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Antibiotic strategy in nosocomial pneumonia


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Antibiotic strategy in nosocomial pneumonia

  1. 1. Antibiotic Strategy in NosocomialPneumoniaGamal Rabie Agmy, MD,FCCPProfessor of Chest Diseases, Assiut universityERS National Delegate of Egypt
  3. 3. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS Mechanism of actioninclude: Inhibition of cell wallsynthesis Inhibition of proteinsynthesis Inhibition of nucleic acidsynthesis Inhibition of metabolicpathways Interference with cellmembrane integrity
  4. 4. MECHANISMS OF ACTION OFANTIBACTERIAL DRUGS Inhibition of Cell wall synthesis Bacteria cell wall unique inconstruction Contains peptidoglycan Antimicrobials that interfere withthe synthesis of cell wall do notinterfere with eukaryotic cell Due to the lack of cell wall inanimal cells and differences in cellwall in plant cells These drugs have very hightherapeutic index Low toxicity with high effectiveness Antimicrobials of this class include β lactam drugs Vancomycin Bacitracin
  5. 5.  Inhibition of protein synthesis Structure of prokaryotic ribosome acts as target formany antimicrobials of this class Differences in prokaryotic and eukaryotic ribosomesresponsible for selective toxicity Drugs of this class include Aminoglycosides Tetracyclins Macrolids ChloramphenicolMECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS
  6. 6.  Inhibition of nucleic acid synthesis These include Fluoroquinolones RifamycinsMECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS
  7. 7. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Inhibition of metabolicpathways Relatively few Most useful are folateinhibitors Mode of actions toinhibit the productionof folic acid Antimicrobials in thisclass include Sulfonamides Trimethoprim
  8. 8. MECHANISMS OF ACTIONOF ANTIBACTERIAL DRUGS Interference with cellmembrane integrity Few damage cellmembrane Polymixn B most common Common ingredient infirst-aid skin ointments Binds membrane of Gram- cells Alters permeability Leads to leakage of celland cell death Also bind eukaryotic cellsbut to lesser extent Limits use to topicalapplication
  9. 9. EFFECTS OFCOMBINATIONS OF DRUGS Sometimes the chemotherapeutic effects oftwo drugs given simultaneously is greater thanthe effect of either given alone. This is called synergism. For example,penicillin and streptomycin in the treatmentof bacterial endocarditis. Damage tobacterial cell walls by penicillin makes iteasier for streptomycin to enter.
  10. 10. EFFECTS OFCOMBINATIONS OF DRUGS Other combinations of drugs can beantagonistic. For example, the simultaneous use of penicillinand tetracycline is often less effective thanwhen wither drugs is used alone. By stoppingthe growth of the bacteria, thebacteriostatic drug tetracycline interfereswith the action of penicillin, which requiresbacterial growth.
  11. 11. EFFECTS OFCOMBINATIONS OF DRUGS Combinations of antimicrobial drugs shouldbe used only for:1. To prevent or minimize the emergence ofresistant strains.2. To take advantage of the synergistic effect.3. To lessen the toxicity of individual drugs.
  12. 12. PharmacologyPharmacokineticsPharmacodynamics
  13. 13. Pharmacokinetics• Time course of drug absorption,distribution, metabolism, excretionHow the drugcomes and goes.
  14. 14. “LADME” is keyPharmacokinetic ProcessesLiberationAbsorptionDistributionMetabolismExcretion
  15. 15. Pharmacodynamics• The biochemical and physiologicmechanisms of drug actionWhat the drugdoes when it gets there.
  16. 16. ConceptsPharmacokinetics– describe how drugs behave in the human hostPharmacodynamics– the relationship between drug concentrationand antimicrobial effect. “Time course ofantimicrobial activity”
  17. 17. Minimum Inhibitory Concentration (MIC)– The lowest concentration of an antibiotic that inhibitsbacterial growth after 16-20 hrs incubation.Minimum Bacteriocidal Concentrations.– The lowest concentration of an antibiotic required tokill 99.9% bacterial growth after 16-20 hrs exposure.C-p– Peak antibiotic concentrationArea under the curve (AUC)– Amount of antibiotic delivered over a specific time.Concepts
  18. 18. Antimicrobial-micro-organisminteractionAntibiotic must reach the binding site ofthe microbe to interfere with the life cycle.Antibiotic must occupy “sufficient” numberof active sites.Antibiotic must reside on the active site for“sufficient” time. Antibiotics are not contactpoisons.
