Antibiotic strategy in lower respiratory tract infections

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  • 1. Antibiotic Strategy in Lower Respiratory Tract Infections Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
  • 2. ANTIMICROBIAL DRUGS
  • 3. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Mechanism of action include:      Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis Inhibition of metabolic pathways Interference with cell membrane integrity
  • 4. A n tib a c te ria l sp e c tru m — R a n g e o f a ctiv ity o f a n a n tim ic rob ia l a g a in s t b ac te ria . A b ro a d -s p ec trum a n tib ac te ria l d ru g c a n in h ib it a w id e v a rie ty o f g ram -p os itiv e a nd g ram -ne g a tiv e b ac teria , w h ere as a n a rro w -sp e ctru m d ru g is ac tiv e o n ly a g a in s t a lim ite d v arie ty o f b a c te ria . A n tib io tic co m b in a tio n s — C om b in a tio n s o f a n tib io tic s th a t m a y b e u s e d (1) to b ro a d e n th e a n tib a c teria l s p ec trum fo r em p iric th e ra p y o r th e tre a tm e n t o f p o lym icro b ia l in fe c tio n s , (2 ) to p rev e n t the em erg e n ce o f re s is ta n t org a n ism s d urin g th era p y, a n d (3 ) to a c h iev e a s yn e rg is tic k illin g e ffe c t. B a c te rio s tatic a ctivity— -T h e lev e l o f a n tim icro-b ia l a c tiv ity th a t in h ib its th e g ro w th o f a n o rg an ism . T h is is d e te rm ine d in v itro b y te s tin g a s ta n d a rd ize d c o nc e n tra tio n of o rg a n ism s a g a in st a s e ries o f a n tim icro b ia l d ilu tio n s . T h e lo w e s t c o nc e n tratio n th a t in h ib its th e g ro w th o f th e o rga n ism is re ferred to as th e m in im u m in h ib ito ry c o n c e n tra tio n (M IC ). A n tib io tic s yn e rg is m — C om b in a tio n s o f tw o a n tib io tic s th a t h av e e n h a nc e d b a c teric id a l a c tiv ity w h e n te s te d to g e the r c om p are d w ith th e a c tiv ity o f e a c h a n tib io tic . B a c te ric id a l a ctivity— T h e le v e l o f a n tim icro b ia l a c tiv ity th a t k ills th e te s t o rg a n ism . T h is is d e term in e d in v itro b y e xp o s in g a s ta n d a rd ize d c o nc e n tratio n o f o rg a n ism s to a s erie s of a n tim icro b ia l d ilu tio n s . T h e lo w es t c o nc e n tratio n th a t k ills 9 9 .9 % o f th e p o p u la tio n is re ferre d to a s th e m in im u m b a c te ric id a l c o n c en tratio n (M B C ). A n tib io tic an ta g o n ism — C om b in a tio n o f a n tib io tic s in w h ic h th e ac tiv ity o f o n e a n tib io tic in te rfe res W ith th e ac tiv ity o f th e o th e r (e.g ., th e s um o f th e a ctiv ity is le s s th a n th e a ctiv ity o f th e in d iv id u a l d ru g s). B e ta-la c tam a s e — A n e n zym e th a t h yd ro lyze s th e b e ta -la c tam rin g in th e b e ta -la c tam c lass o f a n tib io tics , th u s in a c tiv a tin g th e a ntib io tic . T h e en zym e s s p ec ific fo r p e n ic illin s a n d c e p h a lo s po rins a re t h e p e n ic illin a s e s a n d c e p h a lo sp o rin a s e s , re sp e c tiv e ly.
  • 5. Minimal Inhibitory Concentration (MIC) vs. Minimal Bactericidal Concentration (MBC) 32 ug/ml 16 ug/ml 8 ug/ml Sub-culture to agar medium 4 ug/ml 2 ug/ml 1 ug/ml MIC = 8 ug/ml MBC = 16 ug/ml REVIEW
  • 6. EFFECTS OF COMBINATIONS OF DRUGS Sometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone.  This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter. 
  • 7. EFFECTS OF COMBINATIONS OF DRUGS Other combinations of drugs can be antagonistic.  For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth. 
  • 8. EFFECTS OF COMBINATIONS OF DRUGS  Combinations of antimicrobial drugs should be used only for: 1. 2. 3. To prevent or minimize the emergence of resistant strains. To take advantage of the synergistic effect. To lessen the toxicity of individual drugs.
  • 9. Resistance Physiological Mechanisms 1. Lack of entry – tet, fosfomycin 2. Greater exit  efflux pumps  tet (R factors) 3. Enzymatic inactivation  bla (penase) – hydrolysis  CAT – chloramphenicol acetyl transferase  Aminogylcosides & transferases REVIEW
  • 10. Resistance Physiological Mechanisms (cont’d) 4. Altered target     RIF – altered RNA polymerase (mutants) NAL – altered DNA gyrase STR – altered ribosomal proteins ERY – methylation of 23S rRNA 5. Synthesis of resistant pathway  TMPr plasmid has gene for DHF reductase; insensitive to TMP REVIEW
  • 11. The Ideal Drug* 1. Selective toxicity: against target pathogen but not against host  LD50 (high) vs. MIC and/or MBC (low) 2. Bactericidal vs. bacteriostatic 3. Favorable pharmacokinetics: reach target site in body with effective concentration 4. Spectrum of activity: broad vs. narrow 5. Lack of “side effects”  Therapeutic index: effective to toxic dose ratio 6. Little resistance development
  • 12. Management of Adult Lower Respiratory Tract Infections The Consensus Statement of the Egyptian Scientific Society of Bronchology
  • 13. Gamal Rabie Agmy, MD, FCCP
  • 14. Pneumonias – Classification CAP HCAP • Health Care Associated HAP • Hospital Acquired ICUAP • ICU Acquired VAP 17 • Community Acquired • Ventilator Acquired Nosocomial Pneumonias
  • 15. Community Acquired Pneumonia (CAP)  Definition … an acute infection of the pulmonary parenchyma that is associated with some symptoms of acute infection, accompanied by the presence of an acute infiltrate on a chest radiograph, or auscultatory findings consistent with pneumonia, in a patient not hospitalized or residing in a long term care facility for > 14 days before onset of symptoms. 18 Bartlett. Clin Infect Dis 2000;31:347-82.
