2. Acute infections of the lower airways in children Aleksandra Szczawińska-Popłonyk Department of Pediatric Pneumonology, Allergology and Clinical Immunology Karol Marcinkowski University of Medical Sciences Poznań

3. Infection  The specific and nonspecific defense mechanisms keep the bronchial tree sterile beyond the first bronchial bifurcation  A certain amount of microorganisms must both avoid mucociliary clearance and resist destruction by the humoral or cellular defense mechanisms  Large amounts of the organisms reach the LRT through aspiration  The invading microorganisms have particular characteristics- eg. a marked capacity to adhere to epithelium (Influenza virus, other viruses, Mycoplasma pneumoniae, Bordetella pertussis)

4. Infection  Microorganisms avoid immune defence system: - Encapsulated bacteria (pneumococci, Klebsiella pneumoniae, Haemophilus influenzae) are resistant to phagocytosis - Some bacteria are resistant to mechanisms of intracellular killing, other (Haemophilus influenzae, Neisseria, streptococci) produce IgA protease, which degrades IgA antibodies  There is a defect in mucociliary clearance by the inhalation of number of irritants (industrial pollution, tobacco smoke), microorganisms (viruses: Influenza, Morbilli, bacteria: B.pertussis, H.influenzae)

5. Lower respiratory tract infections epidemiological data  A global health problem: four milion children die each year for respiratory tract infections (98-99% in the developing countries)  Children aged 1-5 yrs in an urban area have 6-8 episodes of RTI each year, in the country 3-5  Only a small proportion of these infections concern the lower respiratory tract; the difference between industrialized and developing countries doesn’t concern the incidence but the severity of infections  Even if only in exceptional cases infections lead to serious complications, they cause suffering and impairement of the individual child

6. Lower respiratory tract infections social problems  Respiratory tract infections account for a large proportion of physician consultations  The significant proportion of the resources of out-patient care expand on RTI  Sickness absence and medicine cost society a lot of money: 57% of acute illnesses 50% number of days restricted activity 42% of the lost working days 60% of the lost school days

7. Pneumonia  Definition Pneumonia is defined as inflammation in the lung parenchyma, the portion distal to the terminal bronchioles and comprising the respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli  Pathogenesis Organisms reach the lung to cause pneumonia by one of four routes: - inhalation of microbes present in the air - aspiration of organisms from the naso- or oropharynx (the most common cause of bacterial pneumonia) - hematogenous spread from a distant focus of infection - direct spread from a contiguous site of infection or penetrating injury

8. Pneumonia - classification  By anatomic distribution: lobar, lobular, segmental, bronchopneumonia  By dominant histological lesions: alveolar exudation, involvement of interstitial tissue or both  By etiological factor: infections (viral, bacterial, mycotic, other), aspiration, drug / radiation pneumonia, Loeffler syndrome, hypersensitivity pneumonitis  By the place where infection is acquired: community-acquired pneumonia, hospital- acquired (nosocomial) pneumonia

9. Community-acquired pneumonia  In the United States CAP remains an important cause of morbidity and mortality: -more than 3 million cases occur annually -results in more than 900 000 hospitalizations and more than 60 000 deaths  Only 20-30% of CAP occur in young, previously healthy individuals without comorbidities  Mortality is high (15-30%) in patients with predisposing risk factors including: -old age -history of cigarette smoking and COPD -chronic ethanol abuse -cardiac disease -diabetes mellitus -malignancy -renal insufficiency -corticosteroid or immunosuppressive therapy

10. Etiology of pneumonias Community- acquired Hospital- acquired Strep. pneumoniae Staph. aureus H. influenzae P. aeruginosa Legionella sp. M. pneumoniae Ch. pneumoniae EnterobacteriaceaeAnaerobic30-70%3-9%8-20%<2%2-8%2-15%2-6%4-12%5-15%3-8%10-20%1-8%12-20%<4%rarerare30-50%2-20%

11. Pneumonia of unknown etiology  The newborn Group B Streptococcus Escherichia coli Staphylococci Listeria monocytogenes Tuberculosis Herpes simplex virus TORCH agents

