Antibiotic Strategy in

CAP &AECOPD

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

ANTIMICROBIAL DRUGS

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

ANTIMICROBIAL

SUSCEPTIBILITY TESTING

Probably the most widely used testing method is the disk-diffusion method, also known as the Kirby-Bauer test.

SUSCEPTIBILITY OF BACTERIAL

TO ANTIMICROBIAL DRUG

Conventional disc diffusion method Kirby-Bauer disc diffusion

routinely used to qualitatively determine susceptibility

Standard concentration of strain uniformly spread of standard media

Discs impregnated with specific concentration of antibiotic placed on plate and incubated

Clear zone of inhibition around disc reflects susceptibility

Based on size of zone organism can be described as susceptible or resistant

Antibacterial spectrum—Range of activityof an antimicrobial against bacteria. Abroad-spectrum antibacterial drug caninhibit a wide variety of gram-positive andgram-negative bacteria, whereas anarrow-spectrum drug is active onlyagainst a limited variety of bacteria.

Bacteriostatic activity—-The level ofantimicro-bial activity that inhibits thegrowth of an organism. This is determinedin vitro by testing a standardizedconcentration of organisms against aseries of antimicrobial dilutions. Thelowest concentration that inhibits thegrowth of the organism is referred to asthe minimum inhibitory concentration(MIC).

Bactericidal activity—The level ofantimicrobial activity that kills the testorganism. This is determined in vitro byexposing a standardized concentration oforganisms to a series of antimicrobialdilutions. The lowest concentration thatkills 99.9% of the population is referred toas the minimum bactericidalconcentration (MBC).

Antibiotic combinations—Combinations ofantibiotics that may be used (1) to broadenthe antibacterial spectrum for empirictherapy or the treatment of polymicrobialinfections, (2) to prevent the emergence ofresistant organisms during therapy, and (3)to achieve a synergistic killing effect.

Antibiotic synergism—Combinations oftwo antibiotics that have enhancedbactericidal activity when tested togethercompared with the activity of eachantibiotic.

Antibiotic antagonism—Combination ofantibiotics in which the activity of oneantibiotic interferes With the activity of theother (e.g., the sum of the activity is lessthan the activity of the individual drugs).

Beta-lactamase—An enzyme thathydrolyzes the beta-lactam ring in thebeta-lactam class of antibiotics, thusinactivating the antibiotic. The enzymesspecific for penicillins and cephalosporinsaret he penicillinases andcephalosporinases, respectively.

32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml

Sub-culture to agar medium MIC = 8 ug/ml

MBC = 16 ug/ml

Minimal Inhibitory Concentration (MIC)

vs.

Minimal Bactericidal Concentration (MBC)

REVIEW

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

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

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.

EFFECTS OF

COMBINATIONS OF DRUGS

Combinations of antimicrobial drugs should be used only for:

1. To prevent or minimize the emergence of resistant strains.

2. To take advantage of the synergistic effect.

3. 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

Physiological Mechanisms

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

(cont’d)

REVIEW

Infection of the lung parenchyma in a

person who is not hospitalized or living in

a long-term care facility for ≥ 2 weeks.

This pneumonia develops in the outpatient

setting or within 48 hours of admission to

a hospital.

Definition of CAP

*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

HCAP

The clinical diagnosis of CAP

Symptoms:

May be preceded by URTI

• Respiratory: Cough dry or productive,

mucopurulent sputum , sometimes rusty, dyspnea,

sometimes pleuritic chest pain

• Non-respiratory: Fever, body aches, altered mental

state, vomiting or diarrhea.

The clinical diagnosis of CAP

Signs:

Generally: Fever, sometimes hypothermia,

tachycardia, tachypnea.