  • 16. Guidelines for CAP  American Thoracic Society (ATS)  Guidelines - Management of Adults with CAP (2001)  Infectious Diseases Society of America (IDSA)  Update of Practice Guidelines Management of CAP in Immuno-competent adults (2003)  ATS and IDSA joint effort (we will follow this)  IDSA/ATS Consensus Guidelines on the Management of CAP in Adults (March 2007) 19
  • 17. CAP – The Two Types of Presentations Classical • • • • • • • Sudden onset of CAP High fever, shaking chills Pleuritic chest pain, SOB Productive cough Rusty sputum, blood tinge Poor general condition High mortality up to 20% in patients with bacteremia • S.pneumoniae causative 20 Atypical • • • • • Gradual & insidious onset Low grade fever Dry cough, No blood tinge Good GC – Walking CAP Low mortality 1-2%; except in cases of Legionellosis • Mycoplasma, Chlamydiae, Legionella, Ricketessiae, Viruses are causative
  • 18. CAP – Pathogenesis Inhalation Aspiration Hematogenous 21
  • 19. CAP – Risk Factors for Pneumonia        22 Age Obesity; Exercise is protective Smoking, PVD Asthma, COPD Immuno-suppression, HIV Institutionalization, Old age homes etc Dementia ID Clinics 1998;12:723. Am J Med 1994;96:313
  • 20. Streptococcus pneumonia (Pneumococcus)  Most common cause of CAP  About 2/3 of CAP are due to S.pneumoniae  These are gram positive diplococci  Typical symptoms (e.g. malaise, shaking chills fever, rusty sputum, pleuritic chest pain, cough)  Lobar infiltrate on CXR  May be Immuno suppressed host  25% will have bacteremia – serious effects 23
  • 21. CAP – Special Features – Pathogen wise Typical – S.pneumoniae, H.influenza, M.catarrhalis – Lungs Blood tinged sputum - Pneumococcal, Klebsiella, Legionella H.influenzae CAP has associated of pleural effusion S.Pneumoniae – commonest – penicillin resistance problem S.aureus, K.pneumoniae, P.aeruginosa – not in typical host S.aureus causes CAP in post-viral influenza; Serious CAP K.pneumoniae primarily in patients of chronic alcoholism P.Aeruginosa causes CAP in pts with CSLD or CF, Nosocom Aspiration CAP only is caused by multiple pathogens Extra pulmonary manifestations only in Atypical CAP 24
  • 22. S. aereus CAP – Dangerous  This CAP is not common; Multi lobar Involvement  Post Influenza complication, Class IV or V  Compromised host, Co-morbidities, Elderly  CA MRSA – A Problem; CA MSSA also occurs  Empyema and Necrosis of lung with cavitations  Multiple Pyemic abscesses, Septic Arthritis  Hypoxemia, Hypoventilation, Hypotension common  Vancomycin, Linezolid are the drugs for MRSA 25
  • 23. CAP – Risk Factors for Hospitalization  Older, Unemployed, Unmarried  Recurrent common cold  Asthma, COPD; Steroid or bronchodilator use  Chronic diseases, Diabetes, CHF, Neoplasia  Amount of smoking  Alcohol is NOT related to increased risk for hospitalization 26 ID Clinics 1998;12:723. Am J Med 1994;96:313
  • 24. CAP – Risk Factors for Mortality  Age > 65  Bacteremia (for S. pneumoniae)  S. aureus, MRSA , Pseudomonas  Extent of radiographic changes  Degree of immuno-suppression  Amount of alcohol consumption 27 ID Clinics 1998;12:723. Am J Med 1994;96:313
  • 25. CAP – Evaluation of a Patient Hx. PE, CXR No Infiltrate Alternate Dx. Infiltrate or Clinical evidence of CAP Evaluate need for Admission Out Patient 28 PORT & CURB 65 Medical Ward ICU Adm.