12. Pneumonia of unknown etiology  Infants 1-3 months of age Group B Streptococcus Escherichia coli Haemophilus influenzae type b Streptococcus pneumoniae Chlamydia trachomatis Ureaplasma urealyticum Pneumocystis carinii Cytomegalovirus Respiratory syncytial virus Parainfluenzae virus Adenovirus

13. Pneumonia of unknown etiology  Children 3 months to 5 years of age -respiratory viruses 75% Respiratory syncytial virus Adenovirus Parainfluenzae virus Influenzae virus Streptococcus pneumoniae Haemophilus influenzae type b Klebsiella pneumoniae Staphylococcus aureus

14. Pneumonia of unknown etiology  Children 6 years of age to adults Mycoplasma pneumoniae Respiratory viruses: Parainfluenzae virus, RSV, Adenovirus Influenzae virus Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Klebsiella pneumoniae Chlamydia pneumoniae

15. Mycoplasmal respiratory infection  The most commonly recognized clinical syndrome following Mycoplasma pneumoniae infection is bronchopneumonia Additional respiratory illnesses include pharyngitis, sinusitis, croup, bronchitis, bronchiolitis Superinfection with typical bacteria is infrequent  Treatment: because of the absence of the cell wall, Mycoplasma is resistant to beta-lactams, but is exceptionally sensitive to:  macrolids (Erythromycin, Clarithromycin, Roxithromycin, Azithromycin)  tetracyclines – over the age of 8 yr  quinolones – over the age of 16 yr

16. Staphylococcal respiratory infections  Upper airway infection due to Staph. aureus: pharyngitis, tonsillitis, otitis media, sinusitis, tracheitis complicating viral croup  Pneumonia may be primary (hematogenous) or secondary after viral infection (influenza) Staphylococci lead to necrotizing pneumonia and common complications are: pyopneumothorax, empyema, bronchopleural fistula, pneumatocele Staphylococci lead to necrotizing pneumonia and common complications are: pyopneumothorax, empyema, bronchopleural fistula, pneumatocele  Therapy: always should be initiated with penicillinase-resistant antibiotic – 90% of staphylococci are resistant to penicillin

17. Staphylococcal respiratory infections Recommended antibiotics:  Methicillin, nafcillin, oxacillin  Clindamycin, lincomycin  Vancomycin and its new generation derivative teikoplanine when bacteria are resistant to semisynthetic penicillins (MRSA) Reports of increasing incidence of Vancomycin- resistant strains (Scandinavia, Japan, USA)  Rifampicin  Imipenem  Ciprofloxacin and other quinolones  Trimethoprime-sulfamethoxazole

18. Pneumococcal pneumonia  Streptococcus pneumoniae is the most common cause of bacterial infections of the lungs although the incidence of pneumococcal pneumonia has declined over the last decades  In older children and adults clinical manifestations are typical: shaking chills, high fever, cough, chest pain, and development of lobar pneumonia Pleural effusion and empyema are typical complications  Therapy: drug of choice is penicillin in the dose 100 000 units/kg/24hr parenterally for 2-3 weeks

19. Aspiration pneumonia  Relationship between gastro-esophageal reflux, dysfunctional swallowing, therapy of respiratory disorders (theophylline, oral beta-agonists) and aspiration pneumonia  Superinfection with mouth flora- predominantly anaerobes occurs in previously healthy non-hospitalized patients Treatment: Clindamycin, penicillins  Chronically ill hospitalized patients may be infected with Gram-negative flora (Pseudomonas, Klebsiella, E.coli); in these patients additional coverage with aminoglycosides, imipenem or both is indicated

20. Pneumocystis carinii pneumonia  Epidemic form in infants between 3 and 6 mo  Sporadic form accounts for majority of cases; occurs in children and adults with primary (SCID, XLA) or secondary (AIDS) immunodeficiencies, malignancies (leukemia), organ transplant receipients  In immunocompromised hosts PCP, if untreated, is fatal within 3-4 weeks  Therapy: Trimethoprim (15-20 mg/kg/24hr) + sulfamethoxazole (75-100 mg/kg/24hr) iv for 2-4 weeks For patients who fail to respond to TP-SMX: Pentamidine isethionate 4 mg/kg/24hr 1x daily

