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    Antibioticstrategyinnosocomialpneumonia 130518232107-phpapp02 Antibioticstrategyinnosocomialpneumonia 130518232107-phpapp02 Presentation Transcript

    • Antibiotic Strategy in Nosocomial Pneumonia Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university ERS National Delegate of Egypt
    • ANTIMICROBIAL DRUGS
    • MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Mechanism of action include:  Inhibition of cell wall synthesis  Inhibition of protein synthesis  Inhibition of nucleic acid synthesis  Inhibition of metabolic pathways  Interference with cell membrane integrity
    • MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of Cell wall synthesis  Bacteria cell wall unique in construction  Contains peptidoglycan  Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell  Due to the lack of cell wall in animal cells and differences in cell wall in plant cells  These drugs have very high therapeutic index  Low toxicity with high effectiveness  Antimicrobials of this class include  β lactam drugs  Vancomycin  Bacitracin
    •  Inhibition of protein synthesis  Structure of prokaryotic ribosome acts as target for many antimicrobials of this class  Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity  Drugs of this class include  Aminoglycosides  Tetracyclins  Macrolids  Chloramphenicol MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
    •  Inhibition of nucleic acid synthesis  These include  Fluoroquinolones  Rifamycins MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
    • MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of metabolic pathways  Relatively few  Most useful are folate inhibitors  Mode of actions to inhibit the production of folic acid  Antimicrobials in this class include  Sulfonamides  Trimethoprim
    • MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Interference with cell membrane integrity  Few damage cell membrane  Polymixn B most common  Common ingredient in first-aid skin ointments  Binds membrane of Gram - cells  Alters permeability  Leads to leakage of cell and cell death  Also bind eukaryotic cells but to lesser extent  Limits use to topical application
    • EFFECTS OF COMBINATIONS OF DRUGS  Sometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone.  This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.
    • EFFECTS OF COMBINATIONS OF DRUGS  Other combinations of drugs can be antagonistic.  For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.
    • EFFECTS OF COMBINATIONS OF DRUGS  Combinations of antimicrobial drugs should be used only for: 1. To prevent or minimize the emergence of resistant strains. 2. To take advantage of the synergistic effect. 3. To lessen the toxicity of individual drugs.
    • Pharmacology Pharmacokinetics Pharmacodynamics
    • Pharmacokinetics • Time course of drug absorption, distribution, metabolism, excretion How the drug comes and goes.
    • “LADME” is key Pharmacokinetic Processes Liberation Absorption Distribution Metabolism Excretion
    • Pharmacodynamics • The biochemical and physiologic mechanisms of drug action What the drug does when it gets there.
    • Concepts Pharmacokinetics – describe how drugs behave in the human host Pharmacodynamics – the relationship between drug concentration and antimicrobial effect. “Time course of antimicrobial activity”
    • Minimum Inhibitory Concentration (MIC) – The lowest concentration of an antibiotic that inhibits bacterial growth after 16-20 hrs incubation. Minimum Bacteriocidal Concentrations. – The lowest concentration of an antibiotic required to kill 99.9% bacterial growth after 16-20 hrs exposure. C-p – Peak antibiotic concentration Area under the curve (AUC) – Amount of antibiotic delivered over a specific time. Concepts
    • Antimicrobial-micro-organism interaction Antibiotic must reach the binding site of the microbe to interfere with the life cycle. Antibiotic must occupy “sufficient” number of active sites. Antibiotic must reside on the active site for “sufficient” time. Antibiotics are not contact poisons.
    • Static versus Cidal Control Cidal StaticCFU Time
    • Questions Can this antibiotic inhibit/kill these bacteria? Can this antibiotic reach the site of bacterial replication? What concentration of this antibiotic is needed to inhibit/kill bacteria? Will the antibiotic kill better or faster if we increase its concentration? Do we need to keep the antibiotic concentration always high throughout the day?
    • Can this antibiotic inhibit/kill these bacteria? In vitro susceptibility testing Mixing bacteria with antibiotic at different concentrations and observing for bacterial growth.