  • 26. CAP – Management Guidelines  Rational use of microbiology laboratory  Pathogen directed antimicrobial therapy whenever possible  Prompt initiation of Antibiotic therapy  Decision to hospitalize based on prognostic criteria - PORT or CURB 65 29
  • 27. Clinical Parameter Scoring Clinical Parameter Age in years Example Clinical Findings For Men (Age in yrs) 50 Altered Sensorium 20 points For Women (Age -10) (50-10) Respiratory Rate > 30 20 points NH Resident 10 points SBP < 90 mm 20 points Temp < 350 C or > 400 C 15 points Pulse > 125 per min 10 points Co-morbid Illnesses Neoplasia 30 points Liver Disease 20 points CHF 10 points CVD 10 points Renal Disease (CKD) 10 points PORT Scoring – PSI Pneumonia Patient Outcomes Research Team (PORT) 30 Scoring Investigation Findings Arterial pH < 7.35 30 points BUN > 30 20 points Serum Na < 130 20 points Hematocrit < 30% 10 points Blood Glucose > 250 10 points Pa O2 10 points X Ray e/o Pleural Effusion 10 points
  • 28. Classification of Severity - PORT Class I Predictors Absent Class IV 31 Class II 91 - 130  70 Class V Class III > 130 71 – 90
  • 29. CAP – Management based on PSI Score PORT Class PSI Score Mortality % Treatment Strategy Class I No RF 0.1 – 0.4 Out patient Class II  70 0.6 – 0.7 Out patient Class III 71 - 90 0.9 – 2.8 Brief hospitalization Class IV 91 - 130 8.5 – 9.3 Inpatient Class V > 130 27 – 31.1 IP - ICU 32
  • 30. CURB 65 Rule – Management of CAP CURB 65 Confusion BUN > 30 RR > 30 BP SBP <90 DBP <60 Age > 65 33 CURB 0 or 1 Home Rx CURB 2 Short Hosp CURB 3 Medical Ward CURB 4 or 5 ICU care
  • 31. Who Should be Hospitalized? Class I and II Usually do not require hospitalization Class III May require brief hospitalization Class IV and V Usually do require hospitalization Severity of CAP with poor prognosis RR > 30; PaO2/FiO2 < 250, or PO2 < 60 on room air Need for mechanical ventilation; Multi lobar involvement Hypotension; Need for vasopressors Oliguria; Altered mental status 34
  • 32. CAP – Criteria for ICU Admission Major criteria  Invasive mechanical ventilation required  Septic shock with the need of vasopressors Minor criteria (least 3)  Confusion/disorientation  Blood urea nitrogen ≥ 20 mg%  Respiratory rate ≥ 30 / min; Core temperature < 36ºC  Severe hypotension; PaO2/FiO2 ratio ≤ 250  Multi-lobar infiltrates  WBC < 4000 cells; Platelets <100,000 35
  • 33. CAP – Laboratory Tests • CXR – PA & lateral • CBC with Differential • BUN and Creatinine • FBG, PPBG • Serum electrolytes • Liver enzymes • Gram stain of sputum • Culture of sputum • Pre Rx. blood cultures • Oxygen saturation 36
  • 34. CAP – Value of Chest Radiograph • Usually needed to establish diagnosis • It is a prognostic indicator • To rule out other disorders • May help in etiological diagnosis J Chr Dis 1984;37:215-25 37
  • 35. Infiltrate Patterns and Pathogens CXR Pattern Possible Pathogens Lobar S.pneumo, Kleb, H. influ, Gram Neg Patchy Atypicals, Viral, Legionella Interstitial Viral, PCP, Legionella Cavitatory Anerobes, Kleb, TB, S.aureus, Fungi Large effusion Staph, Anaerobes, Klebsiella 38
  • 36. Normal CXR & Pneumonic Consolidation 39
  • 37. Lobar Pneumonia – S.pneumoniae 40
  • 38. CXR – PA and Lateral Views 41
  • 39. Lobar versus Segmental - Right Side 42
  • 40. Lobar Pneumonia 43
  • 41. Special forms of Consolidation 44
  • 42. Round Pneumonic Consolidation 45
  • 43. Special Forms of Pneumonia 46
  • 44. Special Forms of Pneumonia 47
  • 45. Complications of Pneumonia 48
  • 46. Empyema 49
  • 47. Mycoplasma Pneumonia 50
  • 48. Mycoplasma Pneumonia 51
  • 49. Chlamydia Trachomatis 52
  • 50. Rare Types of Pneumonia 53
  • 51. Pneumonia Posterior intercostal scan shows a hypoechoic consolidated area that contains multiple echogenic lines that represent an air bronchogram.
  • 52. Post-stenotic pneumonia Posterior intercostal scan shows a hypoechoic consolidated area that contains anechoic, branched tubular structures in the bronchial tree (fluid bronchogram).
  • 53. Contrast-enhanced ultrasonography of pneumonia A: Baseline scan shows a hypoechoic consolidated area B: Seven seconds after iv bolus of contrast agent, the lesion shows marked and homogeneous enhancement C: The lesion remains substantially unmodified after 90 s.