  19. 19. Static versus CidalControlCidalStaticCFUTime
  20. 20. QuestionsCan this antibiotic inhibit/kill these bacteria?Can this antibiotic reach the site of bacterial replication?What concentration of this antibiotic is needed toinhibit/kill bacteria?Will the antibiotic kill better or faster if we increase itsconcentration?Do we need to keep the antibiotic concentration alwayshigh throughout the day?
  21. 21. Can this antibiotic inhibit/kill these bacteria?In vitro susceptibility testingMixing bacteria with antibiotic at differentconcentrations and observing for bacterialgrowth.
  22. 22. 32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/mlSub-culture to agar mediumMIC = 8 ug/mlMBC = 16 ug/mlMinimal Inhibitory Concentration (MIC)vs.Minimal Bactericidal Concentration (MBC)REVIEW
  23. 23. What concentration of this antibiotic isneeded 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?TimeConcMIC
  24. 24. Patterns of Microbial KillingConcentration dependent– Higher concentration greater killingAminoglycosides, Flouroquinolones, Ketolides,metronidazole, Ampho B.Time-dependent killing– Minimal concentration-dependent killing (4xMIC)– More exposure more killingBeta lactams, glycopeptides, clindamycin,macrolides, tetracyclines, bactrim
  25. 25. Persistent EffectsPersistent suppression of bacterial growthfollowing antimicrobial exposure.– Moderate to prolonged against all GMpositives (In vitro)– Moderate to prolonged against GM negativesfor protein and nucleic acid synthesisinhibitors.– Minimal or non against GM negatives for betalactams (except carabapenems against P.aeruginosa)
  26. 26. Post-antibiotic sub-MIC effect.– Prolonged drug level at sub-MIC augment thepost-antibiotic effect.Post-antibiotic leukocyte killing enhancement.– Augmentation of intracellular killing byleukocytes.– The longest PAE with antibiotics exhibiting thischaracteristic.Persistent Effects
  27. 27. Patterns of Antimicrobial ActivityConcentration dependent with moderate toprolonged persistent effects– Goal of dosingMaximize concentrations– PK parameter determining efficacyPeak level and AUC– ExamplesAminoglycosides, Flouroquinolones, Ketolides,metronidazole, Ampho B.
  28. 28. Time-dependent killing and minimal tomoderate persistent effects– Goal of dosingMaximize duration of exposure– PK parameter determining efficacyTime above the MIC– ExamplesBeta lactam, macrolides, clindamycin, flucytosine,linezolid.Patterns of Antimicrobial Activity
  29. 29. Patterns of Antimicrobial ActivityTime-dependent killing and prolongedpersistent effects– Goal of dosingOptimize amount of drug– PK parameter determining efficacyAUC– ExamplesAzithromycin, vancomycin, tetracyclines,fluconazole.
  30. 30. PK/PD patternsConcentrationMICTimeAUC AUCC-p C-p
  31. 31. Antibacterial spectrum — Range of activityof an antim icrobial against bacteria. Abroad-spectrum antibacterial drug caninhibit a wide variety of gram -positive andgram -negative bacteria, whereas anarrow -spectrum drug is active onlyagainst a lim ited variety of bacteria.Bacteriostatic activity— -The level ofantim icro-bial activity that inhibits thegrowth of an organism . This is determ inedin vitro by testing a standardizedconcentration of organism s against aseries of antim icrobial dilutions. Thelowest concentration that inhibits thegrowth of the organism is referred to asthe m inim um inhibitory concentration(M IC).Bactericidal activity— The level ofantim icrobial activity that kills the testorganism . This is determ ined in vitro byexposing a standardized concentration oforganism s to a series of antim icrobialdilutions. The lowest concentration thatkills 99.9% of the population is referred toas the m inim um bactericidalconcentration (M BC).Antibiotic com binations— Com binations ofantibiotics that m ay be used (1) to broadenthe antibacterial spectrum for em pirictherapy or the treatm ent of polym icrobialinfections, (2) to prevent the em ergence ofresistant organism s during therapy, and (3)to achieve a synergistic killing effect.Antibiotic synergism — Com binations oftwo antibiotics that have enhancedbactericidal activity when tested togethercom pared with the activity of eachantibiotic.Antibiotic antagonism — Com bination ofantibiotics in which the activity of oneantibiotic interferes W ith the activity of theother (e.g., the sum of the activity is lessthan the activity of the individual drugs).Beta-lactam ase— An enzym e thathydrolyzes the beta-lactam ring in thebeta-lactam class of antibiotics, thusinactivating the antibiotic. The enzym esspecific for penicillins and cephalosporinsaret he penicillinases andcephalosporinases, respectively.
