CAP, HAP, VAP, & HCAP

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1 Objectives Following the presentation, the participant will be able to: CP, HP, VP, & HCP John C. Rotschafer, Pharm. D. Professor College of Pharmacy University of Minnesota 1. Identify typical, atypical, & hospital respiratory pathogens. 2. Identify diagnostic criteria used to establish a diagnosis of pneumonia 3. Identify differences in pathogens causing HP vs CP and the required differences in antibiotic coverage. 4. Identify underlying mechanisms of antibiotic resistance for typical bacterial pathogens 5. Using IDS/TS guidelines for CP & HP/VP/HCP identify appropriate initial antibiotic therapy Pneumonia Community acquired pneumonia (CP) spiration pneumonia Hospital Hospital acquired pneumonia (HP) Ventilator associated pneumonia (VP) Healthcare associated pneumonia (HCP) Patient screening 27 TS/IDS CP Guidelines Mandell, L et al CID 44(suppl 2) 27 Determine whether to treat as outpatient or in-patient (ICU vs Ward) Objective scoring systems Pneumonia Severity Index CURB-65 Confusion Urea > 7 mmol/l Respiratory Rate > 3 / min Blood pressure < 9 mm Hg & diastolic > 6 mm Hg ge > 65 years ICU dmit (3 minor criteria present) Respiratory rate > 3 / min P a O 2 /FIO 2 < 25 Multilobar infiltrates Confusion Uremia Neutropenia Thrombocytopenia Hypothermia Pneumonia Diagnosis Fever, cough, SOB & pleuritic chest pain Chest x-ray infiltrate HP, VP, & HCP Sputum culture should be obtained prior to antibiotics Quantitative or semiquantitative culture required Sputum gram stain & culture <1 epithelial cells & > 25 PMN s per field ppropriate cultures of blood and CSF Bacterial Resistance in Pneumonia Penicillin Resistant S. pneumoniae Macrolide Resistant S. pneumoniae mpicillin Resistant H. influenzae Beta-lactamase producing M. catarrhalis MRS & C-MRS Multiple Drug Resistant Gram Negative Pathogens P. aeruginosa S. maltophilia cinetobacter spp K. pneumoniae or E. coli (ESBL positive) KPC (+) Klebsiella spp 1

2 Potential CP Pathogens Typical S. pneumoniae H. influenzae M. catarrhalis typical C. pneumoniae L. pneumophila Mycoplasma m J Med 16:385-39,1999 Viruses Fungi Less Common pathogens N. meningitidis S. pyogenes M. tuberculosis Chlamydia psittaci Coxiella burnetii B. anthracis Y. pestis F. tularensis C-MRS TS Pathogen Risk Factors for Penicillin NS/R S. pneumoniae > 65 years Multiple co-morbidities lcoholism Exposure to children in day care Immunosuppressed Smoking Use of beta-lactam within last 9 days m J Respir Crit Care Med 163: , 21 Nosocomial Pneumonias Late-onset pneumonia erobic gram-negative bacilli (>6%) Pseudomonas Enterobacter cinetobacter Klebsiella Staphylococcus aureus (~2%) ~8% <1% 1% dapted from Leaf HL. In: Mandell GL, Simberkoff MS, eds. tlas of Infectious Disease. Philadelphia, Pa: Current Medicine. 