    • 32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml Sub-culture to agar medium MIC = 8 ug/ml MBC = 16 ug/ml Minimal Inhibitory Concentration (MIC) vs. Minimal Bactericidal Concentration (MBC) REVIEW
    • What concentration of this antibiotic is needed to inhibit/kill bacteria? In vitro offers some help – Concentrations have to be above the MIC. How much above the MIC? How long above the MIC? Time Conc MIC
    • Patterns of Microbial Killing Concentration dependent – Higher concentration greater killing Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B. Time-dependent killing – Minimal concentration-dependent killing (4x MIC) – More exposure more killing Beta lactams, glycopeptides, clindamycin, macrolides, tetracyclines, bactrim
    • Persistent Effects Persistent suppression of bacterial growth following antimicrobial exposure. – Moderate to prolonged against all GM positives (In vitro) – Moderate to prolonged against GM negatives for protein and nucleic acid synthesis inhibitors. – Minimal or non against GM negatives for beta lactams (except carabapenems against P. aeruginosa)
    • Post-antibiotic sub-MIC effect. – Prolonged drug level at sub-MIC augment the post-antibiotic effect. Post-antibiotic leukocyte killing enhancement. – Augmentation of intracellular killing by leukocytes. – The longest PAE with antibiotics exhibiting this characteristic. Persistent Effects
    • Patterns of Antimicrobial Activity Concentration dependent with moderate to prolonged persistent effects – Goal of dosing Maximize concentrations – PK parameter determining efficacy Peak level and AUC – Examples Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.
    • Time-dependent killing and minimal to moderate persistent effects – Goal of dosing Maximize duration of exposure – PK parameter determining efficacy Time above the MIC – Examples Beta lactam, macrolides, clindamycin, flucytosine, linezolid. Patterns of Antimicrobial Activity
    • Patterns of Antimicrobial Activity Time-dependent killing and prolonged persistent effects – Goal of dosing Optimize amount of drug – PK parameter determining efficacy AUC – Examples Azithromycin, vancomycin, tetracyclines, fluconazole.
    • PK/PD patterns Concentration MIC Time AUC AUC C-p C-p
    • Antibacterial spectrum — Range of activity of an antim icrobial against bacteria. A broad-spectrum antibacterial drug can inhibit a wide variety of gram -positive and gram -negative bacteria, whereas a narrow -spectrum drug is active only against a lim ited variety of bacteria. Bacteriostatic activity— -The level of antim icro-bial activity that inhibits the growth of an organism . This is determ ined in vitro by testing a standardized concentration of organism s against a series of antim icrobial dilutions. The lowest concentration that inhibits the growth of the organism is referred to as the m inim um inhibitory concentration (M IC). Bactericidal activity— The level of antim icrobial activity that kills the test organism . This is determ ined in vitro by exposing a standardized concentration of organism s to a series of antim icrobial dilutions. The lowest concentration that kills 99.9% of the population is referred to as the m inim um bactericidal concentration (M BC). Antibiotic com binations— Com binations of antibiotics that m ay be used (1) to broaden the antibacterial spectrum for em piric therapy or the treatm ent of polym icrobial infections, (2) to prevent the em ergence of resistant organism s during therapy, and (3) to achieve a synergistic killing effect. Antibiotic synergism — Com binations of two antibiotics that have enhanced bactericidal activity when tested together com pared with the activity of each antibiotic. Antibiotic antagonism — Com bination of antibiotics in which the activity of one antibiotic interferes W ith the activity of the other (e.g., the sum of the activity is less than the activity of the individual drugs). Beta-lactam ase— An enzym e that hydrolyzes the beta-lactam ring in the beta-lactam class of antibiotics, thus inactivating the antibiotic. The enzym es specific for penicillins and cephalosporins aret he penicillinases and cephalosporinases, respectively.
    • Resistance Physiological Mechanisms 1. Lack of entry – tet, fosfomycin 2. Greater exit  efflux pumps  tet (R factors) 3. Enzymatic inactivation  bla (penase) – hydrolysis  CAT – chloramphenicol acetyl transferase  Aminogylcosides & transferases REVIEW
    • Resistance Physiological Mechanisms 4. Altered target  RIF – altered RNA polymerase (mutants)  NAL – altered DNA gyrase  STR – altered ribosomal proteins  ERY – methylation of 23S rRNA 5. Synthesis of resistant pathway  TMPr plasmid has gene for DHF reductase; insensitive to TMP (cont’d) REVIEW
    • Resistance to β-Lactams – Gram pos. Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) REVIEW