21. Pneumocystis carinii pneumonia  Alternative treatment of PCP: Atovaquone and trimetexate glucuronate Trimethoprime and dapsone Clindamycin and primaquine  Chemoprophylaxis: Trimethoprim 5 mg/kg/24hr + sulfamethoxazole 25 mg/kg/24hr Pentamidine by aerosol Dapsone and pyrimethamine

22. Pulmonary aspergillosis Depending on the type of exposure and condition of the host, different pulmonary manifestation may ensue:  Allergic bronchopulmonary aspergillosis without infection or tissue invasion (the most common aspergillus-related disease), most cases in patients with chronic pulmonary disease (asthma, CF)  Allergic alveolitis in the case of ongoing exposure in allergic patients  Aspergillus pneumonia if the colonisation occurs and infection develops  Invasive disease or necrotizing pneumonia in immunodeficient patients  Aspergillus mycetoma resulting from infection of an extant cavity

23. Pulmonary aspergillosis Treatment:  Aerosolized amphotericin B or direct instillation of the drug into the trachea (Liposomal amphotericin Ambisome)  Systemic amphotericin B iv or 5- fluorocytosine  Itraconazole with systemic steroids

24. Recurrent bacterial pneumonias  Primary or secondary immunodeficiency  Cystic fibrosis  Ciliary dyskinesia  Tracheo-esophageal fistula  Cleft palate  Congenital bronchiectases  Gastro-esophageal reflux and aspiration syndromes  Increased pulmonary blood flow  Foreign body aspiration

25. Microbiologic implications  Streptococcus pneumoniae is the most important bacterial pathogen in all age groups, accounting for 30-70% of CAP  Mycoplasma pneumoniae is the causative agent in 20-30% of adults younger than age 35, but accounts for only 1-9% of CAP in older adults  Legionella pneumophila accounts for only 2-10% of CAP, but is second to pneumococcus as a cause of death from CAP  Chlamydia pneumoniae is implicated in 2- 8% of CAP, but severe pneumonias are rare with this pathogen  Haemophilus influenzae accounts for 5- 18% of CAP in adults with high rate in smokers with COPD

26. Microbiologic implications  Staphylococcus aureus accounts for 3-8% of CAP in adults, primarily in patients with risk factors and following influenza  Enteric Gram(-) rods, predominantly Enterobacteriaceae account for 3-8% of CAP; only in patients with comorbidities  Moraxella catarrhalis accounts for only 1- 2% of CAP; more common in patients with COPD  Viruses are implicated in 5-15% of CAP; most cases occur in winter months

27. Streptococcus pneumoniae  S. pneumoniae accounts for 30-70% of CAP and has been associated with most fatalities  S. pneumoniae can affect previously healthy individuals, but has a predilection for the elderly and for patients with preexisting disease  Outbreaks of severe, invasive infections may occur in nursing homes, chronic care facilities  S. pneumoniae is the leading cause of pneumonia in all age groups; empiric therapy for CAP should always cover S. pneumoniae  Penicillin-resistant and often multiply antibiotic- resistant strains are increasing and threaten the future efficacy of antibiotics

28. S. pneumoniae - antimicrobial resistance  Resistance to penicillins, tetracyclines, macrolides, trimethoprim/sulfamethoxazole, cephalosporins has increased dramatically over the past three decades  Resistance to antibiotics reflects the pattern of antibiotic use  Penicillin resistance is chromosomally mediated and results from alterations in penicillin-binding proteins  In France, Spain and Eastern Europe 15- 40% of pneumococci exhibit high-grade resistance to penicillin; in the USA high- grade resistance has only recently emerged and is estimated for 1-7%

29. S. pneumoniae - antimicrobial resistance  Risk factors for penicillin resistance: age under 6 yrs, prior use of beta-lactam antibiotics and nosocomial acquisition  Penicillin resistant strains are often resistant to tetracyclines, erythromycin and TMP/SMX  Resistance to quinolones is unrelated to penicillin susceptibility  Erythromycin resistant strains are resistant to other macrolides and are usually resistant to penicilline and tetracycline  Cephalosporin-resistant strains have also increased  Most penicillin- and erythromycin resistant strains remain susceptible to imipenem, cefotaxime amd ceftriaxone  In the USA 6-30% of pneumococci are resistant to tetracycline  All pneumococci are susceptible to vancomycin, irresspective of susceptibilities to other class of antibiotics