1996;6.VI:6.16 Early-onset pneumonia Streptococcus pneumoniae (~5) Haemophilus influenzae (<5%) Miscellaneous naerobes (<3%;( may be present in mixed infections) Legionella (% - 1%) Influenza and B (<1%) Respiratory syncytial virus (<1%) spergillus (<1%) Pneumocystis carinii (<1%) TS Guidelines for HP, VP, & HCP m J Resp Crit Care Med 171: , 25 Risk for MDR Pathogens ntibiotic therapy in previous 9 days Current hospitalization of > 5 days High frequency of antibiotic resistance Risk factors for HCP Hospitalization for > 2 days in previous 9 days Residence in nursing home or ECF Home infusion therapy Chronic dialysis within 3 days Home wound care Family member with MDR pathogen Immunosuppressive disease Effect of Mechanical Ventilation and Prior ntibiotic Use on Development of Multiresistant Pathogens Organisms Multiresistant bacteria P. aeruginosa. baumannii S. maltophilia MRS Other bacteria Group 1 (n=22) MV < 7 BT = no * 41 (1) Group 2 (n=12) MV < 7 BT = yes 6 (3) 4 (2) 1 (5) 1 (5) 14 (7) Group 3 (n=17) MV 7 BT = no 4 (12.5) 2 (6.3) 1 (3.1) 1 (3.1) 28 (87.5) Group 4 (n=84) MV 7 BT = yes 89 (58.6) 33 (21.7) 2 (13.2) 6 (3.9) 3 (19.7) 63 (41.4) dapted from Trouillet JL, et al. m J Respir Crit Care Med ;157: Diagnosis of Suspected VP 413 patients with suspected VP 32% enrolled surgical patients Invasive management BL or bronchoscopic protected specimen brush (PSB) Quantitative sputum cultures 1 4 CFU/mL BL 1 3 CFU/mL PSB Clinical management Clinical criteria Nonquantitatve evaluation of nonbronchoscopic isolates * p <.2 versus Groups 2, 3, or 4 p <.1 versus Group 4 Fagon JY et al. nn Intern Med. 2;132:

3 Diagnosis of Suspected VP Bacteriology End Point Mortality at 14 days, n (%) Mortality at 28 days, n (%) Intention-to-Treat nalysis Invasive Clinical (n=24) (n=29) 33 (16.2) 54 (25.8) 63 (3.9) 81 (38.8) P value Feature or Organism Negative culture Monomicrobial pneumonia Polymicrobial pneumonia P. aeruginosa Invasive (n=24) 55.9% 31.9% 12.3% 22.3% Clinical (n=29) 14.4% 4.2% 45.5% 18.3% ntibiotic-free days at 14 days 5. ± ± 3.5 <.1 S. aureus 16.5% 12.8% ntibiotic-free days at 28 days 11.5 ± ± 7.6 <.1 H. influenzae 7.4% 3.8% Emergence of Candida spp., n (%) 23 (11.3) 47 (22.5).25. baumannii Enterobacter spp. 5.% 3.3% 3.5% 3.8% dapted from Fagon JY et al.. nn Intern Med. 2;132: dapted from Fagon JY et al. nn Intern Med. 2;132: TRUST 12 (28) National ntibiogram: Susceptibility of S. pneumoniae (N=2858) ntimicrobial gent Levofloxacin Moxifloxacin Ceftriaxone (nonmeningitis) mox-clav (nonmeningitis) Tetracycline Cefuroxime (oral) Cefdinir Trimethoprim-sulfa zithromycin Clarithromycin Penicillin (oral) In vitro activity does not necessarily corrrelate with clinical results. ll isolates were vancomycin susceptible. Breakpoints (S/I/R) for other antimicrobials are CLSI. % S % I % R New FD Pneumonia Breakpoints for S. pneumoniae (28) Sensitive PCN MIC < 2 (Previously.6 mg/l) Non-susceptible PCN MIC = 4 (Previously.12 to 1. mg/l) Resistant PCN MIC > 8 mg/l (Previously > 2 mg/l) Meningitis breakpoint for penicillin sensitive remains at <.6mg/L Mechanism of resistance is alteration of penicillin binding proteins not beta-lactamase production Influx-Block Porin Channel Efflux- Pump (mef) Enzyme Inactivation Influx Efflux S. pneumoniae Penicillin Resistance Enzyme P Target lteration(pbp) Environment Factors Metabolic Bypass PBP Target lteration Metabolic Block & Bypass C X D E Influx-Block Porin Channel Efflux- Pump (mef) Enzyme Inactivation Influx Efflux S. pneumoniae Macrolide Resistance Enzyme P Target lteration(ermb) Environment Factors Metabolic Bypass 5S Ribosome Target lteration Metabolic Block & Bypass C X D E = ntibiotic PBP-Penicillin Binding Proteins = ntibiotic 3

