rational use of antibiotic in community-acquired pulmonary ... use of atb, wipa 23 may...
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Reechaipichitkul W. 23 May 2007 1
Rational use of antibiotic in community-acquired pulmonary
infection
Rational use of antibiotic in community-acquired pulmonary
infection รศ.พญ.วิภา รชีัยพิชิตกุล
หนวยโรคระบบทางเดินหายใจและเวชบําบัดวิกฤต
ภาควิชาอายุรศาสตร คณะแพทยศาสตร
มหาวิทยาลัยขอนแกน
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Common cold Bronchitis Pneumonia Sepsis
Respiratory tract infection
No antibiotic Need early antibiotic
Viral Bacterial
Do you OK?
Reechaipichitkul W. 23 May 2007 3
Respiratory tract infection
Over use of antibiotics
Increased costSide effectInduced drug resistance
Under use of antibiotics
Sepsis, septic shockComplication (empyema)Increased cost
Reechaipichitkul W. 23 May 2007 4
Lower respiratory tract infection (LRTI)
Acute bronchitis
Acute exacerbation of asthma
Acute exacerbation of COPD (AECB)
Community-acquired pneumonia (CAP)
Reechaipichitkul W. 23 May 2007 5
Rational antibiotic use in LRTI
Viral vs BacterialNo antibiotic vs Need antibioticWhich antibiotic (s)Oral vs ParenteralDose and Duration
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Population with acute lower respiratory tract illness
in the community (24,000)
Patients consulting with symptoms of lower respiratory
tract illness (8,000)
Community lower respiratory tract
infection treated withantibiotics (2,000)
Pneumonia diagnosed in
community (100)
PneumoniaAdmited to Hospital (20)
Die(1-2) ICU
(1-2)
Hospital
Community
“Iceberg of community-acquired respiratory tract illness, infection and pneumonia”
(Feldman C. Prim Care Respir J 2004; 13: 159-66.)
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LRTI Etiology
Acute bronchitis >95% viral
Acute exacerbation of asthma >95% viral
Acute exacerbation of COPD 30-50% viral
Community-acquired pneumonia 80% bacterial
75%Of antibiotic prescription
Reechaipichitkul W. 23 May 2007 8
Bacterial or viral infection
Symptoms?
Signs?
Chest X-ray?Leukocytosis?
C-reactive protein?
Procalcitonin?
Reechaipichitkul W. 23 May 2007 9
Signs and Symptoms
5-10% of patients withcough = Pneumonia40% of patients with focalauscultation = PneumoniaNegative auscultation =2% PneumoniaChest X-ray: Gold standard
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Bronchitis Pneumonia
Chest X-ray
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Reference standard to diagnose CAP is new infiltrate in CXR
1-Specificity
PCT (0.88; 0.84-0.93)Leukocytosis (0.69; 0.62-0.77)
CRP (0.76; 0.69-0.83)Temperature (0.55; 0.46-0.63)
0 0.25 0.50 0.75 1.00
Clinical signs & symptoms: fever, cough, sputum production, abnormal chest auscultation and dyspnea AUC 0.79 (0.75-0.83)
(Muller B, et al. BMC Infect Dis 2007 Mar 2; 7: 10.)
0.25
0
Sens
itivi
ty
0.50
0.75
1.00
Parameterto detectPneumonia
“Pneumonia in 373 of 545 LRTIs”
PCT
CRP
TempWBCProcalcitonin
AUC 0.88 (0.84-0.93)
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What is Procalcitonin?
Bacterial infections(Proinflammatory cytokines & bacterial toxins)
Viral infections(Interferon γ)
Estimate the present of bacterial infection(Biomarkers)
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Procalcitonin in different infections
Septic shock
Sepsis
Pneumonia
AECOPD
Healthy persons0.01
0.1
0.25
1.0
10
100
PCT (ng/ml)
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Multilevel likelihood ratios for PCT and hsCRP to diagnose CAP without Chest X-ray
N (%) Sensitivity Specificity LR+ LR-PCT (μg/L)>0.1 406 (75) 0.90 0.59 2.22 0.16>0.25 300 (55) 0.74 0.85 4.87 0.31>0.5 225 (41) 0.57 0.93 8.21 0.46>1.0 167 (31) 0.43 0.96 10.57 0.59
N (%) Sensitivity Specificity LR+ LR-hsCRP (mg/L)>40 413 (76) 0.89 0.52 1.86 0.22>50 384 (70) 0.87 0.65 2.44 0.21>100 281 (52) 0.69 0.86 4.94 0.36>200 141 (26) 0.36 0.96 8.83 0.67
hsCRP=highly sensitive CRP (Muller B, et al. BMC Infect Dis 2007 Mar 2; 7: 10.)