30. S. pneumoniae - preferred therapy  For susceptible strains or in areas where rates of of penicillin-resistance are low: -Penicillin G 4-10 million units iv -Penicillin V 500 mg q.i.d. orally  As empiric therapy when penicillin resistance is suspected: -Cefotaxime 1g q8hr or ceftriaxone 1g q24hr  For strains resistant to penicillin and cephalosporins: -Vancomycin (100% active) -Imipenem/cilastin (active against more than 90% of isolates)

31. S. pneumoniae - preferred therapy  Alternative agents: -macrolide antibiotic (eg. erythomycin, clarithromycin, azithromycin) -beta-lactams and clindamycin are usually active -tetracyclines and TMP/SMX inconsistent (6-30% are resistant)  Penicillin G is less expensive and less toxic than alternative agents and should be used for susceptible strains

32. Haemophilus influenzae  H. influenzae accounts for 5-18% of pneumonias, both community- and hospital-acquired  Both typeable (encapsulated, especially type b) and nontypeable (nonencapsulated) strains can cause the disease  H. influenzae is a common commensal- colonizes the oropharynx in 20-40% of healthy individuals  H. influenzae pneumonia and bronchitis characteristically affect smokers, elderly and debilitated patients, but may also afect previously healthy individuals

33. H. influenzae - antimicrobial susceptibility  Antimicrobial resistance has increased dramatically in the past three decades  By the early 1980s, beta-lactamase-producing ampicillin resistant strains emerged  Ist-generation cephalosporins and erythromycin are nor reliable – only 40-60% of strains are susceptible  The activity of tetracyclines is modest  More than 90% of strains are susceptible to TMP/SMX  Virtually all isolates are susceptible to : ampicillin/sulbactam, cefuroxime, IIIrd-generation cephalosporins, imipenem, fluoroquinolones, new macrolides, extended-spectrum penicillins

34. H. influenzae - preferred therapy  1st choice agents -ampicillin/sulbactam, cefuroxime or ceftriaxone -oral agents for mild infections or following initial parenteral therapy: amoxicillin/clavulanate, cefuroxime axetil, TMP/SMX  Alternative agents -TMP/SMX, fluoroquinolones -azithromycin or clarithromycin (activity of erythromycin is inconsistent) -ampicillin or amoxicillin (only for beta- lactamase negative strains)

35. Moraxella catarrhalis  M. catarrhalis is part of normal flora of the upper respiratory tract and is an important pathogen in otitis media, sinusitis and acute exacerbations of chronic bronchitis  M. catarrhalis accounts for 1-3% of CAP; most frequently in the winter months  More than 80% of lower respiratory tract infections caused by M. catarrhalis occur in patients with COPD or underlying diseases  Probably not important as a nosocomial pathogen

36. M. catarrhalis - antimicrobial susceptibility  The first beta-lactamase(penicillinase)-producing strains of M. catarrhalis were described in 1977; now 50-85% of isolates are resistant to penicillin  Penicillins with beta-lactamase inhibitors, TMP/SMX, macrolides, 2nd or 3rd generation cephalosporins, tetracycline, fluoroquinolones are active against beta-lactamase positive or negative strains  Beta-lactamase negative strains are susceptible to penicillin, ampicillin and beta-lactams  Beta-lactamase producing M. catarrhalis may confer antimicrobial resistance among coinfecting pathogens (a phenomenon of indirect pathogenicity) resulting in clinical resistance of beta-lactamase negative strains of H. influenzae and Strep. pneumoniae

37. M. catarrhalis - preferred therapy  1st choice therapy -cefuroxime -ampicillin/sulbactam or amoxicillin/clavulanate  Alternative agents -tetracycline-TMP/SMX-macrolide-fluoroquinolones

38. Atypical pneumonias  Mycoplasma pneumoniae  Chlamydia pneumoniae  Legionella pneumophila  Viruses Other  Pneumocystis carinii  Chlamydia trachomatis  Rickettsiae  Fungi