    • Resistance to β-Lactams – Gram neg. Mechanism of Action CELL WALL SYNTHESIS INHIBITORS (cont’d) REVIEW
    • The Ideal Drug* 1. Selective toxicity: against target pathogen but not against host  LD50 (high) vs. MIC and/or MBC (low) 2. Bactericidal vs. bacteriostatic 3. Favorable pharmacokinetics: reach target site in body with effective concentration 4. Spectrum of activity: broad vs. narrow 5. Lack of “side effects”  Therapeutic index: effective to toxic dose ratio 6. Little resistance development
    • 39 Pneumonias – Classification • Community AcquiredCAP • Health Care AssociatedHCAP • Hospital AcquiredHAP • ICU AcquiredICUAP • VentilatorAcquiredVAP Nosocomial Pneumonias
    • *HAP: diagnosis made > 48h after admission *VAP: diagnosis made 48-72h after endotracheal intubation *HCAP: diagnosis made < 48h after admission with any of the following risk factors: (1) hospitalized in an acute care hospital for > 48h within 90d of the diagnosis; (2) resided in a nursing home or long-term care facility; (3) received recent IV antibiotic therapy, chemotherapy, or wound care within the 30d preceding the current diagnosis; and (4) attended a hospital or hemodialysis clinic Definitions of NP
    • The American Thoracic Society suggests that the diagnosis should be considered in any patient with new or progressive radiological infiltrates and clinical features to suggest infection: •Fever (core temperature >38°C), • Leukocytosis (>10000mm-3) or leukopenia (<4000mm-3), •Purulent tracheal secretions, •Increased oxygen requirements, reflecting new or worsening hypoxaemia. Diagnosis
    • Sensitivity Specificity Clinical estimate 50% 58% CPIS score > 6* 60% 59% BAL Gram stain 85% 74% Telescoping catheter 60% 90% CPIS + BAL Gram stain 85% 49% CPIS + telescoping catheter 78% 36%
    • *Hypotension. *Sepsis syndrome. *End organ dysfunction. *Rapid progression of infiltrates. *Intubation Severe HAP
    • Gram-negative bacilli, particularly enterobacteria, are present in the oropharyngeal flora of patients with chronic underlying illnesses, such as COPD, heart failure, neoplasms, AIDS and chronic renal failure. Infection by P. aeruginosa and other more resistant Gram-negative bacilli such as Acinetobacter baumannii and ESBL-producing enterobacteria should be considered in patients discharged from ICUs, submitted to wide-spectrum antibiotic treatment and in those with severe underlying disease or prolonged hospitalisation in areas with a high prevalence of these microorganisms. Risk Factors
    • An increased risk for Legionella spp. should be considered in immunosuppressed patients (previous treatment with high-dose steroids or chemotherapy. Gingivitis or periodontal disease, depressed consciousness, swallowing disorders and orotracheal manipulation are usually recorded when anaerobes are the causative agents of the pneumonia Coma, head injury, diabetes, renal failure or recent influenza infection are at risk from infection by S. aureus. Risk Factors
    • HAP due to fungi such as Aspergillusmay develop in organ transplant, neutropenic or immunosuppressed patients, especially those treated with corticoids. Risk Factors
    • Risk for ventilator-associated pneumonia due to multidrug-resistant pathogens Hospitalisation Especially if intubated and in the ICU for ≥5 days (late-onset infection) Prior antibiotic therapy Particularly in the prior 2 weeks Recent hospitalisation in the preceding 90 days Other HCAP risk factors From a nursing home Haemodialysis Home-infusion therapy Poor functional status Risk factors for specific pathogens Pseudomonas aeruginosa Prolonged ICU stay Corticosteroids Structural lung disease Methicillin-resistant Staphylococcus aureus Coma Head trauma Diabetes Renal failure Prolonged ICU stay Recent antibiotic therapy
    • The optimal empiric monotherapy for nosocomial pneumonia consists of ceftriaxone, ertapenem, levofloxacin, or moxifloxacin. Monotherapy may be acceptable in patients with early onset hospital- acquired pneumonia. Avoid monotherapy with ciprofloxacin, ceftazidime, or imipenem, as they are likely to induce resistance potential. Empiric monotherapy versus combination therapy
    • Late-onset hospital-acquired pneumonia, ventilator-associated pneumonia, and health care–associated pneumonia require combination therapy using an antipseudomonal cephalosporin, beta lactam, or carbapenem plus an antipseudomonal fluoroquinolone or aminoglycoside plus an agent such as linezolid or vancomycin to cover MRSA Empiric monotherapy versus combination therapy
    • Optimal combination regimens for proven P aeruginosa nosocomial pneumonia include (1) piperacillin/tazobactam plus amikacin or (2) meropenem plus levofloxacin, aztreonam, or amikacin.[12] Avoid using ciprofloxacin, ceftazidime, gentamicin, or imipenem in combination regimens, as combination therapy does not eliminate the resistance potential of these antibiotics. Empiric monotherapy versus combination therapy