  32. 32. ResistancePhysiological Mechanisms1. Lack of entry – tet, fosfomycin2. Greater exit efflux pumps tet (R factors)3. Enzymatic inactivation bla (penase) – hydrolysis CAT – chloramphenicol acetyl transferase Aminogylcosides & transferasesREVIEW
  33. 33. ResistancePhysiological Mechanisms4. Altered target RIF – altered RNA polymerase (mutants) NAL – altered DNA gyrase STR – altered ribosomal proteins ERY – methylation of 23S rRNA5. Synthesis of resistant pathway TMPr plasmid has gene for DHF reductase;insensitive to TMP(cont’d)REVIEW
  34. 34. Resistance to β-Lactams – Gram pos.Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS(cont’d)REVIEW
  35. 35. Resistance to β-Lactams – Gram neg.Mechanism of ActionCELL WALL SYNTHESIS INHIBITORS(cont’d)REVIEW
  36. 36. The Ideal Drug*1. Selective toxicity: against target pathogen butnot against host LD50 (high) vs. MIC and/or MBC (low)2. Bactericidal vs. bacteriostatic3. Favorable pharmacokinetics: reach target sitein body with effective concentration4. Spectrum of activity: broad vs. narrow5. Lack of “side effects” Therapeutic index: effective to toxic dose ratio6. Little resistance development
  37. 37. 39Pneumonias – Classification• Community AcquiredCAP• Health Care AssociatedHCAP• Hospital AcquiredHAP• ICU AcquiredICUAP• VentilatorAcquiredVAPNosocomial Pneumonias
  38. 38. *HAP: diagnosis made > 48h after admission*VAP: diagnosis made 48-72h after endotrachealintubation*HCAP: diagnosis made < 48h after admissionwith 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 carefacility;(3) received recent IV antibiotic therapy,chemotherapy, or wound care within the 30dpreceding the current diagnosis; and(4) attended a hospital or hemodialysis clinicDefinitions of NP
  39. 39. The American Thoracic Society suggests that thediagnosis should be considered in any patient with new orprogressive radiological infiltrates and clinical features tosuggest infection:•Fever (core temperature >38°C),• Leukocytosis (>10000mm-3) or leukopenia (<4000mm-3),•Purulent tracheal secretions,•Increased oxygen requirements, reflecting new orworsening hypoxaemia.Diagnosis
  40. 40. Sensitivity SpecificityClinical estimate 50% 58%CPIS score > 6* 60% 59%BAL Gram stain 85% 74%Telescoping catheter 60% 90%CPIS + BAL Gramstain85% 49%CPIS + telescopingcatheter78% 36%
  41. 41. *Hypotension.*Sepsis syndrome.*End organ dysfunction.*Rapid progression of infiltrates.*IntubationSevere HAP
  42. 42. Gram-negative bacilli, particularly enterobacteria, arepresent in the oropharyngeal flora of patients with chronicunderlying illnesses, such as COPD, heart failure,neoplasms, AIDS and chronic renal failure.Infection by P. aeruginosa and other more resistantGram-negative bacilli such as Acinetobacterbaumannii and ESBL-producing enterobacteria shouldbe considered in patients discharged from ICUs,submitted to wide-spectrum antibiotic treatment and inthose with severe underlying disease or prolongedhospitalisation in areas with a high prevalence of thesemicroorganisms.Risk Factors
  43. 43. An increased risk for Legionella spp. should beconsidered in immunosuppressed patients (previoustreatment with high-dose steroids or chemotherapy.Gingivitis or periodontal disease, depressedconsciousness, swallowing disorders and orotrachealmanipulation are usually recorded when anaerobes arethe causative agents of the pneumoniaComa, head injury, diabetes, renal failure or recentinfluenza infection are at risk from infection by S.aureus.Risk Factors