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Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial
(Christ-Crain M, et al. Am J Respir Care Med 2006; 174: 84-93.)
Procalcitonin initialNo antibiotic Repeated procalcitonin in 6 hr.
Start antibiotic Repeated procalcitonin in 4, 6, 8 d.
Procalcitonin reduced ATB exposure (RR 0.52; 95%CI 0.48-0.55)ATB prescription on admission (85% vs 99%; p<0.001)
ATB treatment duration (5 vs 12 d; p<0.001)Overall success rate similar in both group (83%)
Procalcitonin assay less than 20 min, report within 1 hr, Cost: material 15$, reagents & technicians’ time 30 $
Control group (n=151): received ATB according to usual pratice
Procalcitonin group (n=151): ATB base on serum procalcitonin
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Pneumonia versus uncomplicated LRTI?
Cough plus at least one symptom:
focal chest signdyspneatachypneafever >4 days
Chest X-ray recommended
(Fluckiger U, et al. Internist 2007 Mar 28.)
Reechaipichitkul W. 23 May 2007 17
Fever, Cough, Dyspnea
Lung sign
CXR
Bronchitis Pneumonia
Rhonchi, WheezingCXR: normal
Crepitation, ConsolidationCXR new infiltration
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Pneumonia
CAP HAPDDx-Lupus pneumonitis-Alveolar hemorrhage-Hypersensitivity pneumonitis-Acute tuberculous pneumonitis-ARDS-Acute interstitial pneumonia-BOOP-Bronchioloalveolar cell CA
-Heart failure-Volume over load-ARDS-Atelectasis-Pulmonary embolism-Pulmonary drug reaction-Alveolar hemorrhage-Pulmonary TB
DDx
Reechaipichitkul W. 23 May 2007 19
Chest X-ray
Diagnosed pneumonia Severity Complication
Reechaipichitkul W. 23 May 2007 20
Causative pathogen(s)CBCChest X-raySputum Gram’s stainSputum cultureHemo cultureSerology (M.pneumoniae, C.pneumoniae, L.pneumophila)S.pneumoniae urinary Ag, L.pneumophila urinary AgCold agglutininMelioid titerUltrasound liver (TB , AP )PCR techniqueViral isolation
Reechaipichitkul W. 23 May 2007 21
Initial laboratory investigation of CAPInitial laboratory
investigation of CAP“Lobar
pneumonia”
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The value of sputum Gram’s stainThe value of sputum Gram’s stain“Studying period : January 1999 - December 2000”Only 61.9% (91/147 patients) had adequate sputum examination
(Reechaipichitkul W, et al.Thai J Tuberc Chest Dis 2001; 23: 46-53.)
Over all sensitivity 57.1%
Reechaipichitkul W. 23 May 2007 23
The diagnostic performance of sputum Gram’s stain(Reechaipichitkul W, et al. Thai J Tuberc Chest Dis 2001; 23:46-53.)
62.5%90%
74.1%40%7.1%
66.7%
Streptococcus pneumoniaeStaphylococcus aureusKlebsiella pneumoniaeHaemophilus influenzaeBurkholderia pseudomalleiEscherichia coli
OrganismSpecificity PPVSensitivity NPV
Sputum Gram’s stain
90.7%97.5%71.9%94.7%100%61%
58.8%81.8%56.6%60%100%15.8%
91.9%98.8%86.8%88.9%85.5%94.3%
PPV = positive predictive valueNPV = negative predictive value
*
*
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Sputum Gram’s stainSputum Gram’s stain
S.aureus B.pseudomallei
High specificity
High specificity
Nocardia Strongyloidiasis
Special organismsSpecial
organisms
Reechaipichitkul W. 23 May 2007 25
Chest radiographsChest radiographs
Lobar pneumonia Necrotizing pneumoniaInterstitial pneumonia
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In individual patients, establishing when bacterial infection
is present and antibiotic therapy indicated remains challenging
Patients with acute bronchitis who are young, otherwise
healthy, and do not have any underlying lung disease are
less likely to have bacterial infection (>90% nonbacterial cause)
Who need antibiotics?
