Antibiotic strategy in lower respiratory tract infections

Antibiotic Strategy in Lower
Respiratory Tract Infections

Gamal Rabie Agmy, MD,FCCP
Professor of Chest Diseases, Assiut university

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

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.

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

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.


EFFECTS OF
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.


EFFECTS OF


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.

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

Resistance
(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

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

Management of Adult Lower
Respiratory Tract Infections
The Consensus Statement of the
Egyptian Scientific Society of
Bronchology

Pneumonias – Classification

CAP
HCAP

• Health Care Associated

HAP

• Hospital Acquired

ICUAP

• ICU Acquired

VAP
17

• Community Acquired

• Ventilator Acquired

Nosocomial Pneumonias

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.

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

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

CAP – Pathogenesis

Inhalation
Aspiration
Hematogenous

21

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

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

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

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

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


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


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.

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

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

Classification of Severity - PORT

Class
I
Predictors
Absent

Class
IV

31

Class
II

91 - 130

 70

Class
V

Class
III

> 130

71 – 90

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

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

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

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

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

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

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

Normal CXR & Pneumonic Consolidation

39

Lobar Pneumonia – S.pneumoniae

40

CXR – PA and Lateral Views

41

Lobar versus Segmental - Right Side

42

Special forms of Consolidation

44

Round Pneumonic Consolidation

45

Special Forms of Pneumonia

46

Special Forms of Pneumonia

47

Complications of Pneumonia

48

Pneumonia
Posterior intercostal scan shows a hypoechoic
consolidated area that contains multiple
echogenic lines that represent an air
bronchogram.

Post-stenotic pneumonia
Posterior intercostal scan shows a hypoechoic
consolidated area that contains anechoic,
branched tubular structures in the bronchial tree
(fluid bronchogram).

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.

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 %

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 %

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

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

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

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

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

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

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

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

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

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

Management of Poor Responders
 Consider non-infectious illnesses

 Consider less common pathogens
 Consider serologic testing
 Broaden antibiotic therapy

 Consider bronchoscopy

73

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

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

Acute Exacerbation of COPD
(AECOPD)


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

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.

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.

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

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

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

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

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.

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.

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.

Hospital Acquired Pneumonia
( HAP )


Pneumonias – Classification

CAP
HCAP

• Health Care Associated

HAP

• Hospital Acquired

ICUAP

• ICU Acquired

VAP
89

• Community Acquired

• Ventilator Acquired

Nosocomial Pneumonias

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

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.

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

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.

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

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



Inhibition of nucleic acid synthesis


These include



Fluoroquinolones
Rifamycins



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



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

Pharmacology
Pharmacokinetics
Pharmacodynamics

Pharmacokinetics
• Time course of drug absorption,
distribution, metabolism, excretion
How the drug
comes and goes.

Pharmacokinetic Processes
“LADME” is key
Liberation
Absorption

Distribution

Metabolism
Excretion

Pharmacodynamics
• The biochemical and physiologic
mechanisms of drug action
What the drug
does when it gets there.

Concepts
Pharmacokinetics
– describe how drugs behave in the human host

Pharmacodynamics
– the relationship between drug concentration
and antimicrobial effect. “Time course of
antimicrobial activity”

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.

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.

Static versus Cidal
Control

CFU

Static

Cidal

Time

Can this antibiotic inhibit/kill these bacteria?
In vitro susceptibility testing
Mixing bacteria with antibiotic at different
concentrations and observing for bacterial
growth.

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

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

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

Resistance
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

Severe HAP
*Hypotension.
*Sepsis syndrome.
*End organ dysfunction.
*Rapid progression of infiltrates.
*Intubation

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.

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.

Risk Factors
HAP due to fungi such as Aspergillus may develop in
organ transplant, neutropenic or immunosuppressed
patients, especially those treated with corticoids.

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.
•

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.
•

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.
•

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

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.

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

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.

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).

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

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

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

MSSA
Oxacillin 1g IV q4-6h for 7-14 d or
Nafcillin 1-2 g IV q6h for 7-14 d

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

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

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

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.

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.

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.

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.

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.

Antibiotic strategy in lower respiratory tract infections

Antibiotic strategy in lower respiratory tract infections

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