Seasonality of Antibiotic Resistance and Correlation with Antibiotic Use
Antibiotic strategy in CAP & AECOPD
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Transcript of Antibiotic strategy in CAP & AECOPD
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
24
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
28
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)].