Infectious Disorders of the Lung Parenchyma

1. Infectious Disorders of the Lung Parenchyma Matthew L. Paden, MD Pediatric Critical Care Fellow Emory University Children’s Healthcare of Atlanta at Egleston

2. Objectives • Worldwide epidemiology of the problem • Review common etiologies • Discuss empirical and disease specific treatment

3. Epidemiology • World wide • Leading cause of death in children • More than AIDS, malaria, and measles combined • Most deaths in < 5 yo • United states • 3rd leading cause of hospitalization for kids • 2% of deaths (5% including neonates)

4. http://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/ISBN_92_806_4048_8.htmhttp://www.who.int/child-adolescent-health/publications/CHILD_HEALTH/ISBN_92_806_4048_8.htm

5. Worldwide Epidemiology • Cases • 150 million • Hospitalizations • 11-20 million • Deaths • 2 million

6. Barriers to care • Recognizing there is a problem • Seek appropriate care • Treatment with antibiotics

7. Prevention • Adequate nutrition • Exclusive breastfeeding • Less than 1 yo, get any formula – 5 X increased risk of death from pneumonia • Zinc supplementation

8. Prevention • Immunization • Measles – • Pneumonia is what they die of – often super-infection • World-wide coverage rate – 76% in 2004 • Still having 30-40 million cases a year • HIB – • 2-3 million cases of severe disease a year • In 2003, developed world coverage – 92% • Developing world – 42% • Least developed countries – 8%

9. Prevention • Immunization • Strep pneumo – • 7 –valent vaccine (Prevnar) in the US • 9, 11, or 13 valent vaccine for the rest of the world • Gambia – 17,000 children • 37% reduction in pneumonia • 15% reduction in hospitalization • 16% reduction in mortality

10. Costs involved • More than 1 million deaths a year can be prevented with treatment and prevention • 600,000 lives saved by just treatment alone • Cost analysis • Antibiotic treatment course- • $ 0.27 • $ 600 million total cost including : • Cost of antibiotics • Cost of hospital stays • Increasing training of health care staff • Increasing physical plants to take care of these patients

11. Costs involved • Those costs inflated by Mexico and Brazil • 85% of deaths are in sub-Saharan Africa and southeast Asia • $200 million dollars will expand coverage to those regions only and potentially fix 85% of the problem

12. Potential solutions • One F-22 fighter - $183 million • 1997-2003, Defense Department purchased and then left unused approximately 270,000 fully refundable commercial airline tickets at a total cost of $100 million. • $4,000,000 for the Northern Line Extension • A direct 82 mile train route from North Pole (pop. 1,778 in 2005) to Delta Junction (pop. 840 in 2000) • $9,500,000 for the Extended Cold Weather Clothing System • $8,000,000 added by the Senate for special assistance DOD Dependents Education. • $5,500,000 for The Ernest Gallo Clinic and Research Center at (USCF) to study basic neuroscience and the effects of alcohol and drug abuse on the brain.” • $1,650,000 to improve the shelf life of vegetables “This project will help our troops in the field get fresh tomatoes…”

13. Diagnosis • Tachypnea • Sensitive but not specific • Higher specificity • Decreased breath sounds • Inspiratory rales • Chest wall retractions • Nasal flaring • Absence of fever has high negative predictive value for bacterial pneumonia

14. Etiologies • Streptococcus pneumoniae • Most common cause outside of neonatal period • Nasopharyngeal colonization – 50% of kids • >90 serotypes – majority of invasive disease caused by 10 serotypes • Bacteremia in 25-30% of kids • Gram stain – gram positive lancet shaped diplococci (“gram positive cocci in pairs”)

15. Age differences • Adults – lobar pneumonia • Kids – lobar or bronchopneumonia

16. Treatment - Streptococcus pneumoniae • 2002 CDC Surveillance data • 20% PCN resistant • 4% Cefotaxime resistant • 0% Vancomycin resistant • 2003-2004 FAST Surveillance data • 56% PCN resistant

17. Geographically-based evaluation of multi-drug resistance trends among Streptococcus pneumoniae in the USA: findings of the FAST surveillance initiative (2003-2004). Int J Antimicrob Agents. 2006 Dec;28(6):525-31.