4 Pneumonia Treatment Guidelines 1993-Present merican Thoracic Society (TS) First published 1993 Revision m J Respir Crit Care Med 163: , 21 Infectious Diseases Society of merica (IDS) First published pril 1998 Revision Clin Infect Dis 31: , 2 Revision Clin Infect Dis 37: , 23 New Joint IDS/TS CP Guidelines 27 Mandell, L et al Clin Infect Dis 44(suppl 2) 27 Joint IDS/TS HP/ VP / HCP Guidelines TS/IDS CP Guidelines Mandell, L et al CID 44(suppl 2) 27 Healthy & no risk factors for DRSP Macrolide or Doxycycline Comorbidities present ntibiotic Use in last 9 days, heart, lung, or renal disease, diabetes, DRSP risk factors Respiratory fluoroquinolone Moxifloxacin, Levofloxacin, or Gemifloxacin Macrolide (or doxycycline) & beta-lactam mpicillin + Clavulanate, Ceftriaxone, Cefpodoxime, or Cefuroxime Note: gatifloxacin has been removed from guidelines & no recommendation is offered for telithromycin 27 TS/IDS CP Guidelines Mandell, L et al CID 44(suppl 2) 27 Inpatient Non-ICU Respiratory fluoroquinolone Macrolide (or Doxcycline) plus beta-lactam Cefotaxime, Ceftriaxone, mpicillin, or Ertapenem Inpatient ICU zithromycin or respiratory fluoroquinolone plus betalactam Cefotaxime, Ceftriaxone, or mpicillin/sulbactam 27 TS/IDS CP Guidelines Mandell, L et al CID 44(suppl 2) 27 Community cquired MRS (C-MRS) Common following a viral infection Check Gram stain & Check X-ray for cavitary infiltrates C-MRS prolific toxin producer Treatment (No preference given) Vancomycin Possible issues with lung penetration, slow kill rate, failure to shut down toxin production, & cell lysis upon death Linezolid ntibiotic recommendations for pneumonia different than S/STI recommendations Daptomycin binds to surfactant & can t be used for pneumonia Possible Tip Offs for Patients with C-MRS Pneumonia Patients tend to be younger Contact with C-MRS carrier or infection Previous or concomitant influenza Not current on influenza vaccination Gram positive cocci on Gram stain Multi-lobar involvement Cavitary pneumonia Evidence of airway hemorrhage CP Prevention Mandell, L et al CID 44(suppl 2) 27 MMWR December 15, 26 Vol 55 Persons > 5yrs, healthcare workers, risk patients should receive annual influenza vaccination Persons > 65 yrs or at risk should receive pneumococcal vaccine CDC recommends T dap for adults years Vaccination status should be evaluated at time of admission Patients should be offered influenza vaccination at discharge or outpatient treatment in the fall and winter Smoking cessation should be offered to patients who smoke Smokers should be vaccinated against pneumococci & influenza Suggest appropriate respiratory hygiene & IC practices to patients with a cough 4

5 Document CP Hospital Quality Standards Influenza vaccination Pneumococcal vaccination Offer of smoking cessation therapy (if patient a smoker) ppropriate diagnostics & monitoring used Initial antibiotics consistent with CP guidelines ntibiotics started at site of CP diagnosis (ED) for hospitalized patients (Old standard 4 hours) May initially need broad spectrum coverage May be able to de-escalate after pathogen known Duration Prophylaxis for thromboembolic disease 75-mg, Short-Course Levofloxacin for CP: Clinical Success by PSI Class Clinical Success n=122 n= n= n= n= n=32 Class I/II Class III Class IV Patients in Each PSI Class 75 mg 5 mg Dunbar et al Clin Infect Dis. 23;37: CP ntibiotic Overview Pathogen