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					Rising tide of resistance:
implications for treatment

Robert G Masterton
              Antibiotic resistance:
              the global perspective

                                                               Klebsiella pneumoniae
                                   Enterococcus faecium        cefotaxime resistance
        Enterococcus faecium
                                   vancomycin resistance          Germany 1983            Vancomycin intermediate
            oxazolidinone
                                       France 1988                                         Staphylococcus aureus
             resistance
                                                                                             (VISA) Japan 1996
              USA 2001
                                 Neisseria meningitidis
                                  penicillin resistance       Salmonella typhi
    Staphylococcus aureus             Spain 1988              multiresistance
    vancomycin resistance                                        India 1990
      (VRSA) USA 2002

               Vibrio cholerae              Shigella dysenteriae                           Neisseria gonorrhoeae
               multiresistance                multiresistance                                penicillin resistance
               Ecuador 1993                    Burundi 1992                                 The Philippines 1976


                                   Streptococcus pneumoniae                      Streptococcus pneumoniae
                                         multiresistance                             penicillin resistance
2                                       South Africa 1977                              Australia 1967
         The rising tide of Gram-positive infections
       Rate (%)                   Gram-positive
        80                        Gram-negative


          60


          40


          20


            0
                1973–76 1977–80 1980–83 1986–87 1988–90 1991–92 1993–94


3   Single-organism bacteraemia           European Organisation for Research and Treatment of Cancer data
           S. aureus bacteraemia
         No. of cases of bacteraemia
         2000              MSSA
                                   MRSA
         1500
                                                                                         69%

         1000


           500
                                                                                         31%
              0
               88       89      90      91   92   93 94   95   96     97      98      99
                                                   Year
    MSSA = methicillin-sensitive S. aureus                      Scottish Centre for Infection and
4   MRSA = methicillin-resistant S. aureus                         Environmental Health (2001)
    The rising tide of Gram-positive
    infections
    12-year study (1980–1992) involving 260 834 patients
    with nosocomial infections
    • Isolation of coagulase-negative staphylococci (CNS),
      S. aureus or enterococci
       – 1981–1983: 42% of 663 isolates
       – 1990–1992: 54% of 1291 isolates

    • Decrease in isolation of Gram-negative bacilli
    • Blood cultures
       – Gram-positive cocci isolates increased x 2.5
       – Gram-negative isolates unaltered
5                                     Pittet et al. Arch Intern Med 1995;155:1177–1184
       The rising tide of nosocomial infections
       in ICU patients
      Vancomycin/enterococci                           25.9
          Methicillin/S. aureus                                              54.5
               Methicillin/CNS                                                         86.7        
              3rd ceph/E. coli         3.2
      3rd ceph/K. pneumoniae              8.9
       Imipenem/P. aeruginosa                     18.5
      Quinolone/P. aeruginosa                       23.0
        3rd ceph/P. aeruginosa                    20.0
    3rd ceph/Enterobacter spp.                                  36.4

                                  0      10      20    30 40 50 60                   70       80       90
         January–May 1999                               Resistance (%)

6          1994–1998 (+ standard deviation)
                                                               Weinstein. Emerg Infect Dis 2001;7:188–192
           Vancomycin-resistant enterococci
          Resistance (%)
           30                   Non-ICU
             25                 ICU

             20

             15

             10

               5

               0
                      89 90 91 92 93 94 95 96 97 98 99 00
                                      Year
7   ICU = intensive care unit             National Nosocomial Infections Surveillance (NNIS) data
    Third-generation cephalosporin-resistant
    Klebsiella pneumoniae
    Resistance (%)
     14              Non-ICU
     12              ICU
     10
       8
       6
       4
       2
       0
            89 90 91 92 93 94 95 96 97 98 99 00
                            Year
8                                                 NNIS data
    Fluoroquinolone-resistant
    Pseudomonas aeruginosa
    Resistance (%)
     30              Non-ICU
     25              ICU

     20

     15

     10

       5

       0
            89 90 91 92 93 94 95 96 97 98 99 00
                            Year
9                                            NNIS data (2002)
            Nosocomial ICU infections:
            1999 versus 1994–1998
       Percentage increase in proportion of pathogens resistant to
       indicated antimicrobial
      Organism                                          Increase (%)
      Fluoroquinolone-resistant Pseudomonas spp.              49

      3rd-generation cephalosporin-resistant E. coli          48

      MRSA                                                    40

      VRE                                                     40

      Imipenem-resistant Pseudomonas spp.                     20


10   VRE = vancomycin-resistant enterococci                   NNIS data
         Know your ‘local’ pathogen
         The Alexander Project: S. pneumoniae

                                                 Resistance (%)
                            Penicillin-             Penicillin-              Penicillin-
                            sensitive             intermediate               resistant
     Erythromycin               5.8                      25.9                     30.2

     Doxycycline                4.9                      33.4                     41.0

     Chloramphenicol            3.5                      25.4                     53.2

     Ciprofloxacin             12.1                      16.7                       7.7

     Co-trimoxazole            11.2                      53.1                     96.8


11                              Goldstein et al. J Antimicrob Chemother 1996;38(Suppl. A):71–84
     Know your ‘local’ pathogen
      San Francisco General Hospital 1996–1997:
      fluoroquinolone-resistant E. coli
     Resistant patient isolates (%)
       50