Acute bronchitis Viral infection is more likely(Martinez FJ. Acute bronchitis: state of the art diagnosis and therapy. Compr Ther 2004; 30: 55-69.) (Gonzales R, et al. Appropriate antibiotic use in acute bronchitis. Ann Intern Med 2001; 134: 521-529.)
Reechaipichitkul W. 23 May 2007 27
Major Pathogen of Common Cold and Acute Bronchitis
Common Cold Acute BronchitisPicornaviruses Influenza virusesRhinoviruses PicornavirusesEnteroviruses Rhinoviruses
Coronaviruses EnterovirusesAdenoviruses AdenovirusesRespiratory syncytial virus Mycoplasma pneumoniaeInfluenza viruses Chlamydia pneumoniaeParainfluenza viruses Bordetella pertussis
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Atypical pathogen infection in adults with acute exacerbation of bronchial asthma
(Lieberman D, et al. Am J Respir Crit Care Med 2003; 167: 406-10.)
A serologically based prospective study: Asthma (N=100) vs Control group (N=100)
Pathogen Asthma Control p-valueViral agents, %Influenza virus type A 11 2 0.01Influenza virus type B 5 1 NSParainfluenza virus type 1 3 0 NSParainfluenza virus type 2 2 0 NSParainfluenza virus type 3 1 0 NSAdenovirus 6 1 NSRespiratory syncytial virus 2 0 NS
Bacterial agent, %Streptococcus pneumoniae 3 3 NS
Atypical bacterial agents, %Legionella spp. 5 3 NSMycoplasma pneumoniae 18 3 0.0006Chlamydia pneumoniae 8 6 NS
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Who need antibiotics?
AECB: Adults >50 years of age
: Current or past history of smoking >20 pack-years
: Clinical chronic bronchitis
(chronic cough and sputum production on most days for
3 consecutive months for >2 consecutive years)
: Purulent sputum
(>25 PMN/low power field on Gram stain)
: Anthonisen criteria > 2/3 AECB Bacterial infection is more likely
(Martinez FJ. Int J Antimicrob Agents 2005; 26: S156-S163.)
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1. Increased dyspnea2. Increased sputum volume3. Increased sputum purulence
Meta-analysis :Antibiotics are benefit in COPD patients
who have at least 2 of 3 cardinal symptoms of exacerbation
(Anthonisen NR, et al. Ann Intern Med 1987; 106: 196-204.)
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Etiology of AECOPDSputum culture
S.pneumoniae
H.influenzae
M.catarrhalis
Virus
Chlamydia
Pseudomonas
Gram-neg
H.parainfluenzae
Non-infectious
(Obaji AZ Sethi S. Drug and Aging: 2001; 18: 1-11.)
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120
100
80
60
40
20
0
M.pneumoniae C.pneumoniae
Pneumococcus Haemophilus spp.
H.influenzae M.catarrhalis
H.influenzae plusResistant GN bacilli& P.aeruginosa
AECB-I AECB-II AECB-III AECB-IVFEV1
(% o
f pr
edicte
d)AECB & Severity assessment & Etiology
(Grossman RF. Semin Respir Crit Care 2000; 21: 113-22.)
FEV1/FVC < 70%
FEV1>80% 50%<FEV1<80% 30%<FEV1<50% FEV1<30%
Reechaipichitkul W. 23 May 2007 33
Increase in: DyspneaSputum volumeSputum purulence
Type IAll three present,
antibiotic recommended
Type IITwo of three present,
antibiotic recommended
if includes purulence
Type IIIOne of three present,
antibiotic notrecommended
(Anthonisen NR, et al. Ann Intern Med 1987; 106: 196-204.)
“Anthonisen criteria”
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0
10
20
30
40
50
G+/G- Virus Atypicalbacteria
Multiplepathogens
Non-infectious
Microbiology
Freq
uenc
y (%
)
InfluenzaeParainfluenzaeRhinovirus
C.Pneumoniae<10%
30%
(Bruton S, et al. Am J Manag Care 2004; 10: 689-96.)