BL MC FQ DOX Ket S. pneumoniae PCN-R Macro-R H. influenzae M. catarrhalis typicals minoglycoside or Ciprofloxacin ntibiotic Treatment Presence of MDR bacteria? Combination Therapy ntipseudomonal Beta-lactam + + Glycopeptide or Linezolid ntibiotic choice highly dependent on specific agent selected For S. pneumoniae with PCN MIC >2 mg/l, vancomycin, FQ, or ketolide probably best choice depending on circumstances BL-beta-lactam, MC-macrolide, FQ-fluoroquinolone, DOX-doxycycline, & Ket-ketolide Höffken G, Niederman MS. Chest.. 22;122: TS Guidelines for HP, VP, & HCP m J Resp Crit Care Med 171: , 25 Initial empiric therapy for HP, VP, & HCP in patients with late onset or risk for MDR Cefepime (1-2Gm Q8-12H) or Ceftazidime (2Gm Q8H) Imipenem (5mg Q6H) or Meropenem (1Gm Q8H) Piperacillin/Tazobactam (4.5Gm Q6H) One of the above plus Gentamicin or Tobramycin 7 mg/kg/day mikacin 2 mg/kg/day Levofloxacin 75 mg QD or Ciprofloxain 4 mg Q8H One of the above plus Vancomycin 15 mg/kg Q12H or Linezolid 6 mg Q12H Daptomycin binds to lung surfactant & should not be used Vancomycin Treatment Guidelines Guideline Organ Dose Trough (mg/l) HP/VP TS 15 mg/kgq12h 15-2 Meningitis IDS 15-2* Endocarditis BSC 1GmQ12H 1-15 Endocarditis H 15 mg/kgq12h 1-15* * Graded Recommendation 5

6 Vancomycin Trough Recommendations from Treatment Guidelines Guidelines recommending vancomycin trough concentration of 1-2 mg/l based on expert opinion not clinical trial data No data that empiric doses will produce desired vancomycin trough concentrations No data that higher vancomycin trough concentrations are safe &/or more effective Would FD allow a change in the vancomycin product insert? Superior results for linezolid vs vancomycin in ventilator-associated associated pneumonia (VP) Clinical cure (%) (excluding missing and indeterminate) P=.7 Linezolid/aztreonam 36.7 Intent-to-treat VP (n=434) S. aureus VP (n=179) Vancomycin/aztreonam P=.6 P= MRS VP (n=7) 21.2 TS Guidelines for HP, VP, & HCP m J Resp Crit Care Med 171: , 25 Combination vs Monotherapy Synergy only documented in-vitro, in patients with neutropenia, or bacteremic patients Clinical relevance is unclear Preventing the emergence of resistance during therapy not well documented Meta-analysis of >12/7586 patients with HP/VP betalactam monotherapy vs combination beta-lactam plus aminoglycoside, clinical failure more common with combination therapy No advantage for P. aeruginosa Combination therapy did not prevent emergence of resistance More nephrotoxicity with combination Summary LRTI/URTI s remain a serious and expensive problem Level of antibiotic resistance among common respiratory pathogens is concerning & could grow Need better diagnostic methods ntibiotics often over utilized in URTI & LRTI Need to be more responsible with antibiotic resources Increase the rate of vaccination for S. pneumoniae Use oral therapy whenever possible Use antibiotics for as short a time as possible Remain watchful for antibiotic resistance & DR s Summary Optimizing Therapy: Get in quick with appropriate empiric antibiotics Hit hard with definitive therapy once pathogen is identified and dose appropriately Get out SP limiting collateral damage 5 days of therapy for CP 7 days of therapy for HP, VP, & HCP for non- MDR pathogens Streamline therapy per culture results 6