  44. 44. HAP due to fungi such as Aspergillusmay develop inorgan transplant, neutropenic or immunosuppressedpatients, especially those treated with corticoids.Risk Factors
  45. 45. Risk for ventilator-associated pneumoniadue to multidrug-resistant pathogensHospitalisationEspecially if intubated and in the ICU for ≥5 days (late-onsetinfection)Prior antibiotic therapyParticularly in the prior 2 weeksRecent hospitalisation in the preceding 90 daysOther HCAP risk factorsFrom a nursing homeHaemodialysisHome-infusion therapyPoor functional statusRisk factors for specific pathogensPseudomonas aeruginosaProlonged ICU stayCorticosteroidsStructural lung diseaseMethicillin-resistant Staphylococcus aureusComaHead traumaDiabetesRenal failureProlonged ICU stayRecent antibiotic therapy
  46. 46. The optimal empiric monotherapy for nosocomialpneumonia consists of ceftriaxone, ertapenem,levofloxacin, or moxifloxacin. Monotherapy may beacceptable in patients with early onset hospital-acquired pneumonia.Avoid monotherapy with ciprofloxacin,ceftazidime, or imipenem, as they are likely toinduce resistance potential.Empiric monotherapy versuscombination therapy
  47. 47. Late-onset hospital-acquired pneumonia,ventilator-associated pneumonia, and healthcare–associated pneumonia requirecombination therapy using an antipseudomonalcephalosporin, beta lactam, or carbapenemplus an antipseudomonal fluoroquinolone oraminoglycoside plus an agent such as linezolidor vancomycin to cover MRSAEmpiric monotherapy versuscombination therapy
  48. 48. Optimal combination regimens for proven Paeruginosa nosocomial pneumonia include (1)piperacillin/tazobactam plus amikacin or (2) meropenemplus levofloxacin, aztreonam, or amikacin.[12]Avoid using ciprofloxacin, ceftazidime, gentamicin, orimipenem in combination regimens, as combinationtherapy does not eliminate the resistance potential ofthese antibiotics.Empiric monotherapy versuscombination therapy
  49. 49. When selecting an aminoglycoside for a combinationtherapy regimen, amikacin once daily is preferred togentamicin or tobramycin to avoid resistance problems.When selecting a quinolone in a combination therapyregimen, use levofloxacin, which has very good anti– Paeruginosa activity (equal or better than ciprofloxacin ata dose of 750 mg).Empiric monotherapy versuscombination therapy
  50. 50. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyPseudomonas aeruginosa*Piperacillin-tazobactam 4.5 g IV q6h plus amikacin 20 mg/kg/dayIV plus levofloxacin 750 mg IV q24h or*Cefepime 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin750 mg IV q24h or*Imipenem 1 g q6-8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750mg IV q24h or*Meropenem 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin750 mg IV q24h or*Aztreonam 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin750 mg IV q24hDuration of therapy: 10-14d
  51. 51. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyKlebsiella pneumoniaeCefepime 2 g IV q8h orCeftazidime 2 g IV q8h orImipenem 500 mg IV q6h orMeropenem 1 g IV q8h orPiperacillin-tazobactam 4.5 g IV q6hExtended-spectrum beta-lactamase (ESBL)strainImipenem 500 mg IV q6h orMeropenem 1 g IV q8hK pneumoniae carbapenemase (KPC) strainColistin 5 mg/kg/day divided q12h orTigecycline 100 mg IV, then 50 mg IV q12hDuration of therapy: 8-14d