      40

      30

      20

      10

        0
                   Trauma      Diabetes      Homeless      Paediatric
            HIV/AIDS      COPD        Dialysis Injection drug use
12                                                  Centers for Disease Control (2002)
            Know your ‘local’ pathogen
            Febrile neutropenia blood culture isolates
       Percentage                                                             Paediatrics
        100                                                                   Oncology
                                                                              Haematology
         80

         60

         40

         20

           0
                Gram-positive Gram-negative bacilli  MRSE                 Resistant
                   bacteria       P. aeruginosa/                      Gram-negative bacilli
                             Enterobacteriaceae spp.                        (cip/gen/mer)
     cip = ciprofloxacin
     gen = gentamicin
     mer = meropenem
13   MRSA = methicillin-resistant S. aureus   O’Connell et al. J Antimicrob Chemother 1998;42:677–678
          Know your ‘local’ pathogen                                                  Medical ICU
                                            Enterococcus                              Surgical ICU
         Susceptibility (%)                     spp.       Acinetobacter              Trauma ICU
                                                               spp.
          100                                    *                             P. aeruginosa
                                                                *
                                                                                       *
           80

           60
                     S. aureus
           40              *

           20

             0
                     Methicillin            Vancomycin      Imipenem            Ceftazidime


14   *Significant difference between ICUs                           Namias et al. J Trauma 2000;49:638–645
             Targeted antibiotic policy

             Carbapenem-baseda


         Cephalosporin-baseda

                Antipseudomonal
                 penicillin-baseda

             Monobactam-baseda

                                     0   20          40          60              80           100
                                                    Susceptibility (%)

15   aPlus   amikacin + vancomycin       Trouillet et al. Am J Respir Crit Care Med 1998;157:531–539
     The steps to redemption

     • Prevent infections

     • Diagnose and treat effectively

     • Practice prudent antimicrobial prescribing

     • Practice effective infection control to
       prevent transmission


16
          The steps to redemption


                                           12 Contain contagion
                                       11 Isolate the pathogen
                                                                   Prevent transmission
                                    10 Stop treatment when cured
                               9 Know when to say ‘no’ to vanco
                            8 Treat infection, not colonisation
                         7 Treat infection, not contamination
                                                                   Use antimicrobials wisely
                     6 Access the experts
                  5 Use local data
               4 Practice antimicrobial control                    Diagnose and treat
           3 Target the pathogen                                   effectively
        2 Get the catheters out
     1 Vaccinate
                                                                   Prevent infections



17                                                                    Centers for Disease Control (2002)
        Hand decontamination and resistance
     Year   Author       Setting      Impact on organisms
     1982   Maki         Adult ICU    Decreased
     1984   Massanari    Adult ICU    Decreased
     1990   Simmons      Adult ICU    No effect
     1992   Doebbeling   Adult ICU    Decreased with one versus
                                      another hand hygiene product
     1994   Webster      Neonatal ICU MRSA eliminated
     1999   Pittet       Hospital     MRSA decreased



18                                        Pittet. Emerg Infect Dis 2001;7:234–240
                                            Drivers for resistance



                                            20
     No. of days until acquisition of VRE




                                            16


                                            12

                                                                                                                                       25
                                             8


                                                                                                                               50
                                             4


                                             0                                                                         75
                                                 25   30   35    40    45     50    55     60      65     70     75

                                                                Days with cephalosporin use (%)
19                                                                                              Weinstein. Emerg Infect Dis 2001;7:188–192
     Gain a better understanding of resistance
     to improve outcomes


     • Early recognition of infection
     • Selection of appropriate antibiotic
       (eg through in vitro susceptibility determination)
     • Optimisation of antibiotic therapy




20
       Optimisation of antibiotic therapy

     • Essential therapeutic considerations:
        – assessment of susceptibility: minimum inhibitory
          concentration (MIC)
        – behaviour of antibiotic in body: pharmacokinetics
        – relationship between antibiotic concentration and
          its bactericidal effect: pharmacodynamics

     • Relationship between antibiotic concentration and
       resistance: mutant prevention concentration (MPC)

21
     The rising tide of antibiotic resistance

     • Prolonged hospitalisation
     • Increased risk of death
     • More toxic/expensive therapy needed
     • Increased chance of inappropriate therapy
        – independent risk factor for increased mortality

     • Increased costs


22
     Turning back the tide

     • Surveillance for early warning and action against
       resistance

     • Prudent antimicrobial prescribing to preserve our
       antibiotic armamentarium and improve outcomes
        – maximise the reduction in bacterial load with the aim of
          bacterial eradication

        – pharmacodynamic parameters assist in selection of
          appropriate antibacterial agent and dosage

     • Enhanced infection control to reduce spread of
       resistance and nosocomial infections
23
     Antibiotic resistance:
     implications for treatment
     • Start with the appropriate empiric antibiotic first in
       nosocomial infections
     • Administer antibiotics at the right dose for the
       appropriate duration
     • If appropriate, change antibiotic dosage or therapy
       based on resistance and pathogen information
     • Recognise that prior antimicrobial administration is a
       risk factor for the presence of resistant pathogens
     • Know the unit’s resistance profile and choose
       antibiotics accordingly
24

				
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