2. Hospital Acquired Pneumonia(HAP): is defined as a pneumonia which occurs after 48 hours of admission to hospital. Hospital Acquired Pneumonia(HAP): is defined as a pneumonia which occurs after 48 hours of admission to hospital. Ventilator-associated Pneumonia (VAP): is defined as pneumonia occurring 48 to 72 hours after intubation. Ventilator-associated Pneumonia (VAP): is defined as pneumonia occurring 48 to 72 hours after intubation. HCAP occurs in patients from the community who reside in long-term care facilities or nursing homes; visit hemodialysis clinics or hospitals; were hospitalized for ≥2 days within the last 90 days; or received intravenous (IV) antibiotic therapy, chemotherapy, or wound care within the past 30 days.

3. Nosocomial pneumonia is the 2 nd most common hospital-acquired infections after UTI. Accounting for 31 % of all nosocomial infections. Nosocomial pneumonia is the leading cause of death from hospital-acquired infections. The incidence of nosocomial pneumonia is highest in ICU. The incidence of nosocomial pneumonia in ventilated patients was 10-fold higher than non-ventilated patients The reported crude mortality for HAP is 30% to greater than 70%.

4. Mortality for VAP range from 24% to 76% Risk factors for increased mortality due to VAP: 1.for patients infected with pathogens such as Acinetobacter species, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). 2.Advanced age. 3.prolonged intubation. 4.underlying cardiopulmonary compromise. 5.immunosuppression.

5. Classification of HAP Early-onsetLate-onset Occurs during the first 4 days More than 4 days S. Pneumoniae MSSA (methicillin- sensitive S aureus) H. Influenza anaerobes. G(-) organisms, esp. P.aeruginosa, Acinetobacter Enterobacteriaceae (klebsiella, Enterobacter, Serratia) MRSA. MonotherapyCombination therapy

6. Classification of VAP Early-onsetLate-onset within 48-72 hours after tracheal intubation, which complicates the intubation process after 72 hours

7. Most initial therapy is empiric because no pathogen is identified or results are not available when antimicrobial decisions are made in most patients. Treatment Initially be treated with a broad-spectrum antibiotic regimen aimed at covering all likely bacterial pathogen This regimen should subsequently be narrowed, according to the result of culture (de-escalate)

9. The mortality can be reduced with early appropriate empiric therapy.(Form 30 % with appropriate therapy to more than 90 % with inappropriate therapy) Inappropriate initial antibiotic therapy was associated with: 1. Higher crude hospital mortality (60.7 vs. 47.3%) 2. Longer ICU stay in survivors (20 vs. 12 days) 3. Longer duration of mechanical ventilator

10. Monotherapy combination therapy Early onset mild-to-moderate HAP Early onset mild-to-moderate HAP Late onset For severe HAP in which infection with resistant organisms is likely. combination therapy probably should be instituted until culture result are available. Late onset For severe HAP in which infection with resistant organisms is likely. combination therapy probably should be instituted until culture result are available. Treatment of HAP, VAP, and HCAP is based on onset of disease and risk factors for MDR organisms. Treatment

12. combination  Antipseudomonal cephalosporin cefepimecefepime (2 g Q8H) or ceftazidime (2 g Q8H)ceftazidime OR carbapenem imipenem (500 mg Q6H) or meropenem (1 g Q8H) meropenem OR beta-lactam Piperacillin-tazobactamPiperacillin-tazobactam (4.5 g Q6H)  Antipseudomonal Legionella Fluoroquinolone levofloxacinlevofloxacin (750 mg QD) or ciprofloxacin (400 mg Q8H) ciprofloxacin OR Aminoglycoside gentamicingentamicin or tobramycin (7 mg/kg QD adjusted to a trough level <1 µg/mL) or amikacin (20 mg/kg QD adjusted to a trough level <4-5 µg/mL)tobramycinamikacin  MRSA is suspected LinezolidLinezolid (600 mg Q12H) OR VancomycinVancomycin (15 mg/kg Q12H, dosed so that trough levels are 15 to 20 µg/mL)

14. Treatment Combination of antipseudomonal drugs is controversial: 1.Traditional: antipseudomonal beta-lactam + an Aminoglycoside. Synergy but potential  nephrotoxicity. 2. Another approach: antipseudomonal beta-lactam + a Fluoroquinolone. No benefit of synergy but  nephrotoxicity, and quinolone gets into the lungs at higher concentrations.

15. Treatment Patients for S. aureus infection, agents against this organism are necessary, including Vancomycin if MRSA is suspected. Linezolid is comparable with Vancomycin. The advantage of Linezolid is less possible nephrotoxicity ---- current opinion in infectious disease 2002, 15:387-94, copyright LWW

16. Treatment Results: 1. Some pathogens, such as H. influenzae, cure rate is high, and 7 to 10 days is adequate. 2. Highly resistant G(-) organisms (Acinetobacter or pseudomonas) require prolonged combination therapy for 21 days. 3. MRSA, requiring prolonged therapy.

17. Response of Therapy

18. Because of the delays in clinical response of treatment, it is thought that unless there is significant clinical deterioration or new microbiologic information, therapy should not be changed for at least the first 48 to 72 hours Measured by quantitating the bacterial load in the lower respiratory tract at the initiation of therapy and several days later. Bacterial concentrations decreased or no growth -- clinical improvement Elevated -- experienced clinical failure

19. NEW AGENTS FOR THE TREATMENT OF HAP Doripenem Tigecycline

20. Doripenem Doripenem is a carbapenem antibacterial with broad in vitro activity similar to imipenem and meropenem. It has in vitro potency against Enterobacteriaceae similar to that of ertapenem and meropenem but is 2-fold more potent in vitro than imipenem. Doripenem has activity similar to that of meropenem against P aeruginosa but is again 2-fold more potent in vitro than imipenem. In vitro activity against MSSA has been demonstrated to be similar to that of imipenem. Doripenem is a carbapenem antibacterial with broad in vitro activity similar to imipenem and meropenem. It has in vitro potency against Enterobacteriaceae similar to that of ertapenem and meropenem but is 2-fold more potent in vitro than imipenem. Doripenem has activity similar to that of meropenem against P aeruginosa but is again 2-fold more potent in vitro than imipenem. In vitro activity against MSSA has been demonstrated to be similar to that of imipenem.

21. Tigecycline Tigecycline is a glycylcycline antimicrobial a synthetic derivative of minocycline with in vitro activity against Enterobacteriaceae and resistant gram-positive bacteria, including MRSA. However, this agent lacks appreciable activity against P aeruginosa and Proteus species. On May 29, 2008, FDA issued an approvable letter for tigecycline for the treatment of community-acquired pneumonia (CAP). Tigecycline is a glycylcycline antimicrobial a synthetic derivative of minocycline with in vitro activity against Enterobacteriaceae and resistant gram-positive bacteria, including MRSA. However, this agent lacks appreciable activity against P aeruginosa and Proteus species. On May 29, 2008, FDA issued an approvable letter for tigecycline for the treatment of community-acquired pneumonia (CAP).