39. Respiratory manifestations of mycoplasmal infection  Pharyngitis  Sinusitis  Myringitis  Otitis media  Croup  Bronchitis  Bronchiolitis  Bronchopneumonia  Pneumonia with pleural effusion

40. Mycoplasma pneumoniae  M. pneumoniae accounts for 2-14% of CAP  M. pneumoniae has a striking predilection for younger patients; often spares older individuals  M. pneumoniae accounts for 20-30% of CAP in adolescents and adults younger than age 35; 2-9% of CAP among adults age 40-60 and only 1% of pneumonias in adults over age 60  Epidemics of M. pneumoniae infections may occur in families, schools, institutions; prolonged contact is necessary for transmission of infection  Pneumonia caused by M. pneumoniae occurs in only 3-10% of exposed individuals  M. pneumoniae is rarely implicated as a nosocomial pathogen

41. Characteristic features of Mycoplasma pneumoniae lower airway infection  Infections occur throughout the year  The occurence of mycoplasmal illness is closely related to the patient’s age: -mild or subclinical infections in children younger than 4 yrs -the peak incidence in schoolchildren 5-15 yrs of age  Recurrent infections in adults every 4-7 yrs  Respiratory route of infection  Incubation period 1-3 wk  Gradual onset of the respiratory illness: headache, general malaise, upper airway infection symptoms, dyspnea, dry hacking cough intensifying in the course of the disease, fever  The severity of symptoms usually greater than the condition suggested by the physical signs

42. M. pneumoniae – preferred therapy  Because Mycoplasma spp. lack a cell wall, beta-lactams and other cell-wall active antibiotics have no significant activity  1st choice therapy -macrolide antibiotic (erythromycin, azithromycin, clarithromycin) -doxycycline 100 mg bid orally or iv  Alternative agents -fluoroquinolones (ciprofloxacin, ofloxacin)

43. Nonrespiratory manifestations of mycoplasmal infection  Skin: -erythema multiforme -maculopapular rush -Stevens-Johnson syndrome  CNS: -meningoencephalitis -aseptic meningitis -transverse myelitis -cerebellar ataxia -Guillain-Barre syndrome  Blood: -hemolytic anaemia -thrombocytopenia -coagulation defects

44. Nonrespiratory manifestations of mycoplasmal infection  Gastrointestinal tract -hepatitis-pancreatitis -protein-losing hypertrophic gastropathy  Cardiovascular system -myocarditis-pericarditis -cardiac dilatation with heart failure  Joints -monoarticular transient arthritis

45. Chlamydia pneumoniae  Within the genus Chlamydia there are three species recognized: Ch.pneumoniae, Ch.psittacci, Ch.trachomatis  Clinical features are similar to M. pneumoniae; fever and cough occur in 50- 80% of patients  Infections are often asymptomatic (antichlamydial antibodies present in 26% of schoolchildren)  Associations of Chlamydia infections and coronary artery disease, carotid atherosclerosis, asthma, sarcoidosis have been suggested  Ch. pneumoniae may be an important infection trigger for asthma, CF and COPD

46. Chlamydia pneumoniae – preferred therapy  Beta-lactams and aminoglycosides have no activity  Tetracyclines and macrolids may shorten the duration of illness  Preferred therapy: -doxycycline or tetracycline orally for 14- 21 days  Alternative agents: -oral macrolides -fluoroquinolones  Empiric therapy with tetracyclines should be considered for patients with protracted bronchitis or CAP refractory to beta- lactams

47. Legionella pneumophila  Legionella spp. are endemic in the community, accounting for 2-10% of CAP; nosocomial legionellosis is rare in most hospitals  Risk factors for legionellosis and more severe disease include advanced age, renal failure, cigarette smoking, ethanol abuse, organ transplantation, corticosteroids and severe underlying disease  Clinically pneumonia caused by Legionella is indistinguishable from other bacterial pneumonias; common feture of CAP caused by Legionella is progression of pneumonia while taking antimicrobials

48. Legionella pneumophila – preferred therapy  Beta-lactams and aminoglycosides are not active against Legionella  1st choice antibiotics: -intravenous erythromycin 1g q6hr iv; substitute oral erythromycin 500mg qid following clinical improvement and defervescence for 21 days -rifampin may be synergistic in combination with erythromycin in immunocompromised hosts  Alternative therapy -clarithromycin 500-1000mg bid for 21 days -ciprofloxacin 750mg bid or ofloxacin 400mg bid for 21 days