  52. 52. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyMRSAVancomycin 15 mg/kg IV q12h for 7-14 d orLinezolid 600mg IV or PO q12h for 7-14 dTargocid 400mg IV once daily for 7-14 d
  53. 53. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyMSSAOxacillin 1g IV q4-6h for 7-14 d orNafcillin 1-2 g IV q6h for 7-14 d
  54. 54. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyLegionella pneumophilaLevofloxacin 750 mg IV q24h, then 750 mg/day PO for 7-14d orMoxifloxacin 400 mg IV or PO q24h for 7-14d orAzithromycin 500 mg IV q24h for 7-10d
  55. 55. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyAcinetobacter baumanniiImipenem 1 g IV q6h orMeropenem 1 g IV q8h orDoripenem 500 mg IV q8h orAmpicillin-sulbactam 3 g IV q6h orTigecycline 100 mg IV in a single dose, then 50 mg IVq12h orColistin 5 mg/kg/day IV divided q12hDuration of therapy: 14-21d
  56. 56. Hospital-Acquired, Health Care-Associated, and Ventilator-Associated Pneumonia Organism-Specific TherapyStenotrophomonas maltophiliaTrimethoprim-sulfamethoxazole 15-20 mg/kg/day of TMPIV or PO divided q8h orTicarcillin-clavulanate 3 g IV q4h orCiprofloxacin 750 mg PO or 400 mg IV q12h orMoxifloxacin 400 mg PO or IV q24hDuration of therapy: 8-14d
  57. 57. Category Circumstances TreatmentSevere HAP# Severity criteriaCefepime 2 g every 8 h + aminoglycoside (Amikacin20 mg·kg−1·day−1) or quinolone (Levofloxacin 750 mg i.v.HAP with risk factors forGram-negative bacilli Chronic underlying disease Antipseudomonal β-lactam± aminoglycoside or quinoloneCefepime 1–2 g every 8–12 h i.v.Carbapenems¶: imipenem 500 mg every 6 h or 1 g every8 h i.v.; or meropenem 1 g every 8 h i.v.; orertapenem+ 1 g·day−1i.v.P. aeruginosaand multi-resistant Gram-negativebacilliWide-spectrum antibiotics, severeunderlying disease, ICU stayAntipseudomonal β-lactam±aminoglycoside or quinoloneCefepime 1–2 g every 8–12 h i.v.β-lactamic/β-lactamase inhibitor: piperacillin-tazobactam4.5 g every 6 hi.v.Carbapenems¶: imipenem 500 mg every 6 h or 1 g every8 h i.v.; or meropenem 1 g every 8 h i.v.Legionella#Hospital potable water colonisation and/orprevious nosocomial LegionellosisLevofloxacin 500 mg every 12–24 h i.v.or 750§ mg every24 h i.v. or azitromycin 500 mg·day−1 i.v.AnaerobesGingivitis or periodontal disease,depressed consciousness, swallowingdisorders and orotracheal manipulationCarbapenems¶: imipenem 500 mg every 6 h or 1 g every8 h i.v.; or meropenem 1 g every 8 h i.v.; orertapenem+ 1 g·day−1i.v.β-lactam/β-lactamase inhibitor amoxicillin/clavulanate 2 gevery 8 hi.v.¶; piperacillin-tazobactam 4.5 g every 6 h i.v.MRSARisk factors for MRSA or high prevalenceof MRSAVancomycin 15 mg·kg−1 every 12 h i.v.Linezolid 600 mgevery 12 h i.v.AspergillusCorticotherapy, neutropenia ortransplantationAmphotericyn B desoxicolate 1 mg·kg−1·day−1 i.v. oramphotericyn liposomal 3–5 mg·kg−1·day−1 i.v.Voriconazol6 mg·kg−1 every 12 h i.v.(day 1) and 4 mg·kg−1 every12 h i.v.(following days)Early-onset HAP <5 days Without risk factors and non-severeβ-lactam/β-lactamase inhibitor: amoxicillin/clavulanate 1–2 gevery 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. or750§ mg·day−1 i.v.Late-onset HAP ≥ 5 days Without risk factors and non-severeAntipseudomonal cephalosporin (including pneumococcus):cefepime 2 g every 8 h i.v.Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or750§ mg·day−1 i.v.