Etiology of Acute Exacerbation of Chronic BronchitisH.influenzaeS.pneumoniaeM.catarrhalis
40-60%
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(Blasi F,et al. Pulm Pharmacol Ther 2006; 19: 361-9.)
“ATB use in AECB”Simple
chronic bronchitis
Complicatedchronic bronchitis
Complicated AECB& risk for P.aeruginosa
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• Continuous sputum through year(patients with chronic bronchial sepsis)
• FEV1 <30%
Simple chronic bronchitis
Complicatedchronic bronchitis
Complicated AECB& risk for P.aeruginosa
• FEV1 >50%• Increased sputum volumeand purulence
• FEV1 <50%• Advanced age•>4 exacerbations/yr• Significant comorbidity
AmoxicillinDoxycyclineNewer macrolidesCephalosporins Amoxicillin/clavulanate
New fluoroquinolones Ciprofloxacin Anti-pseudomonal ATB
FEV1 = Forced expiratory volume in 1 second.
Antimicrobial Therapies for AECB
(Blasi F,et al. Pulm Pharmacol Ther 2006; 19: 361-9.)
H.influenzaeM.catarrhalisS.pneumoniae
H.influenzaeM.catarrhalisS.pneumoniae(concern for resistant strains)
H.influenzaeM.catarrhalisS.pneumoniaeEnterobacteriaceaeP.aeruginosa
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Etiology of CAP in adults
S.pneumoniae
H.influenzae S.aureus
Other Gram-negbacilli
Miscellaneous
Atypicals
Virus
Aspiration
(Bartlett GJ, et al. N Eng J Med 1995; 333: 1618-24.)
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Most common causative agent in CAP by site of care (from 12 papers)
Most common causative agent in CAP by site of care (from 12 papers)
Out patients (mild) Non-ICU inpatients ICU (severe)
S.pneumoniae S.pneumoniae S.pneumoniaeM.pneumoniae M.pneumoniae Legionella sppH.influenzae C.pneumoniae H.influenzaeC.pneumoniae H.influenzae Gram-negative bacilli
Viruses* Legionella spp S.aureusAspirationViruses*
* Viruses: influenza A and B, adenovirus, RSV, parainfluenza
(File TMJr. Community-acquired pneumonia. Lancet 2003; 362: 1991-2001.)
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(Clin Infect Dis 2007 Mar 1; 44 Suppl 2: S27-S72.)
“CAP 2007: IDSA/ATS”
Concern DRSPHistory of previous ATB use in 3 months
Start first dose antibiotic at emergency room,as soon as possible
2/3 of patients meetthe criteria to switchtherapy in 3 days
Pathogen-directed therapy
Discharge as soon as clinical stable Observation while receiving oral therapy is not neccessary
IDSA/ATS consensus guidelines on the management of CAP in adults, 2007
Outpatient 1. Previously healthy and no use of ATB within previous 3 months
- macrolide (azithro, clarithro, erythro)- doxycycline
2. Presence of comorbidities such as chronic heart, lung, liver or renal disease, DM, alcoholism, malignancy, asplenia, use of immunosuppressive drugs, use of ATB within previous 3 months- respiratory fluoroquinolone (moxifloxacin, gemifloxacn,levofloxacin 750 mg)
- β-lactam plus macrolide (β-lactam=2ndor 3rd Cef, high dose amoxicillin or amoxicillin-clavulanate) 3. In regions with high rate (>25%) of high-level (MIC>
(Mandell LA, et al. Clin Infect Dis 2007; 44: S27-S72.)
16 μg/mL)macrolide-resistant S.pneumoniae, consider use of above (2)for patients without comorbidities
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IDSA/ATS consensus guidelines on the management of CAP in adults, 2007
Inpatients, non-ICU treatment - respiratory fluoroquinolone (moxifloxacin, gemifloxacn,levofloxacin 750 mg)
- β-lactam plus macrolideInpatient, ICU treatment
- β-lactam (cefotaxime, ceftriazone, ampicillin-sulbactam, amoxicillin-clavulanate, ertapenem)plus either azithromycin or respiratory fluoroquinolone
Special concernsIf P.aeruginosa is consideration
-antipneumococcal, antipseudomonal β-lactam (piperacillin,tazobactam, cefepime, imipenem, meropenem) pluseither ciprofloxacin or levofloxacin (750 mg)
-above β-lactam plus aminoglycoside and azithromycin(Mandell LA, et al. Clin Infect Dis 2007; 44: S27-S72.)