49. Empiric (initial) therapy for CAP  In most cases of pneumonia therapy is empiric  Initial treatment of CAP should be -sufficiently broad to cover most likely pathogens -avoiding polypharmacy and toxic or excessively expensive antimicrobials  Choice of empiric therapy should be modified based on clinical features as: -age -the presence of underlying disease -radiographic appearance -prior use of antimicrobials -severity of pneumonia

50. Empiric (initial) therapy for CAP  Parenteral antibiotics are preferred as initial therapy in neonates, infants and children with serious associated disease  Other factors warranting parenteral therapy include: respiratory distress, multilobar pneumonia, hypoxemia, hypotension, non- compliance  Oral therapy should be reserved for patients: -presenting no gastrointestinal symptoms that preclude predictable oral absorption -clinically not toxic, hypotensive, severely ill -presenting pneumonia confined to a segment or bronchopneumonia -with no prior underlying disease

51. Empiric (initial) therapy for CAP Empiric strategies for CAP patients with no comorbidities Mild CAP not requiring hospitalization:  Penicillin or ampicillin may be adequate for Strep. pneumoniae in communities where the rate of penicillin resistant pneumococci is low  2nd generation oral cephalosporin or amoxicillin/ clavulanate  Oral macrolide antibiotic is also recommended: covers atypicals, Strep. pneumoniae and most strains of H. influenzae  Activity of fluoroquinolones against Strep. pneumoniae is modest

52. Empiric (initial) therapy for CAP Moderate CAP requiring hospitalization  Iv ampicillin/sulbactam, cefuroxime, ceftriaxone or cefotaxime plus an oral macrolide  Ofloxacin for penicillin-allergic patients Severe life threatening or multilobar CAP requiring hospitalization  Ceftriaxone plus high-dose iv erythromycin  Ceftriaxone plus iv fluoroquinolone (ofloxacin, ciprofloxacin)  Piperacillin/tazobactam plus iv eythromycin  Piperacillin/tazobactam plus a fluoroquinolone  Fluoroquinolone (ofloxacin, ciprofloxacin) for penicillin-allergic patients

53. Anaerobic pleuropulmonary infections  Anaerobes may have a primary role in a spectrum of pleuropulmonary syndromes: acute pneumonitis, necrotizing pneumonia with cavitation, lung abscess, empyema  Anaerobes have been implicated as either sole or concomittant pathogens in 70-97% of aspiration pneumonias or primary lung abscess  In aspiration occuring in the comunity, streptococci, H. influenzae and anaerobes may be involved  Aspiration pneumonia in patients in hospitals and with comorbidities may include an admixture of anaerobes and enteric Gram negative bacilli

54. Antibacterial susceptibility of anaerobes  Bacteroides fragilis and virtually all anaerobes are susceptible to: imipenem, metronidazole, extended-spectrum penicillins with beta- lactamase inhibitors  Clindamycin is active against most anaerobes  Penicillin G and ampicillin have exquisite activity against normal oral anaerobes, but more than 90% of B. fragilis are resistant  Activity of cephalosporins against anaerobes is modest; the most active are cephamycins (cefotetan, cefoxitin)  Aztreonam, fluoroquinolones, TMP/SMX have poor anaerobic activity

55. Preferred therapy for community-acquired lung abscess and aspiration pneumonia  Community-acquired aspiration pneumonia or lung abscess in patients without serious associated diseases can be treated with narrow- spectrum agents:  Penicillin G for uncomplicated cases  Clindamycin for complicated lung abscess or penicillin failure  Ampicillin/sulbactam when concomittant infection with enteric Gram(-) bacilli suspected  Oral antibiotics (penicillin V, clindamycin, amoxicillin/clavulanate) may be substituted following clinical response to parenteral therapy  Alternatively: cefotetan and extended-spectrum penicillins with beta-lactamase inhibitors when infection with Gram(-) enteric bacilli coexists