  • 54. CAP – Gram’s Stain of Sputum Good sputum samples is obtained only from 39% 83% show only one predominant organism Efficiency of test S. pneumoniae H. influenza Sensitivity 82 % Specificity 97 % 99 % Positive Predictive Value 95 % 93 % Negative Predictive Value 61 57 % 71 % 96 %
  • 55. Mortality of CAP – Based on Pathogen  P. aeruginosa  K. pneumoniae - 35.7 %  S. aureus - 31.8 %  Legionella - 14.7 %  S. pneumoniae - 12.0 %  C. pneumoniae - 9.8 %  H. influenza 62 61.0 % 7.4 %
  • 56. Antibiotics of choice for CAP Macrolide -M • Azithromycin • Clarithromycin • Erythromycin • Telithromycin • Doxycycline 63 Fluroquinolone-FQ • Levofloxacin Betalactum B • Moxifloxacin • Ceftriaoxone • Cefotaxime • Gemifloxacin • B Inhibitor BI • Trovafloxacin • Sulbactam • Tazobactam • Piperacillin
  • 57. Antibiotic Dosage, Route, Frequency and Duration Doxyclycline 100-200 mg PO/IV BID for 7 to 10 days Azithromycin 500 mg OD IV –3 days + 500 mg OD PO for 7-10 days Clarithromycin 250 – 500 mg BID PO for 7 – 14 days Telithromycin 800 mg PO OD for 7 – 10 days Levofloxacin 750 mg PO/IV OD for 5 days Moxifloxacin 400 mg PO or IV OD for 5 to 7 days Gemifloxacin 320 mg PO OD for 5 – 7 days Amoxyclav 2 g of Amoxi +125 mg of Clauv PO BID for 7 to 10 days Ceftriaxone 2 g IV BID for 3 to 5 days + PO 3G CS Ertapenum 1 g OD IV or IM for 7 to 14 days 64
  • 58. Empiric Treatment – Outpatient Healthy and no risk factors for DR S.pneumoniae 1. Macrolide or Doxycycline Presence of co-morbidities, use of antimicrobials within the previous 3 months, and regions with a high rate (>25%) of infection with Macrolide resistant S. pneumoniae 1. Respiratory FQ – Levoflox, Gemiflox or Moxiflox 2. Beta-lactam (High dose Amoxicillin, AmoxicillinClavulanate is preferred; Ceftriaxone, Cefpodoxime, Cefuroxime) plus a Macrolide or Doxycycline 65
  • 59. Empiric Treatment – Inpatient – Non ICU 1. A Respiratory Fluoroquinolone (FQ) or 2. A Beta-lactam plus a Macrolide (or Doxycycline) (Here Beta-lactam agents are 3 Generation Cefotaxime, Ceftriaxone, Amoxiclav) 3. If Penicillin-allergic Respiratory FQ or Ertapenem is another option 66
  • 60. Empiric Treatment: Inpatient in ICU 1. A Beta-lactam (Cefotaxime, Ceftriaxone, or Ampicillin-Sulbactam) plus either Azithromycin or Fluoroquinolone 2. For penicillin-allergic patients, a respiratory Fluoroquinolone and Aztreonam 67
  • 61. Empiric Rx. – Suspected Pseudomonas 1. Piperacillin-Tazobactam, Cefepime, Carbapenums (Imipenem, or Meropenem) plus either Cipro or Levo 2. Above Beta-lactam + Aminoglycoside + Azithromycin 3. Above Beta-lactam + Aminoglycoside + an antipseudomonal and antipneumococcal FQ 4. If Penicillin allergic - Aztreonam for the Beta-lactam 68
  • 62. Empiric Rx. – CA MRSA For Community Acquired Methicillin-Resistant Staphylococcus aureus (CA-MRSA)  Vancomycin or Linezolid Neither is an optimal drug for MSSA  For Methicillin Sensitive S. aureus (MSSA) B-lactam and sometimes a respiratory Fluoroquinolone, (until susceptibility results).  Specific therapy with a penicillinase-resistant semisynthetic penicillin or Cephalosporin 69
  • 63. Duration of Therapy • Minimum of 5 days • Afebrile for at least 48 to 72 h • No > 1 CAP-associated sign of clinical instability • Longer duration of therapy If initial therapy was not active against the identified pathogen or complicated by extra pulmonary infection 70
  • 64. Strategies for Prevention of CAP • Cessation smoking • Influenza Vaccine (Flu shot – Oct through Feb) It offers 90% protection and reduces mortality by 80% • Pneumococcal Vaccine (Pneumonia shot) It protects against 23 types of Pneumococci 70% of us have Pneumococci in our RT It is not 100% protective but reduces mortality Age 19-64 with co morbidity of high for pneumonia Above 65 all must get it even without high risk 71 • Starting first dose of antibiotic with in 4 h & O2 status
  • 65. Switch to Oral Therapy  Four criteria     Improvement in cough, dyspnea & clinical signs Afebrile on two occasions 8 h apart WBC decreasing towards normal Functioning GI tract with adequate oral intake  If overall clinical picture is otherwise favorable, hemodynamically stable; can switch to oral therapy while still febrile. 72
  • 66. Management of Poor Responders  Consider non-infectious illnesses  Consider less common pathogens  Consider serologic testing  Broaden antibiotic therapy  Consider bronchoscopy 73
  • 67. CAP – Complications  Hypotension and septic shock  3-5% Pleural effusion; Clear fluid + pus cells  1% Empyema thoracis pus in the pleural space  Lung abscess – destruction of lung - CSLD  Single (aspiration) anaerobes, Pseudomonas  Multiple (metastatic) Staphylococcus aureus  Septicemia – Brain abscess, Liver Abscess  Multiple Pyemic Abscesses 74
  • 68. CAP – So How Best to Win the War?  Early antibiotic administration within 4-6 hours  Empiric antibiotic Rx. as per guidelines (IDSA / ATS)  PORT – PSI scoring and Classification of cases  Early hospitalization in Class IV and V  Change Abx. as per pathogen & sensitivity pattern  Decrease smoking cessation - advice / counseling  Arterial oxygenation assessment in the first 24 h  Blood culture collection in the first 24 h prior to Abx.  Pneumococcal & Influenza vaccination; Smoking X 75
  • 69. Acute Exacerbation of COPD (AECOPD) Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
  • 70. Definitions: Acute exacerbation of chronic bronchitis (AECB) is a distinct event superimposed on chronic bronchitis and is characterized by a period of unstable lung function with worsening airflow and other symptoms. Chronic bronchitis is a subset of disease within the broader category of chronic obstructive pulmonary disease (COPD), which is is a chronic, slowly progressive disorder characterized by airflow obstruction. Chronic bronchitis defined clinically as productive cough for consecutive months for 2 successive years. at least 3
  • 71. Burden of the disease:      The average number of episodes of AECB per year is reported to range from 1.5 to 3. The overall rate of emergency department visits for chronic bronchitis increased 28% between 1992 and 2000. The rate increased in all age groups, particularly in persons aged 55 to 64 years; in fact, the rate in this group now approaches the rate in persons aged 65 years or older. The health and socioeconomic consequences are enormous. A retrospective analysis involving more than 280 000 patients with AECB showed that the total cost of treatment in 1994 was approximately $1.6 billion. Outpatient care accounted for only $40 million (2.5% of the total cost) or approximately $70 per visit.