Local: signs of consolidation

Severity of CAP

22

PORT Scoring – PSI

Clinical Parameter Scoring

Age in years Example

For Men (Age in yrs) 50

For Women (Age -10) (50-10)

NH Resident 10 points

Co-morbid Illnesses

Neoplasia 30 points

Liver Disease 20 points

CHF 10 points

CVD 10 points

Renal Disease (CKD) 10 points

Clinical Parameter Scoring

Clinical Findings

Altered Sensorium 20 points

Respiratory Rate > 30 20 points

SBP < 90 mm 20 points

Temp < 350 C or > 400 C 15 points

Pulse > 125 per min 10 points

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

Pneumonia Patient Outcomes

Research Team (PORT)

23

Classification of Severity - PORT

Predictors Absent

Class I

70

Class II

71 – 90

Class III

91 - 130

Class IV

> 130

Class V

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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

25

CURB 65 Rule – Management of CAP

CURB 65

Confusion

BUN > 30

RR > 30

BP SBP <90

DBP <60

Age > 65

CURB 0 or 1 Home Rx

CURB 2 Short Hosp

CURB 3 Medical Ward

CURB 4 or 5 ICU care

Indications for admitting CAP patients to ICU

Major Criteria(1/2 sufficient)

• Acute respiratory failure(mechanical ventilation)

• Severe sepsis or septic shock(need of vasopressors)

Minor Criteria (ICU admission

recommended if ≥3) • Respiration rate ≥ 30/min • Multi lobar involvement

• PaO2:FiO2 ≤250 +/-SaO2 <90% with 6 L O2

• Confusion/ disorientation • Uremia BUN ≥20 mg/dl

• Leukopenia WBC < 4 x 109/L

• Thrombocytopenia Tc < 100.000 / mm3

• Hypothermia core temp< 36°

• Hypotension requiring aggressive fluid resuscitation

27

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

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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

29

Normal CXR & Pneumonic Consolidation

30

Lobar Pneumonia – S.pneumoniae

31

CXR – PA and Lateral Views

32

Lobar versus Segmental - Right Side

33

Lobar Pneumonia

34

Special forms of Consolidation

35

Round Pneumonic Consolidation

36

Special Forms of Pneumonia

37

Special Forms of Pneumonia

38

Complications of Pneumonia

39

Empyema

40

Mycoplasma Pneumonia

41

Mycoplasma Pneumonia

42

Chlamydia Trachomatis

43

Rare Types of Pneumonia

Chest sonography

Chest sonography

Post-stenotic pneumonia Posterior intercostal scan shows a

hypoechoic consolidated area that contains

anechoic, branched tubular structures in the

bronchial tree (fluid bronchogram).

Chest sonography

Chest sonography

49

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

• 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

Atypical

50

CAP – Pathogenesis

Inhalation

Aspiration

Hematogenous

51

Age

Obesity; Exercise is protective

Smoking, PVD

Asthma, COPD

Immuno-suppression, HIV

Institutionalization, Old age homes etc

Dementia

CAP – Risk Factors for Pneumonia

ID Clinics 1998;12:723. Am J Med 1994;96:313

Diagnostic testing:

Outpatient setting: Routine diagnostic tests

to identify an etiologic diagnosis are optional

for outpatients with CAP. Microbiological tests

are not recommended.

• Inpatient setting: Routine diagnostic tests to

identify an etiologic diagnosis are required in

critically ill CAP and when specific pathogens are

suspected (e.g. TB) that would likely change

individual antibiotic management.

Cultures to identify the causative organism:

Sputum cultures are not recommended in

cases of CAP except in certain occasions:

• Patients admitted in hospital or ICU.

• Patients who do not respond to empirical

antibiotic therapy.

• Suspect of resistant strains of S.pneumoniae.

Sputum Gram stain

is a rapid and inexpensive test that can

help a lot:

• Differentiate Gm –ve from Gm +ve bacteria.

• Excess pus cells without organism suspect

atypical infection.

Blood Culture

:

Recommended for all patients with moderate and

high severity CAP, preferably before antibiotic

therapy is commenced.

