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    MDR Pathogens in ICU: Azit Kumar Pulagurtha

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    Ajitkumar Pulagurtha
    1. MDR Gram-negative rods like Acinetobacter baumanii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia are increasingly problematic in ICUs as they are resistant to most classes of antimicrobials. 2. Pan drug resistant (PDR) strains resistant to all 7 classes of antipseudomonal agents have been reported in Pseudomonas and Acinetobacter. 3. Colistin, originally discovered in 1947, has seen renewed use for treating infections caused by these MDR and PDR Gram-negative bacteria, though its use requires careful dosage adjustment in renal impairment to avoid toxicity.

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    MDR Pathogens in ICU: Azit Kumar Pulagurtha

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    Ajitkumar Pulagurtha
    16 views37 pages
    1. MDR Gram-negative rods like Acinetobacter baumanii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia are increasingly problematic in ICUs as they are resistant to most classes of antimicrobials. 2. Pan drug resistant (PDR) strains resistant to all 7 classes of antipseudomonal agents have been reported in Pseudomonas and Acinetobacter. 3. Colistin, originally discovered in 1947, has seen renewed use for treating infections caused by these MDR and PDR Gram-negative bacteria, though its use requires careful dosage adjustment in renal impairment to avoid toxicity.

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    1. MDR Gram-negative rods like Acinetobacter baumanii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia are increasingly problematic in ICUs as they are resistant to most classes of antimicrobials. 2. Pan drug resistant (PDR) strains resistant to all 7 classes of antipseudomonal agents have been reported in Pseudomonas and Acinetobacter. 3. Colistin, originally discovered in 1947, has seen renewed use for treating infections caused by these MDR and PDR Gram-negative bacteria, though its use requires careful dosage adjustment in renal impairment to avoid toxicity.

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    16 views37 pages

    MDR Pathogens in ICU: Azit Kumar Pulagurtha

    Uploaded by

    Ajitkumar Pulagurtha
    1. MDR Gram-negative rods like Acinetobacter baumanii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia are increasingly problematic in ICUs as they are resistant to most classes of antimicrobials. 2. Pan drug resistant (PDR) strains resistant to all 7 classes of antipseudomonal agents have been reported in Pseudomonas and Acinetobacter. 3. Colistin, originally discovered in 1947, has seen renewed use for treating infections caused by these MDR and PDR Gram-negative bacteria, though its use requires careful dosage adjustment in renal impairment to avoid toxicity.

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    MDR Pathogens in ICU

    AZIT KUMAR PULAGURTHA


    MDR Gram Negative Rods
     MDR gram negative rods are defined as
    isolates that are susceptible to no more than
    one class of antimicrobial agents (excluding
    colistin).
     Increasingly problematic
     Acinetobacter baumanii
     Stenotrophomonas maltophilia
     Pseudomonas aeruginosa
    PAN DRUG RESISTANCE :

    Resistance to 7 classes of antipseudomonal agents

    antipseudomonal penicillins,
    cephalosporins,
    carbapenems,
    monobactams,
    quinolones,
    aminoglycosides and
    polymyxins (??)

    Pan resistance is reported in Pseudomonas and


    Acinetobacter spps
    Bad bugs, No drugs

    Pre antibiotic era

    Antibiotic era

    Pan drug resistance

    Multi drug resistance Post antibiotic age


    What is incidence
    of Pan Drug
    Resistance?
    N= 254
    4
    PDR Pseudomonas

    22
    MDR Pseudomonas

    0 5 10 15 20 25

    %
    Imipenem Resistant
    PGIMER Chandigarh; Nosocomial UTIs

    18.5
    Acinetobacter
    baumannii

    42
    Pseudomonas
    aeruginosa

    0 10 20 30 40 50
    % Resistant
    Clinical samples : BAL, Blood, Urine, tracheal aspirates, soft tissue
    samples

    6 Meropenem Imipenem
    Enterobacer spp

    4.3
    Klebsiella spps 6.9

    2.1
    E.coli 3.5

    27.2

    Acinetobacter spps 34.7

    30
    Pseudomonas spps 37.6

    0 10 20 30 40 50
    % Resistant
    % R to b lactams in GNB -ICU cultures Jan- Sep 07

    Kleb E.coli Pseudo Acineto Others


    103 118 205 58 62
    ESBL 72 88 43 13 16
    70% 75% 21% 22% 27%
    10
    Only Carbap 10% 5 10 1 7
    Sus 4% 5% 2% 12%

    MDR 2 1 97 27 4
    2% 1% 47% 47% 7%
    Mechanisms of resistance
    MDR A. baumannii and P. aeruginosa

     Various mechanisms of resistance :

     production of beta-lactamases

     efflux pumps

     lower permeability of the outer membrane

     mutations in antibiotic targets (e.g., for quinolones)


    Mutations in P.aeruginosa
    Mutational event ceftaz imipen mero quino

    Derepression of Amp C R - - -

    Upreg of MexAB OprM r - r R

    upreg of MexEF OprN - r r R

    Loss of Opr D - R - -

    Loss of Opr D plus


    upreg of Mex AB OprM R R R R
    REVIVAL OF COLISTIN

    600 520

    500

    Number of 400 320


    articles
    published on 300
    colistin in
    Pubmed 200
    139
    107 110

    100

    0
    1969-1974 1975-1980 1981-1985 1986-1991 1998-2008
    Early 2000
     Results 24 patients (mean age 44.3 years, mean APACHE II score
    20.6) received 26 courses of colistin.
     Clinical response was observed for 73% of the treatments.
     Survival at 30 days was 57.7%.
     Deterioration in renal function was observed in 14.3% patients who
    were not already receiving renal replacement therapy, but in only one
    case did this deterioration have serious clinical consequences.
     Conclusion. This drug has an acceptable safety profile and its use
    should be considered in severe infections with multiresistant Gram-
    negative bacilli.
    Our experience on colistin in three sentences