  • 72. Burden of the disease:  This clearly demonstrates that hospitalization due to AECB accounts for the vast majority of total expenditures.  A more recent report found the cost of inpatient hospitalization for AECB ranged from $6285 to $6625.  The impact on families and informal caregivers also is substantial because they provide an average of 5.1 hours per week of informal care to patients with emphysema.  Undoubtedly, the impact is even greater during the period when a patient with chronic bronchitis has an episode of AECB.
  • 73. Etiology:  Bacterial pathogens are cultured from lower airway secretions in approximately 50% of exacerbations.  Haemophilus influenzae : is isolated in 30% to 70% of all AECB  Moraxella catarrhalis and together they account for another 33% of isolates in AECB  Streptococcus pneumoniae  Atypical Bacteria (Chlamydia and Mycoplasma species) are responsible for fewer than 10% of exacerbations.  Viral pathogens
  • 74. Clinical Picture: The purpose of the initial clinical assessment of patients with AECB is twofold. – First, it should serve to determine whether the worsening respiratory status is due to a concomitant disease or a trigger for an acute exacerbation. – Second, it should determine the severity of illness so as to guide management and predict prognosis. Key Assessment Factors: •Age •Triggers •Comorbid diseases •Response to previous medical therapy •Overall pulmonary function •Oxygenation •Character and severity of previous exacerbation •Bacterial colonization status •Previous need for mechanical ventilation •Local antimicrobial susceptibility pattern
  • 75. Clinical Picture: The diagnosis of AECB generally is made on clinical grounds  Shortness of breath  Sputum production  In sputum purulence  Cough Symptom-related Severity of Acute Exacerbation of Chronic Bronchitis 1 symptom Mild exacerbation 2 symptoms Moderate exacerbation 3 symptoms Severe exacerbation
  • 76. Clinical Tip An exacerbation characterized by increased sputum production or purulence, and associated with neutrophilic inflammation, is likely to be Increased dyspnea, cold symptoms, and sore throat are associated with Bacterial in nature Viral exacerbation
  • 77. Investigations Sputum Culture •The diagnostic usefulness of a culture remains contentious because bacterial pathogens can be isolated from the sputum of patients with stable chronic bronchitis •A sputum culture may, however, be useful in certain situations such as recurrent AECB, an inadequate response to therapy, and before starting treatment with prophylactic antibiotics. CXR •Is not used to diagnose AECB. •It may be helpful in patients who have an atypical presentation and in whom community-acquired pneumonia is suspected. •To identify comorbidities that may contribute to the acute exacerbation. Assessment of oxygen saturation Is important to guide therapy Spirometry •The role of spirometry in diagnosis of AECB is less clear than it is in diagnosis of COPD •Evidence show that measurement of lung function using spirometry is valuable to assess the degree of airway obstruction.
  • 78. Management of AECB: Numerous options are available for the management of AECB. Although not part of the acute management of AECB, none is more important on a long term basis than a concerted effort to encourage the patient to stop smoking. In fact, the acute exacerbation might provide a “teachable moment” in which to reaffirm the smoking cessation message. In addition, pneumococcal vaccination and an annual influenza vaccination are essential for comprehensive care.
  • 79. Management of AECB: Antibiotics: – Patients who have at least 2 of the following: increased dyspnea, increased sputum volume, and increased sputum purulence are candidates for antibiotic therapy. Amoxicillin/clavulanate (high-dose) Respiratory fluoroquinolones Macrolides Cephalosporins Adjunctive Treatment: •Removal of irritants •Use of a bronchodilator •Use of oxygen therapy. •Hydration •Use of a systemic corticosteroid •Chest physical therapy.
  • 80. Hospital Acquired Pneumonia ( HAP ) Gamal Rabie Agmy, MD,FCCP Professor of Chest Diseases, Assiut university
  • 81. Pneumonias – Classification CAP HCAP • Health Care Associated HAP • Hospital Acquired ICUAP • ICU Acquired VAP 89 • Community Acquired • Ventilator Acquired Nosocomial Pneumonias
  • 82. Definitions of NP *HAP: diagnosis made > 48h after admission *VAP: diagnosis made 48-72h after endotracheal intubation *HCAP: diagnosis made < 48h after admission with 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 care facility; (3) received recent IV antibiotic therapy, chemotherapy, or wound care within the 30d preceding the current diagnosis; and (4) attended a hospital or hemodialysis clinic
  • 83. Diagnosis of HAP • Full medical history & physical examination to all patients. • Arterial oxygen saturation measurement in all patients. • Laboratory studies (complete blood count, serum electrolytes, renal and liver function). • ± Thoracentesis.