56. Nosocomial pneumonia  Pneumonia develops in 0,5-2% of hospitalized patients and has been associated with mortality rate of 30-60%  Aerobic enteric Gram(-) bacilli are responsible for 65-85% of nosocomial pneumonias  Enterobacteriaceae (Klebsiella, Enterobacter) account for 30-50% of nosocomial pneumonias  15-20% are caused by Pseudomonas aeruginosa  Staphylococci and streptococci account for 10-25% of cases, usually in the context of polymicrobial pneumonia  Sporadic cases and epidemic outbreaks of nosocomial pneumonia are caused by Legionella, Pneumocystis carinii, Mycobacterium tuberculosis, viruses and invasive fungi  Anaerobes are less important as primary pathogens, but may coexist in polymicrobial infections

57. Acinetobacter sp.  Acinetobacter accounts for only 1-3% of nosocomial pneumonias, but the rate is higher- 5-15% in mechanically ventilated ICU patients primarily newborns  Mortality rates for Acinetobacter pneumonia exceed 50%  Antimicrobial susceptibility: - Acinetobacter are highly resistant to multiple antibiotics: ampicillin, 1st and 2nd generation cephalosporins and in a lesser extent to aminoglycosides - Activity of 3rd generation cephalosporins is variable

58. Acinetobacter – preferred therapy  1st choice agents: -imipenem/cilastatin, antipseudomonal penicillins, ceftazidime in combination with aminoglycosides to confer synergy  Alternative agents: -TMP/SMX, fluoroquinolones may be active but variable  Choice of agent should depend on results of susceptibility testing

59. Klebsiella pneumoniae  K. pneumoniae accounts for 5-9% of nosocomial pneumonias and for 1-5% of CAP in debilitated patients  High rate of bacteriemia and and suppurative complications are noted  Antimicrobial susceptibility: - Resistant to penicillin and ampicillin - Highly susceptible to cefuroxime, 3rd generation cephalosporins, imipenem, aztreonam, fluoroquinolones, aminoglycosides, TMP/SMX - Klebsiella pneumoniae producing plasmid- mediated extended spectrum beta-lactamases that confer resistance to ceftazidime have been isolated in Europe and in the USA

60. Klebsiella pneumoniae – preferred therapy  1st choice antibiotics: -2nd or 3rd generation cephalosporins -aminoglycosides may be added for synergy in fulminant or refractory cases  Alternative agents: -imipenem, fluoroquinolone, aztreonam, TMP/SMX  Epidemics of infections caused by beta- lactamase producing K. pneumoniae correlate with extensive use of cephalosporin monotherapy and may be curtailed by switching to extended- spectrum penicillins or imipenem/cilastatin

61. Pseudomonas aeruginosa  P. aeruginosa accounts for 15-20% of nosocomial pneumonias; the rates are even higher in ventilated ICU patients (20- 30%)  P. aeruginosa is a rare cause of CAP except among patients with specific risk factors: bronchiectasis, CF, tracheostomy, granulocytopenia, immunosuppressive or corticosteroid therapy, iv drug abuse  Mortality from P. aeruginosa pneumonia is 50-70%  In 30-50% of patients relapses or antimicrobial resistance develops

62. P. aeruginosa – antimicrobial susceptibility  P. aeruginosa is resistant to most antibiotics  Antipsedomonal penicillins are active against 80-95% of strains; piperacillin is the most potent  Among cephalosporins only ceftazidime and cefoperazone are considered active  Other agents with antipseudomonal activity include imipenem, aztreonam, ciprofloxacin and aminoglycosides  Piperacillin and ceftazidime in combination with an aminoglycoside are preferred therapy; imipenem/cilastatin or ciprofloxacin should be reserved for infections resistant to beta-lactams

63. P. aeruginosa – preferred therapy  The preferred therapy is piperacillin or ceftazidime in combination with aminoglycoside  Imipenem in combination with aminoglycoside should be reserved for resistant strains  Alternative agents: ciprofloxacin or aztreonam combined with aminoglycoside  Imipenem or ciprofloxacin used as monotherapy may lead to rapid development of resistance  Aminoglycosides are inadequate as single agents but are important to confer with synergistic killing