    • When selecting an aminoglycoside for a combination therapy regimen, amikacin once daily is preferred to gentamicin or tobramycin to avoid resistance problems. When selecting a quinolone in a combination therapy regimen, use levofloxacin, which has very good anti– P aeruginosa activity (equal or better than ciprofloxacin at a dose of 750 mg). Empiric monotherapy versus combination therapy
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy Pseudomonas aeruginosa *Piperacillin-tazobactam 4.5 g IV q6h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Cefepime 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Imipenem 1 g q6-8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Meropenem 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Aztreonam 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h Duration of therapy: 10-14d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy Klebsiella pneumoniae Cefepime 2 g IV q8h or Ceftazidime 2 g IV q8h or Imipenem 500 mg IV q6h or Meropenem 1 g IV q8h or Piperacillin-tazobactam 4.5 g IV q6h Extended-spectrum beta-lactamase (ESBL)strain Imipenem 500 mg IV q6h or Meropenem 1 g IV q8h K pneumoniae carbapenemase (KPC) strain Colistin 5 mg/kg/day divided q12h or Tigecycline 100 mg IV, then 50 mg IV q12h Duration of therapy: 8-14d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy MRSA Vancomycin 15 mg/kg IV q12h for 7-14 d or Linezolid 600mg IV or PO q12h for 7-14 d Targocid 400mg IV once daily for 7-14 d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy MSSA Oxacillin 1g IV q4-6h for 7-14 d or Nafcillin 1-2 g IV q6h for 7-14 d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy Legionella pneumophila Levofloxacin 750 mg IV q24h, then 750 mg/day PO for 7- 14d or Moxifloxacin 400 mg IV or PO q24h for 7-14d or Azithromycin 500 mg IV q24h for 7-10d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy Acinetobacter baumannii Imipenem 1 g IV q6h or Meropenem 1 g IV q8h or Doripenem 500 mg IV q8h or Ampicillin-sulbactam 3 g IV q6h or Tigecycline 100 mg IV in a single dose, then 50 mg IV q12h or Colistin 5 mg/kg/day IV divided q12h Duration of therapy: 14-21d
    • Hospital-Acquired, Health Care-Associated, and Ventilator- Associated Pneumonia Organism-Specific Therapy Stenotrophomonas maltophilia Trimethoprim-sulfamethoxazole 15-20 mg/kg/day of TMP IV or PO divided q8h or Ticarcillin-clavulanate 3 g IV q4h or Ciprofloxacin 750 mg PO or 400 mg IV q12h or Moxifloxacin 400 mg PO or IV q24h Duration of therapy: 8-14d
    • Category Circumstances Treatment Severe HAP# Severity criteria Cefepime 2 g every 8 h + aminoglycoside (Amikacin 20 mg·kg−1·day−1) or quinolone (Levofloxacin 750 mg i.v. HAP with risk factors for Gram-negative bacilli Chronic underlying disease Antipseudomonal β-lactam± aminoglycoside or quinolone Cefepime 1–2 g every 8–12 h i.v. Carbapenems¶: imipenem 500 mg every 6 h or 1 g every 8 h i.v.; or meropenem 1 g every 8 h i.v.; or ertapenem+ 1 g·day−1i.v. P. aeruginosaand multi- resistant Gram-negative bacilli Wide-spectrum antibiotics, severe underlying disease, ICU stay Antipseudomonal β-lactam±aminoglycoside or quinolone Cefepime 1–2 g every 8–12 h i.v. β-lactamic/β-lactamase inhibitor: piperacillin-tazobactam 4.5 g every 6 hi.v. Carbapenems¶: imipenem 500 mg every 6 h or 1 g every 8 h i.v.; or meropenem 1 g every 8 h i.v. Legionella# Hospital potable water colonisation and/or previous nosocomial Legionellosis Levofloxacin 500 mg every 12–24 h i.v.or 750§ mg every 24 h i.v. or azitromycin 500 mg·day−1 i.v. Anaerobes Gingivitis or periodontal disease, depressed consciousness, swallowing disorders and orotracheal manipulation Carbapenems¶: imipenem 500 mg every 6 h or 1 g every 8 h i.v.; or meropenem 1 g every 8 h i.v.; or ertapenem+ 1 g·day−1i.v. β-lactam/β-lactamase inhibitor amoxicillin/clavulanate 2 g every 8 hi.v.¶; piperacillin-tazobactam 4.5 g every 6 h i.v. MRSA Risk factors for MRSA or high prevalence of MRSA Vancomycin 15 mg·kg−1 every 12 h i.v.Linezolid 600 mg every 12 h i.v. Aspergillus Corticotherapy, neutropenia or transplantation Amphotericyn B desoxicolate 1 mg·kg−1·day−1 i.v. or amphotericyn liposomal 3–5 mg·kg−1·day−1 i.v.Voriconazol 6 mg·kg−1 every 12 h i.v.(day 1) and 4 mg·kg−1 every 12 h i.v.(following days) Early-onset HAP <5 days Without risk factors and non-severe β-lactam/β-lactamase inhibitor: amoxicillin/clavulanate 1–2 g every 8 hi.v. Third generation non-pseudomonal cephalosporin: ceftriaxone 2 g·day−1i.v./i.m. or cefotaxime 2 g every 6–8 hi.v. Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or 750§ mg·day−1 i.v. Late-onset HAP ≥ 5 days Without risk factors and non-severe Antipseudomonal cephalosporin (including pneumococcus): cefepime 2 g every 8 h i.v. Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or 750§ mg·day−1 i.v.