Examination of sputum for Mycobacterium

Tuberculosis should be considered for patients

with a persistent productive cough, especially

if malaise, weight loss or night sweats, or risk

factors for tuberculosis (e.g., ethnic origin,

social deprivation, elderly) are present.

57

Objective 2 Objective 1

Avoid emergence

of

multidrug resistant

microorganisms

Immediate Rx.

of patients with

serious sepsis

The Therapy Conundrum

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, Amoxicillin-

Clavulanate is preferred; Ceftriaxone, Cefpodoxime,

Cefuroxime) plus a Macrolide or Doxycycline

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

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

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

62

Empiric Rx. – CA MRSA

For Community Acquired Methicillin-Resistant

Staphylococcus aureus (CA-MRSA)

Targocid,Vancomycin or Linezolid

For Methicillin Sensitive S. aureus (MSSA)

B-lactam and sometimes a respiratory

Fluoroquinolone, (until susceptibility results).

Switching from intravenous to oral

Patients treated initially with parenteral

antibiotics should be transferred to an oral

regimen when they are hemodynamically stable

and improving clinically, are able to ingest

medications, and have a normally functioning

gastrointestinal tract.

Duration of the Treatment:

Patients with CAP should be treated for a

minimum of 5 days, should be afebrile for 48–72

h, and should have no more than 1 CAP-

associated sign of clinical instability before

discontinuation of therapy. Lengthening of

therapy to a minimum of 14 days is

recommended in some cases according to

severity.

Criteria for clinical stability

Temperature≤37.8_C

Heart rate ≤100 beats/min

Respiratory rate≤24 breaths/min

Systolic blood pressure ≥90 mm Hg

Arterial oxygen saturation ≥90% or pO2 ≥60

mm Hg on room air

Ability to maintain oral intake*

Normal mental status*

What to Do When a Patient with Community

Acquired Pneumonia Fails to improve?

Treatment failure is a matter of

particular concern in the management of

CAP.

Treatment failure is associated with high

morbidity and mortality rates.

Its detection and management require

careful clinical assessment.

Definition

Lack of response or worsening of clinical

status (i.e., hemodynamic instability,

incidence of respiratory failure, need for

mechanical ventilation, radiographic

progression , or appearance of new

metastatic infectious foci)

Definition

Failure to respond to antimicrobial

treatment was classified as

nonresponding or progressive

pneumonia.

Definition

◙Nonresponding pneumonia was defined as

persistent fever > 38°C and/or clinical symptoms

(malaise, cough, expectoration, dyspnea) after at

least 72 hours of antimicrobial treatment.

◙Progressive pneumonia was defined as clinical

deterioration in terms of the development of either

or both septic shock and acute respiratory failure

requiring ventilator support after at least 72 hours

of treatment.

Types

1-Early Failure: within 72 hours

2-Late failure: after 72 hours

Incidence

2.4 to 31% for early failure and

from 3.9 to 11% for late failure.

Factors associated with treatment failure

◙ High-risk pneumonia

◙ Liver disease ,neurological, neoplasia and

aspiration

◙ Multilobar infiltrates

◙ Legionella pneumonia

◙ Gram-negative pneumonia

◙ Pleural effusion

◙ Cavitation

◙ Leucopenia, and

◙ Discordant antimicrobial therapy.

Lower risk of failure

◙ Influenza vaccination

◙Initial treatment with

fluoroquinolones, and

◙ Chronic obstructive pulmonary

disease

Laboratory markers for treatment failure

1-Procalcitonin

2-CRP

3- IL6, IL8

4- IL1

5-Pleural effusion

6-Multilobar affection

7-CURB 65>3

Predicting treatment failure in patients with community acquired pneumonia: a case-

control study. Loeches et al, Respiratory Research2014 ,15:75

Evaluating a patient who is not responding to therapy

◙Repeating the history (including travel and pet

exposures to look for unusual pathogens), chest

radiograph, and sputum cultures, blood cultures, and

urine antigen testing for Streptococcal pneumoniae and

Legionella if not previously done .