  • 84. Criteria for clinical diagnosis New or progressive radiographic pulmonary infiltrate and 2 of the following (fever, leukocytosis, purulent sputum). • Exclude conditions that mimic pneumonia. • Define the severity of Pneumonia
  • 85. Radiological Diagnosis • Good quality CXR should be obtained and compared with previous CXRs if available. • CXR can help to define the severity of pneumonia. • CT scanning may assist in the differential diagnosis and guide management in patients who are not responding to treatment and who have a complex CXR.
  • 86. ANTIMICROBIAL DRUGS
  • 87. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Mechanism of action include:      Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis Inhibition of metabolic pathways Interference with cell membrane integrity
  • 88. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of Cell wall synthesis  Bacteria cell wall unique in construction   Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell   Due to the lack of cell wall in animal cells and differences in cell wall in plant cells These drugs have very high therapeutic index   Contains peptidoglycan Low toxicity with high effectiveness Antimicrobials of this class include    β lactam drugs Vancomycin Bacitracin
  • 89. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of protein synthesis  Structure of prokaryotic ribosome acts as target for many antimicrobials of this class   Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity Drugs of this class include     Aminoglycosides Tetracyclins Macrolids Chloramphenicol
  • 90. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of nucleic acid synthesis  These include   Fluoroquinolones Rifamycins
  • 91. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Inhibition of metabolic pathways   Relatively few Most useful are folate inhibitors   Mode of actions to inhibit the production of folic acid Antimicrobials in this class include   Sulfonamides Trimethoprim
  • 92. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS  Interference with cell membrane integrity  Few damage cell membrane  Polymixn B most common  Common ingredient in first-aid skin ointments  Binds membrane of Gram - cells  Alters permeability  Leads to leakage of cell and cell death  Also bind eukaryotic cells but to lesser extent  Limits use to topical application
  • 93. EFFECTS OF COMBINATIONS OF DRUGS Sometimes the chemotherapeutic effects of two drugs given simultaneously is greater than the effect of either given alone.  This is called synergism. For example, penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter. 
  • 94. EFFECTS OF COMBINATIONS OF DRUGS Other combinations of drugs can be antagonistic.  For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth. 
  • 95. EFFECTS OF COMBINATIONS OF DRUGS  Combinations of antimicrobial drugs should be used only for: 1. 2. 3. To prevent or minimize the emergence of resistant strains. To take advantage of the synergistic effect. To lessen the toxicity of individual drugs.
  • 96. Pharmacology Pharmacokinetics Pharmacodynamics
  • 97. Pharmacokinetics • Time course of drug absorption, distribution, metabolism, excretion How the drug comes and goes.
  • 98. Pharmacokinetic Processes “LADME” is key Liberation Absorption Distribution Metabolism Excretion
  • 99. Pharmacodynamics • The biochemical and physiologic mechanisms of drug action What the drug does when it gets there.
  • 100. Concepts Pharmacokinetics – describe how drugs behave in the human host Pharmacodynamics – the relationship between drug concentration and antimicrobial effect. “Time course of antimicrobial activity”
  • 101. Concepts Minimum Inhibitory Concentration (MIC) – The lowest concentration of an antibiotic that inhibits bacterial growth after 16-20 hrs incubation. Minimum Bacteriocidal Concentrations. – The lowest concentration of an antibiotic required to kill 99.9% bacterial growth after 16-20 hrs exposure. C-p – Peak antibiotic concentration Area under the curve (AUC) – Amount of antibiotic delivered over a specific time.
  • 102. Antimicrobial-micro-organism interaction Antibiotic must reach the binding site of the microbe to interfere with the life cycle. Antibiotic must occupy “sufficient” number of active sites. Antibiotic must reside on the active site for “sufficient” time. Antibiotics are not contact poisons.
  • 103. Static versus Cidal Control CFU Static Cidal Time
  • 104. Can this antibiotic inhibit/kill these bacteria? In vitro susceptibility testing Mixing bacteria with antibiotic at different concentrations and observing for bacterial growth.
  • 105. Minimal Inhibitory Concentration (MIC) vs. Minimal Bactericidal Concentration (MBC) 32 ug/ml 16 ug/ml 8 ug/ml Sub-culture to agar medium 4 ug/ml 2 ug/ml 1 ug/ml MIC = 8 ug/ml MBC = 16 ug/ml REVIEW
  • 106. What concentration of this antibiotic is needed 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? Conc MIC Time
  • 107. Patterns of Microbial Killing Concentration dependent – Higher concentration greater killing Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B. Time-dependent killing – Minimal concentration-dependent killing (4x MIC) – More exposure more killing Beta lactams, glycopeptides, clindamycin, macrolides, tetracyclines, bactrim
  • 108. The Ideal Drug* 1. Selective toxicity: against target pathogen but not against host  LD50 (high) vs. MIC and/or MBC (low) 2. Bactericidal vs. bacteriostatic 3. Favorable pharmacokinetics: reach target site in body with effective concentration 4. Spectrum of activity: broad vs. narrow 5. Lack of “side effects”  Therapeutic index: effective to toxic dose ratio 6. Little resistance development
  • 109. Resistance Physiological Mechanisms 1. Lack of entry – tet, fosfomycin 2. Greater exit  efflux pumps  tet (R factors) 3. Enzymatic inactivation  bla (penase) – hydrolysis  CAT – chloramphenicol acetyl transferase  Aminogylcosides transferases REVIEW
  • 110. Resistance Physiological Mechanisms (cont’d) 4. Altered target     RIF – altered RNA polymerase (mutants) NAL – altered DNA gyrase STR – altered ribosomal proteins ERY – methylation of 23S rRNA 5. Synthesis of resistant pathway  TMPr plasmid has gene for DHF reductase; insensitive to TMP REVIEW
  • 111. Severe HAP *Hypotension. *Sepsis syndrome. *End organ dysfunction. *Rapid progression of infiltrates. *Intubation
  • 112. Risk Factors Gram-negative bacilli, particularly enterobacteria, are present in the oropharyngeal flora of patients with chronic underlying illnesses, such as COPD, heart failure, neoplasms, AIDS and chronic renal failure. Infection by P. aeruginosa and other more resistant Gram-negative bacilli such as enterobacteria should be considered in patients discharged from ICUs, submitted to wide-spectrum antibiotic treatment and in those with severe underlying disease or prolonged hospitalisation in areas with a high prevalence of these microorganisms.
