This document discusses antibiotic strategy and management of lower respiratory tract infections. It provides information on various topics related to antimicrobial drugs including their mechanisms of action, spectrum of activity, synergism, antagonism, and resistance. It also discusses community acquired pneumonia (CAP) and nosocomial pneumonias, describing criteria for diagnosis and guidelines for management based on prognostic scoring systems like PORT and CURB-65. The document aims to provide an overview of approaches to treatment of lower respiratory infections.
5. 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
6. 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.
7. 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
8. 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.
9. 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.
10. 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.
12. 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
13. 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
14. Management of Adult Lower
Respiratory Tract Infections
The Consensus Statement of the
Egyptian Scientific Society of
Bronchology
17. Pneumonias – Classification
CAP
HCAP
• Health Care Associated
HAP
• Hospital Acquired
ICUAP
• ICU Acquired
VAP
17
• Community Acquired
• Ventilator Acquired
Nosocomial Pneumonias
18. 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.
19. 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
20. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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.
29. 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
30. 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
31. Classification of Severity - PORT
Class
I
Predictors
Absent
Class
IV
31
Class
II
91 - 130
70
Class
V
Class
III
> 130
71 – 90
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
38. 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
57. Pneumonia
Posterior intercostal scan shows a hypoechoic
consolidated area that contains multiple
echogenic lines that represent an air
bronchogram.
58.
59. Post-stenotic pneumonia
Posterior intercostal scan shows a hypoechoic
consolidated area that contains anechoic,
branched tubular structures in the bronchial tree
(fluid bronchogram).
60. 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.
61. 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 %
62. 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 %
63. 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
64. 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
65. 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
66. 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
67. 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
68. 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
69. 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
70. 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
71. 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
72. 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
73. Management of Poor Responders
Consider non-infectious illnesses
Consider less common pathogens
Consider serologic testing
Broaden antibiotic therapy
Consider bronchoscopy
73
74. 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
75. 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
76. Acute Exacerbation of COPD
(AECOPD)
Gamal Rabie Agmy, MD,FCCP
Professor of Chest Diseases, Assiut university
77. 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
78. 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.
79. 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.
80. 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
81. 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
82. 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
83. 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
84. 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.
85. 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.
86. 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.
89. Pneumonias – Classification
CAP
HCAP
• Health Care Associated
HAP
• Hospital Acquired
ICUAP
• ICU Acquired
VAP
89
• Community Acquired
• Ventilator Acquired
Nosocomial Pneumonias
90. 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
91.
92. 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.
93. 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
94.
95. 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.
98. 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
99. 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
100. 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
101. MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
Inhibition of nucleic acid synthesis
These include
Fluoroquinolones
Rifamycins
102. 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
103. 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
104. 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.
105. 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.
106. 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.
111. Concepts
Pharmacokinetics
– describe how drugs behave in the human host
Pharmacodynamics
– the relationship between drug concentration
and antimicrobial effect. “Time course of
antimicrobial activity”
112. 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.
113. 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.
115. Can this antibiotic inhibit/kill these bacteria?
In vitro susceptibility testing
Mixing bacteria with antibiotic at different
concentrations and observing for bacterial
growth.
116. 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
117. 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
118. 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
119. 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
124. 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.
125. 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.
126. Risk Factors
HAP due to fungi such as Aspergillus may develop in
organ transplant, neutropenic or immunosuppressed
patients, especially those treated with corticoids.
127. 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.
•
128. 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.
•
129. 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.
•
130. 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
131. 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.
132. 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
133. 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.
134. 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).
135. 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
136. 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
137. 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
138. 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
139. 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
140. 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
141. 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
142. 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.
143.
144. 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.
145. 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.
146. 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.
147. 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.