18. 2006 CHOA Data Percent of organisms tested that have intermediate or resistant sensitivity patterns

19. Treatment – Strep pneumo • Mechanism of resistance – • PCN and Cephalosporins – change in penicillin binding proteins (NOT beta lactamase) • Empiric : 3rd generation cephalosporin + vancomycin until sensitivities are confirmed

20. Etiologies • Staphylococcus aureus • Common cause of ventilator associated and nosocomial pneumonia • Community acquired disease usually coincident with viral infection (influenza) • Viral hemagglutinins – inhibit neutrophil and monocyte activation • Gram stain – gram positive cocci in grape like clusters

21. Diagnosis – Staphylococcal pneumonia • Classically a lobar consolidation on CXR • Raise suspicion of staph • Pneumatoceles • Pleural effusion • Air fluid levels • Necrosis

23. Treatment – Staphylococcus aureus • Treatment has changed over the past 5 years with emergence of caMRSA • Empiric therapy with Vancomycin • VISA (1996, Japan, 1997 US) • Mechanism – thickening of cell membrane – decreased penetration of vancomycin – unclear mechanism • VRSA (2002, US) • Mechanism – VanA from enterococcus – changes d-alanine, d-alanine terminus to d-alanine, d-lactate – reduces affinity by 1,000 fold • VDSA

24. 2006 CHOA Data • ECH total % MRSA 53% SRH total % MRSA 51% * Not adjusted for inducible resistance

25. Staph Aureus treatment • Get off Vancomycin if MSSA • MSSA much more susceptible to Nafcillin • Use of Vancomycin or first-generation Cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis. 2007 Jan 15;44(2):190-6. • Treatment failure - Vancomycin 31.2% vs. Ancef 13% ; p=.02 • Multivariable analysis - factors independently associated with treatment failure included Vancomycin use (odds ratio, 3.53; 95% confidence interval, 1.15-13.45)

26. Staph aureus treatment • Get off Vancomycin if MSSA • Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia. Am Heart J. 2004 Mar;147(3):536-9. • MSSA bacteremia is associated with higher rates of endocarditis than MRSA. • Comparative activity of cloxacillin and vancomycin against methicillin-susceptible Staphylococcus aureus experimental endocarditis.J Antimicrob Chemother. 2006 Nov;58(5):1066-9. • Cloxacillin produced a greater decrease in the number of staphylococci than vancomycin • 41% of rabbits had sterile vegetations in comparison with 0% with vancomycin (p=0.035)

27. New horizons • Anti-MRSA beta-lactams in development, with a focus on ceftobiprole: the first anti-MRSA beta-lactam to demonstrate clinical efficacy. Expert Opin Investig Drugs. 2007 Apr;16(4):419-29. • Investigational beta-lactam antibiotic against methicillin-resistant staphylococci, enterococcus faecalis, penicillin-resistant streptococci and many Gram-negative pathogens. • Completed Phase III therapeutic trials • PPI0903 - injectable pro-drug of a broad-spectrum cephalosporin with anti-MRSA activity • RO4908643 - a carbapenem with anti-MRSA activity

28. Etiologies • Pseudomonas aeruginosa • Common cause of bacterial nosocomial pneumonia • More common in CF, tracheostomy dependant, or immunocompromised • Oxidase positive gram negative rod

29. Pseudomonas treatment • Antibiotic resistance common • Mechanism – extended spectrum beta-lactamase • Implication – serious or life-threatening infections should not be treated with an anti-pseudomonal synthetic penicillin/cephalosporin/carbapenem alone • Empiric therapy – anti-pseudomonal PCN + an aminoglycoside • Role of monotherapy has not been well defined.

30. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • Ticarcillin +/- clavulanate • Piperacillin +/- tazobactam

31. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • Ticarcillin +/- clavulanate • Piperacillin +/- tazobactam • Mechanism of Action • Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins • Inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls • Clavulanate and tazobactam prevents degradation of the PCN by binding to beta-lactamases

32. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Ceftazidime – 2nd generation with pseudomonas activity

33. Pseudomonas treatment • Antibiotic choices • 4th generation cephalosporin – cefepime • Mechanism of Action • Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins • Inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls

34. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Carbapenems – imipenem-cilastatin or meropenem

35. Pseudomonas treatment • Antibiotic choices • Carbapenems – imipenem-cilastatin or meropenem • Mechanism of Action • Inhibits cell wall synthesis by binding to penicillin-binding proteins (PBPs) with its strongest affinities for PBPs 2, 3 and 4 of E. coli and P. aeruginosa and PBPs 1, 2 and 4 of S. aureus • Meropenem reduces valproate levels by ~40%

36. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Carbapenems – imipenem-cilastatin or meropenem • Aztreonam

37. Pseudomonas treatment • Antibiotic choices • Aztreonam • Mechanism of Action • Binds to penicillin-binding protein 3 which produces filamentation of the bacterium inhibiting bacterial cell wall synthesis and causing cell wall destruction

38. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Carbapenems – imipenem-cilastatin or meropenem • Aztreonam • Fluroquinolones – ciprofloxacin, levofloxacin, etc.

39. Pseudomonas treatment • Antibiotic choices • Fluroquinolones – ciprofloxacin, levofloxacin, etc. • Mechanism of Action • Inhibits DNA-gyrase and topoisomerase IV in susceptible organisms; inhibits relaxation of supercoiled DNA and promotes breakage of double-stranded DNA

40. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Carbapenems – imipenem-cilastatin or meropenem • Aztreonam • Fluroquinolones – ciprofloxacin, levofloxacin, etc. • Aminoglycosides – amikacin, gentamicin, tobramycin

41. Pseudomonas treatment • Antibiotic choices • Aminoglycosides – amikacin, gentamicin, tobramycin • Mechanism of Action • Inhibits cellular initiation of bacterial protein synthesis by binding to 30S and 50S ribosomal subunits resulting in a defective bacterial cell membrane

42. Pseudomonas treatment • Antibiotic choices • Anti-pseudomonal synthetic penicillin • 4th generation cephalosporin – cefepime • Carbapenems – imipenem-cilastatin or meropenem • Aztreonam • Fluroquinolones – ciprofloxacin, levofloxacin, etc. • Aminoglycosides – amikacin, gentamicin, tobramycin So which to choose?

43. 2006 CHOA Data - Pseudomonas * No CF patients included

44. 2006 CHOA Data - Pseudomonas * No CF patients included

45. Etiologies • “Atypical” Pneumonias • Mycoplasma pneumoniae • Chlamydia pneumoniae • Legionella pneumophilia • Common cause of pneumonia in school age children • Persistent cough (for weeks after infection has cleared)

46. “Atypical” Pneumonia diagnosis • Mycoplasma – clinical picture + serologic testing • Cold agglutinins are not specific • Complications – arthritis, hemolysis, pericardial effusions, myocarditis, encephalitis, Stevens-Johnson syndrome • Antibiotic therapy has not been conclusively shown to help non-pulmonary manifestations

47. “Atypical” Pneumonia diagnosis • Legionella pneumophilia • Severe disease in immunocompromised • Respiratory failure, pericarditis • Classic history triggers – exposure to travel, hot tubs, or hospitalization • DFA, culture, and serology available • Urinary antigen – good sensitivity and specificity

48. “Atypical” Pneumonia treatment • Macrolide antibiotics • Erythromycin • Azithromycin • Mechanism of Action • Inhibits bacterial RNA-dependent protein synthesis by binding to the 50S ribosomal subunit which results in the blockage of transpeptidation

49. Etiologies • Viral • Respiratory syncytial virus • Parainfluenza • Influenza • Adenovirus • Human metapneumovirus • Hantavirus

50. Respiratory syncytial virus • Enveloped, single stranded, negative polarity RNA paramyxovirus • Seasonality – November through May