  • 113. Risk Factors An increased risk for Legionella spp. should be considered in immunosuppressed patients (previous treatment with high-dose steroids or chemotherapy. Gingivitis or periodontal disease, depressed consciousness, swallowing disorders and orotracheal manipulation are usually recorded when anaerobes are the causative agents of the pneumonia Coma, head injury, diabetes, renal failure or recent influenza infection are at risk from infection by S. aureus.
  • 114. Risk Factors HAP due to fungi such as Aspergillus may develop in organ transplant, neutropenic or immunosuppressed patients, especially those treated with corticoids.
  • 115. Blood cultures Blood culture should not be routinely performed to all patients, but it should be preserved to those who are unresponsive to the initial therapy. •
  • 116. LRT secretions sampling : LRT secretions samples should be submitted from all patients at time of clinical diagnosis of suspected HAP, or HCAP before initiating antibiotic treatment. The microbiological investigation may include gram stain, qualitative and quantitative culture of respiratory secretions. •
  • 117. Invasive versus Non-invasive LRT secretions sampling : Invasive diagnostic techniques are not essential or routinely recommended. It is recommend that the least expensive, least invasive method requiring minimal expertise be used for microbiological diagnosis. •
  • 118. Risk for Hospital-associated pneumonia due to multidrug-resistant pathogens Hospitalisation Especially if intubated and in the ICU for ≥5 days (late-onset infection) Prior antibiotic therapy Particularly in the prior 2 weeks Recent hospitalisation in the preceding 90 days Other HCAP risk factors From a nursing home Haemodialysis Home-infusion therapy Poor functional status Risk factors for specific pathogens Pseudomonas aeruginosa Prolonged ICU stay Corticosteroids Structural lung disease Methicillin-resistant Staphylococcus aureus Coma Head trauma Diabetes Renal failure Prolonged ICU stay Recent antibiotic therapy
  • 119. Empiric monotherapy versus combination therapy The optimal empiric monotherapy for nosocomial pneumonia consists of ceftriaxone, ertapenem, levofloxacin, or moxifloxacin. Monotherapy may be acceptable in patients with early onset hospitalacquired pneumonia. Avoid monotherapy with ciprofloxacin, ceftazidime, or imipenem, as they are likely to induce resistance potential.
  • 120. Empiric monotherapy versus combination therapy Late-onset hospital-acquired pneumonia, and health care–associated pneumonia require combination therapy using an antipseudomonal cephalosporin, beta lactam, or carbapenem plus an antipseudomonal fluoroquinolone or aminoglycoside plus an agent such as linezolid or vancomycin to cover MRSA
  • 121. Empiric monotherapy versus combination therapy combination regimens for proven P aeruginosa nosocomial pneumonia include (1) piperacillin/tazobactam plus amikacin or (2) meropenem plus levofloxacin, aztreonam, or amikacin. Optimal Avoid using ciprofloxacin, ceftazidime, gentamicin, or imipenem in combination regimens, as combination therapy does not eliminate the resistance potential of these antibiotics.
  • 122. Empiric monotherapy versus combination therapy When selecting an aminoglycoside for a combination therapy regimen, amikacin once daily is preferred to gentamicin or tobramycin to avoid resistance problems. When selecting a quinolone in a combination therapy regimen, use levofloxacin, which has very good anti– P aeruginosa activity (equal or better than ciprofloxacin at a dose of 750 mg).