64. Staphylococcus aureus  Coagulase-positive Staph. aureus may cause both community- and hospital-acquired pneumonia  Staphylococci rarely cause CAP in previously healthy hosts; specific risk factors include: influenza, diabetes mellitus, iv drug abuse, iv lines and catheters, malignancies  Staph. aureus accounts for 15-30% of nosocomial pneumonia; these infections are often polymicrobial  15-40% of nosocomial isolates are methicillin- resistant (MRSA); risk factors for acquisition of MRSA include: prior antibiotic use, prior nasal carriage, transmission from medical personnel, trauma, diabetes, renal failure, burns and use of corticosteroids  Prognosis for pneumonia depends on the severity and extend of comorbidities: mortality rates for pneumonia caused by methicillin-sensitive Staph. aureus range from 5 to 15%, in patients with MRSA may exceed 40%

65. Common complications of staphylococcal pneumonia  Empyema  Pyopneumothorax  Pneumatoceles  Bronchopleural fistula  Septic lesions in other organs  Metastatic abscesses in soft tissues

66. Staph. aureus – antimicrobial susceptibility  Most isolates are resistant to penicillin and ampicillin, but are susceptible to antistaphylococcal penicillins: oxacillin, nafcillin, cloxacillin and cefazolin  Ceftazidime has only modest activity against staphylococci  MRSA is resistant to all beta-lactams  The antipseudomonal penicillins and imipenem/cilastin are active against methicillin-sensitive strains  Clindamycin, fluoroquinolones or TMP/SMX may be active against methicillin-sensitive or methicillin-resistant strains, but this is variable

67. Methicillin-resistant Staph. aureus – antimicrobial susceptibility  Methicillin resistance results from alterations of PBPs, which also confer resistance to cephalosporins  MRSA strains are commonly resistant to other classes of antibiotics: erythromycin, clindamycin, tetracycline, aminoglycosides  Vancomycin is highly active against MRSA strains and is the drug of choice; teicoplanin has similar activity, less toxicity and a longer half-life  Clindamycin, quinolones, TMP/SMX may be used to treat some strains of MRSA

68. Staph. aureus –preferred therapy Methicillin-susceptible Staph. aureus:  Preferred therapy -oxacillin or cloxacillin only for monomicrobial infections caused by methicillin-susceptible strains -vancomycin uniformly active for both methicillin-susceptible and resistant strains  Alternative agents: cefazolin, clindamycin, imipenem Methicillin-resistant Staph. aureus:  Preferred therapy: vancomycin  Alternatively for patients intolerant of vancomycin: clindamycin, imipenem, TMP/SMX

69. Empiric therapy for nosocomial pneumonia  Monotherapy with broad-spectrum beta-lactams -Monotherapy with ceftazidime, cefoperazone or imipenem/cilastin is associated with favorable response in 65-88% of cases of nosocomial pneumonia - Alternative agents: antipseudomonal penicillins/ beta-lactamase inhibitors, imipenem/ cilastin - In nosocomial pneumonias when Pseudomonas aeruginosa, Acinetobacter or Serratia is a causative agent, monotherapy is associated with high rate of clinical and bacteriologic failure and is not recommended - Monotherapy with beta-lactam may be adequate for nosocomial pneumonia caused by E. coli, Klebsiella and Proteus  Combination of beta-lactams with aminoglycosides limits the emergence of antimicrobial resistance and ensures synergistic microbicidal activity

70. Pulmonary complications of HIV infection  Viral CMV, RSV, HSV, Parainfluenza, Influenza, Adenovirus  Bacterial Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Mycobacterium avium- intracellulare complex  Fungal Pneumocystis carinii, Candida, Aspergillus, Histoplasma, Cryptococcus, Coccidioides

71. Conditions leading to or mimicking pneumonia  Aspiration syndromes  Inhalation of toxic fumes, burn injuries  Radiation injury  Drug-induced pulmonary disease  Alveolitis (hypersensitivity pneumonitis)  ARDS  Haemosiderosis and pulmonary haemorrhage  Prominent or persistent thymus beyond the age of 4 yrs  Congenital abnormalities  Bronchiolitis obliterans organizing pneumonia  Connective tissue diseases, granulomatous vasculitides  Pulmonary embolism  Pulmonary edema  Pulmonary neoplasms

72.  Thank you for your attention