◙If this is unrevealing, then further diagnostic

procedures,, such as chest computed tomography [CT],

bronchoscopy, and lung biopsy can be performed.

Chest sonography

Chest sonography

Post-stenotic pneumonia Posterior intercostal scan shows a

hypoechoic consolidated area that contains

anechoic, branched tubular structures in the

bronchial tree (fluid bronchogram).

Chest sonography

Chest sonography

Chest CT

Chest CT can detect pleural effusion, lung abscess, or

central airway obstruction, all of which can cause

treatment failure.

It may also detect noninfectious causes such as

bronchiolitis obliterans organizing pneumonia .

Since empyema and parapneumonic effusion can

contribute to nonresponse, thoracentesis should be

performed in all nonresponding patients with

significant pleural fluid accumulation.

Chest CT

Bronchoscopy

Bronchoscopy can evaluate the airway for

obstruction due to a foreign body or

malignancy, which can cause a postobstructive

pneumonia.

Protected brushings and bronchoalveolar lavage

(BAL) may be obtained for microbiologic and

cytologic studies; in some cases, transbronchial

biopsy may be helpful.

Bronchoscopy

In addition, BAL may reveal evidence of

noninfectious disorders or, if there is a

lymphocytic rather than neutrophilic

alveolitis, viral or Chlamydia infection

Thoracoscopic lung biopsy

Thoracoscopic or open lung biopsy may be

performed if all of these procedures are

nondiagnostic and the patient continues to be ill.

The advent of thoracoscopic procedures has

significantly reduced the need for open lung

biopsy and its associated morbidity.

87

Age > 65

Bacteremia (for S. pneumoniae)

S. aureus, MRSA , Pseudomonas

Extent of radiographic changes

Degree of immuno-suppression

Amount of alcohol consumption

CAP – Risk Factors for Mortality

ID Clinics 1998;12:723. Am J Med 1994;96:313

AECOPD Most exacerbations of COPD are caused by

viral or bacterial infection. Approximately 50%

of exacerbations are caused by bacterial

infection. Mild to moderate exacerbations is

often caused by Haemophilus influenzae,

Streptococcus pneumoniae, Moraxella

catarrhalis,

A severe exacerbation is often caused by

Pseudomonas aeruginosa and Enterobacteriacea

AECOPD Sputum cultures should not be routinely performed

expect in patients with frequent exacerbations,

worsening clinical status or inadequate response

after 72 hours on initial empiric antibiotic, and /or

exacerbation requiring mechanical ventilation

Uncomplicated AECOPD

H. influenzae

S. pneumoniae

M. catarrhalis

• Floroquinolones

• Advanced macrolide

(azythromycin, clarithromycin)

• Cephalosporins 2nd or 3rd

generation

Complicated AECOPD

As in Uncomplicated

AECOPD plus presence

of resistant organisms (s

– lactamase producing,

penicillin-resistant S.

pneumoniae), Entero-

bacteriaceae (K.

pneumoniae, E. coli,

Proteus, Enterobacter,

etc)

ß-lactam/ß-lactamase

inhibitor (Co-amoxiclav,

ampicillin/ sulbactam)

• Fluoroquinolone

(Gemifloxacin,

Levofloxacin,

Moxifloxacin)

Complicated AECOPD

As in complicated

AECOPD plus

P. aeruginosa Fluoroquinolone

(Ciprofloxacin,

Levofloxacin –

high dose^)

• Piperacillin-

tazobactam

Risk factors for poor outcome in

patients with AECOPD

presence of comorbid diseases, severe

COPD, frequent exacerbations (>3/yr), and

antimicrobial use within last 3 months.

P. aeruginosa should be considered

in the presence of at least two of the

following [recent hospitalization, frequent

(>4 courses per year) or recent

administration of antibiotics (last 3 months),

severe disease (FEV1 < 30%), oral steroid

use (>10 mg of prednisolone daily in the last

2 weeks)].