  • 123. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy Pseudomonas aeruginosa *Piperacillin-tazobactam 4.5 g IV q6h IV plus levofloxacin 750 mg IV q24h or *Cefepime 2 g IV q8h plus 750 mg IV q24h or plus amikacin 20 mg/kg/day amikacin 20 mg/kg/day IV plus levofloxacin *Imipenem 1 g q6-8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Meropenem 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h or *Aztreonam 2 g IV q8h plus amikacin 20 mg/kg/day IV plus levofloxacin 750 mg IV q24h Duration of therapy: 10-14d
  • 124. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy Klebsiella pneumoniae Cefepime 2 g IV q8h or Ceftazidime 2 g IV q8h or Imipenem 500 mg IV q6h or Meropenem 1 g IV q8h or Piperacillin-tazobactam 4.5 g IV q6h Extended-spectrum beta-lactamase (ESBL)strain Imipenem 500 mg IV q6h or Meropenem 1 g IV q8h K pneumoniae carbapenemase (KPC) strain Colistin 5 mg/kg/day divided q12h or Tigecycline 100 mg IV, then 50 mg IV q12h Duration of therapy: 8-14d
  • 125. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy MRSA Targocid 400mg IV once daily for 7-14 d Linezolid 600mg IV or PO q12h for 7-14 d Vancomycin 15 mg/kg IV q12h for 7-14 d or
  • 126. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy MSSA Oxacillin 1g IV q4-6h for 7-14 d or Nafcillin 1-2 g IV q6h for 7-14 d
  • 127. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy Legionella pneumophila Levofloxacin 750 mg IV q24h, then 750 mg/day PO for 714d or Moxifloxacin 400 mg IV or PO q24h for 7-14d or Azithromycin 500 mg IV q24h for 7-10d
  • 128. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy Acinetobacter baumannii Imipenem 1 g IV q6h or Meropenem 1 g IV q8h or Doripenem 500 mg IV q8h or Ampicillin-sulbactam 3 g IV q6h or Tigecycline 100 mg IV in a single dose, then 50 mg IV q12h or Colistin 5 mg/kg/day IV divided q12h Duration of therapy: 14-21d
  • 129. Hospital-Acquired, Health Care-Associated, and VentilatorAssociated Pneumonia Organism-Specific Therapy Stenotrophomonas maltophilia Trimethoprim-sulfamethoxazole 15-20 mg/kg/day of TMP IV or PO divided q8h or Ticarcillin-clavulanate 3 g IV q4h or Ciprofloxacin 750 mg PO or 400 mg IV q12h or Moxifloxacin 400 mg PO or IV q24h Duration of therapy: 8-14d
  • 130. Category Circumstances Severe HAP# HAP with risk factors for Severity criteria Gram-negative bacilli Chronic underlying disease Treatment Cefepime 2 g every 8 h + aminoglycoside (Amikacin 20 mg·kg−1·day−1) or quinolone (Levofloxacin 750 mg or 500mg/12 hours) i.v. Antipseudomonal β-lactam± aminoglycoside or quinolone Cefepime 1–2 g every 8–12 h i.v. Carbapenems¶: imipenem 500 mg every 6 h or 1 g every 8 h i.v.; or meropenem 1 g every 8 h i.v.; or ertapenem+ 1 g·day−1i.v. Antipseudomonal β-lactam±aminoglycoside or quinolone Cefepime 1–2 g every 8–12 h i.v. β-lactamic/β-lactamase inhibitor: piperacillin-tazobactam 4.5 g every 6 hi.v. P. aeruginosaand multi¶: imipenem 500 mg every 6 h or 1 g every resistant Gram-negative Wide-spectrum antibiotics, severe Carbapenems bacilli underlying disease, ICU stay 8 h i.v.; or meropenem 1 g every 8 h i.v. Hospital potable water colonisation and/or Levofloxacin 500 mg every 12–24 h i.v.or 750§ mg every Legionella# previous nosocomial Legionellosis 24 h i.v. or azitromycin 500 mg·day−1 i.v. Gingivitis or periodontal disease, Carbapenems¶: imipenem 500 mg every 6 h or 1 g every depressed consciousness, swallowing 8 h i.v.; or meropenem 1 g every 8 h i.v.; or Anaerobes disorders and orotracheal manipulation ertapenem+ 1 g·day−1i.v. β-lactam/β-lactamase inhibitor amoxicillin/clavulanate 2 g every 8 hi.v.¶; piperacillin-tazobactam 4.5 g every 6 h i.v. Targocid 400mg IV once daily for 7-14 d Risk factors for MRSA or high prevalence or Vancomycin 15 mg·kg−1 every 12 h i.v.Linezolid 600 mg MRSA every 12 h i.v. of MRSA Amphotericyn B desoxicolate 1 mg·kg−1·day−1 i.v. or amphotericyn liposomal 3–5 mg·kg−1·day−1 i.v.Voriconazol Corticotherapy, neutropenia or 6 mg·kg−1 every 12 h i.v.(day 1) and 4 mg·kg−1 every Aspergillus 12 h i.v.(following days) transplantation β-lactam/β-lactamase inhibitor: amoxicillin/clavulanate 1–2 g Early-onset HAP <5 days Without risk factors and non-severe every 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. or 750§ mg·day−1 i.v. Antipseudomonal cephalosporin (including pneumococcus): Late-onset HAP ≥ 5 days Without risk factors and non-severe cefepime 2 g every 8 h i.v. Fluoroquinolones: levofloxacin 500 mg every 12–24 h i.v. or 750§ mg·day−1 i.v.
  • 131. Normal Pattern of Resolution: Resolution can be defined either clinically generally becomes evident in the first 48–72 h of treatment (most reliable parameters are leukocyte count, oxygenation and central temperature) or microbiologically. Repeat the microbiological cultures 72 h after initiating treatment for possibility of isolation of new pathogens at significant concentrations. The radiological resolution has limited value.
  • 132. Lack of response to empirical treatment can be defined according to one of the following criteria in the first 72 h of treatment: (1) no improvement in oxygenation or need for tracheal intubation; (2) persistence of fever or hypothermia together with purulent secretions; (3) increase in radiological lung infiltrates ≥50%; or (4) appearance of septic shock or multi-organ dysfunction.
  • 133. Causes of deterioration or lack of response to empirical treatment may be due to microorganisms or antibiotics factor, presence of other infections, presence of noninfectious causes or host related factors. Diagnostic testing should be directed to whichever of these causes is likely.
  • 134. Switching from intravenous to oral: Initial therapy should be intravenously, with a switch to oral/enteral therapy in patients with a good clinical response and a functioning intestinal tract.