    1. From 10/2000 to 03/2008, more than 600 patients


    received treatment with IV colistin for infections
    due to MDR Gram-negative bacteria (mainly A.
    baumannii, P. aeruginosa, and K. pneumoniae in
    critically ill patients)

    2. Mortality was about 25% in our patients

    3. The observed toxicity was less that previously


    thought
    Polymyxins
    History

    Polymyxins are polypeptide antibiotics; there are 5


    chemically different compounds (polymyxin A, B, C,
    D, and E)
    They were discovered in 1947 in the United States
    They are all produced by different species of Bacillus
    polymyxa
    Colistin (Polymyxin E)
    Bacillus colistinus
    Forms of colistin available
     Colistin sulfate
     orally (tablets or syrup)

     bowel decontamination
     Topically (powder)

     bacterial skin infections


     Colistimethate sodium
     Parenteral formulations

     Intravenously
     Intramuscularly
     Nebulization
    Structure-activity relationship

    Ø    The L-α-γ-diaminobutyric acid (Dab)


    molecules, contained in the molecule of
    polymyxins, are positively charged

    Ø    The lipopolysaccharide (LPS)


    molecules, which are present in the cell
    wall of Gram-negative bacteria, are
    negatively charged
    Colistin : Mechanism of action
    Colistin interacts with LipoPolysaccharides (LPS) of Gram
    negative

    Displaces Ca+2 and Mg+2 ions of LPS

    Local disturbance of the cell membrane

    Cell death Synergistic activity Anti-endotoxin activity

    Rapid acting, bactericidal agent


    Unique MOA : Self promoted uptake
    Pharmacodynamic
    Properties
    COLISTIN: Spectrum of activity

    Bactericidal

    Highly active against

    P Pseudomonas aeruginosa
    A Acinetobacter baumannii
    K Klebsiella pneumoniae
    Pharmacokinetic
    Properties
    Therapeutic efficacy
    AEROSOLIZED
    TREATMENT
    Safety and Tolerability
    Known Adverse Effects : Colistimethate
    Sodium

    Skin rash
    Hypersensitivity reactions
    Generalized itching
    Nephrotoxicity
    Neurotoxicity
    What are the possible explanations for the
    difference between old and new safety
    reports ?
    During 1970, CMS vial for IM administration contained
    dibucaine hydrochloride, which potentiated neurotoxicity.

    Same formulation was used for IV administration.

    Considerably higher dosages were used 2800 mg/day vs


    recommended 480 mg (UK) - 800 mg (USA)

    Co-administered with potentially nephrotoxic and


    neurotoxic drugs

    No dose adjusment done in renally impaired patients


    What are the recommended
    dosage guidelines ?
    Systemic Treatment : Normal Renal
    Function
    Dose determined by
     severity & type of infection,
     age, weight & renal function of the patient

    Children and Adults (Including the Elderly):


     Up to 60kg

     50,000 to 75,000 IU/kg/day in 3 div doses at 8 hrs


     Over 60kg
     1-2 MIU (TID)

    However 3 MIU t.i.d is found to be more effective


    and safe
    Systemic Treatment : Renal
    Impairment
     excretion of CMS is delayed
     dose & interval adjusted to prevent accumulation
      Creatinine Clearance  
    Grade (ml/min) Over 60 kg Bodyweight

    Mild 20-50 1-2 MIU TID


     

    Moderate 10-20 1 MIU every 12-18 hours


     

    Severe <10 1 MIU every 18-24 hours


     
    Combination therapy with Colistin
     Synergy of colistin with rifampicin has been demonstrated
    in vitro against multidrug-resistant A baumannii.

     Petrosillo and colleagues investigated the clinical outcome


    in 14 patients with VAP caused by carbapenem-resistant A
    baumannii, P aeruginosa, or both, who were treated with
    intravenous colistimethate sodium (2 million units every 8
    h, ) and rifampicin (600 mg every 24 h).

     The treatment resulted in microbiological clearance of


    carbapenem-resistant infection in nine (64%) of the patients,
    with limited side-effects
    Novel Antibiotic Combinations
     A Baumanii :
     Colistin + (Rifampicin or Imipenem or Azithro)
     Sulbactam + (Rifampicin or Azithro or Quinolone)
     Rifampicin + Azithromycin
     Colistin + Imipenem + Rifampicin

    Pseudomonas :

    Polymixin B + Rifampicin
    Cefepime + Quinolone
    Ceftazidime + Colistin
    Azithromycin + (Tobramycin or Doxy or Rifampicin)
    Synergy: In Vitro vs MDR Gram
    negative
    Combination of colistin + piperacillin Combination of colistin + rifampin

    Filled Circle: Control Filled Circle: Control


    Empty Square: Colistin Empty Triangle: Rifampin
    Empty Square: Colistin
    Filled Triangle: Piperacillin
    Filled Square: Colistin + Rifampin
    Small Filled Square: Colistin + Piperacillin

    4-8 times lower than the MIC for the individual drugs.
    Which is the best combination
    with colistin?
    Colistin should always be used with one that shows maximum susceptibility
    For MDR Pseudomonas
    colistin + ceftazidime
    colistin + piperacillin/tazobactam
    colistin + amikacin
    colistin + aztreonam ( For MBLs producers)
    For MDR Acinetobacter
    colistin + meropenem (If MIC for meropenem is in intermediate range)
    colistin + sulbactam/ampicillin
    colistin + rifampin + carbapenem or sulbactam (If MIC for carbapenem
    is in highly resistant range)
    colistin + tigecycline

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