapenemase-producing bacteria Nordmann P et al. LID 2009

13 Carbapenemase-producing Enterobacteriaceae in the UK NDM (New Delhi Metallo-) β-lactamase: repeated importation from Indian subcontinent 21 UK producers comprise K. pneumoniae (14) E. coli (4) Enterobacter spp (1) C. freundii (2) NDM-1 has become the most frequent carbapenemase in isolates referred to UK ARMRL

14 New Delhi Metallo-β-lactamase (NDM-1) in Enterobacteriaceae Surveillance for NDM-1 positive strains among the carbapenem resistant Enterobacteriaceae isolates at tertiary care centre in Mumbai In 3 months 22 NDM-1 carbapenem resistant gram-neg identified Klebsiella spp, E. coli E. cloacae and M. morganii Deshpande P et al. JAPI 2010

15 The Gram Positives Staphylococcus aureus MRSA Reduced-vancomycin susceptibility MRSA

16 MRSA DeLeo and Chambers JCI 2009 adapted from Klevens et al. JAMA I2007

17 Worldwide Prevalance of MRSA Among S. aureus Isolates Grundmann H et al. Lancet 2006;368:874.

18 Does Resistance Matter?

19 Mortality and delay in effective therapy associated with ESBL in Enterobacteriaceae bacteraemia: a systematic review and meta-analysis 16 studies met inclusion criteria crude RRs demonstrated significantly increased: mortality in ESBL-associated bacteraemia (pooled RR 1.85, 95% CI , P < 0.001) incidence of delay in effective therapy in ESBL-associated bacteremia (pooled RR 5.56, 95% CI , P < 0.001) Schwaber MJ and Carmeli Y JAC 2007

20 Increased mortality in ESBLassociated bacteraemia Schwaber MJ and Carmeli Y JAC 2007

21 Strategies for Reducing Resistance in the Hospital Setting

22 Antimicrobial Cycling In theory, a class of antibiotics or a specific antibiotic drug is withdrawn from use for a defined period and reintroduced at a later point in time in an attempt to limit bacterial resistance to the cycled antibiotic agents This offers the potential for antibiotic classes to be used that possess greater overall activity against the predominant pathogens Kollef M. Chest 2006

23 The Success

24 Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital For 10 years the 700-bed Minneapolis Veterans Affairs Medical Center has conducted a policy of carefully controlled aminoglycoside usage and monitoring of resistance of over 25,000 aerobic and facultative gram-negative bacillary isolates to the aminoglycosides Gerding D et al. AAC 1991

25 Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital Gerding D et al. AAC 1991

26 Scheduled Change of Antibiotic Classes A Strategy to Decrease the Incidence of VAP 680 patients with VAP The 6-mo period before-period ceftazidime used for the empiric treatment of suspected gram-negative followed by a 6-mo period ciprofloxacin The incidence of VAP decreased in the after-period (6.7 versus 11.6%; p 0.028) due to reduction in the incidence of VAP attributed to antibiotic-resistant gram-negative bacteria (ARGN) (0.9 versus 4.0%; p 0.013) Observed a lower incidence of bacteremia due to ARGN the after-period (0.3 versus 1.7%; p 0.125) Kollef M et al. Amer J Resp Crit Care 1997

27 Scheduled Change of Antibiotic Classes A Strategy to Decrease the Incidence of VAP Kollef M et al. Amer J Resp Crit Care 1997

28 The Partial Success Stories

29 Class Restriction of Cephalosporin Use to Control Total Cephalosporin Resistance in Nosocomial Klebsiella A new antibiotic guideline excluded the use of cephalosporins An 80% reduction in hospital-wide cephalosporin use occurred Squeezing the Balloon This was accompanied by a 44% reduction in the incidence of ceftazidime-resistant Klebsiella infection and colonization throughout the medical center A concomitant 69% increase in the incidence of imipenem-resistant P. aeruginosa occurred throughout the medical center (P,.01) Rahal J et al. JAMA 1998

30 The Failures

31 Antibiotic Rotation and Development of Gram-Negative Antibiotic Resistance Cycled 2 different antibiotic classes (fluoroquinolone and β-lactam) in a surgical ICU during four 4-month cycling periods, obtaining respiratory aspirates and rectal swabs for culture 388 patients were evaluated along with 2520 culture results Good adherence to the antibiotic protocol, but overall antibiotic use increased by 24% van Loon HJ et al. Amer Resp Crit Care Med 2005

32 The Half Levo_R; Success diamonds Cfp_Rsquares Ptz_R; triangles Levo Cefpir Levo Pip/taz van Loon HJ et al. Amer Resp Crit Care Med 2005

33 Why Has Antimicrobial Cycling Failed Implementation Convincing clinicians Compliance Resistance is not necessarily costly Some mutations are cost free Decreased fitness caused by resistance may be rapidly counterbalanced by compensatory mutations Carriage of multiple resistance mechanism on the same plasmid/integron Patient may be source of resistant organism

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