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CAP at Srinagarind Hospital, Khon KaenCAP at Srinagarind Hospital, CAP at Srinagarind Hospital, KhonKhon KaenKaenPathogen Severe CAP* Hospitalized CAP** Out-patient CAP***
(1999-2001) (2001-2002) (2003)N = 105 N = 254 N = 44
S.pneumoniae 13.3% 11.4% 27.3%B.pseudomallei 19.0% 11.0% 2.3%K.pneumoniae 12.3% 10.2% 9.1%C.pneumoniae - 8.7% 22.7%H.influenzae 7.6% 4.3% 31.8%H.parainfluenzae - - 27.3%M.pneumoniae 1.0% 3.9% 2.3%S.aureus 3.8% 3.5% 2.3%L.pneumophila - - 6.8%Other 7.6% 10.2% 20.4%Unknown 41.0% 42.9% 9.1%
* 6 patients infected with more than one organism** 16 patients infected with more than one organism
*** 22 patients infected with more than one organism
(Reechaipichitkul W, et al.)
Reechaipichitkul W. 23 May 2007 43
PRSP pneumonia hospitalized at Srinagarind Hospital
1995-200464 S.pneumoniae pneumonia cases
22 cases were PRSP (34.4%)
51.6% resist cotrimoxazole26.6% resist tetracycline20.6% resist erythromycin
MIC level between 0.25 and 0.75 μg/ml
(Reechaipichitkul W, et al. Southeast Asian J Trop Med Public Health 2006; 37: 320-6.)
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Univariate and multivariate analysis ofrisk factors associated with PRSP pneumonia
Variable Cruded OR Adjusted OR 95%CI P-valueAge >65 years 0.36 0.23 0.04 to 1.21 0.08
Co-morbidity >2 diseases 1.03 3.70 0.87 to 15.80 0.08
Previous antibiotic use 23.43 40.83 3.71 to 449.41 0.002*
within 3 monthsSteroid use 0.37 0.45 0.07 to 2.93 0.41
(>10 mg pred/day) Alcoholism 5.88 8.82 1.25 to 62.46 0.03**P-value <0.05
(Reechaipichitkul W, et al. Southeast Asian J Trop Med Public Health 2006; 37: 320-6.)
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Quick reference guide for CAP(Thailand)
Quick reference guide for CAP(Thailand)
ประเภทผูปวย ยาที่เลือกใช
1. การรักษาแบบผูปวยนอก
1.1 เดิมแข็งแรงดีและอายุ < 65 ป 1.1 doxycycline หรือ macrolide
1.2 มีโรคอื่นอยูเดมิหรือ อายุ > 65 ป 1.2.1 2nd , 3rd cephalosporin หรือamoxicillin/clavulanate
+ doxycycline หรอื + macrolideหรือ 1.2.2 monotherapy with
new fluoroquinolone
Reechaipichitkul W. 23 May 2007 46
Quick reference guide for CAP(Thailand)
Quick reference guide for CAP(Thailand)
ประเภทผูปวย ยาที่เลือกใช2. การรักษาแบบผูปวยใน 2.1 อาการไมรุนแรง 2.1 3rd cephalosporin หรอื
amoxicillin/clavulanate+ doxycycline หรือ + macrolide
2.2 อาการรุนแรง 2.2.1 - 3rd cephalosporin หรือ
amoxicillin/clavulanate+ macrolide หรือ + doxycycline
หรอื 2.2.2 - anti-pneumococcal fluoroquinolone+ 3rd cephalosporin
Reechaipichitkul W. 23 May 2007 47
ทั้งนี้มีขอพิจารณาเพิ่มเติมในผูปวยบางราย คือ
มีภูมลิาํเนาอยูในภาคตะวันออกเฉียงเหนอืในระยะฤดฝูน
โดยเฉพาะรายที่มีโรครวม เชน เบาหวาน หรือ ไตวายเรื้อรัง
ควรพิจารณาใหยาที่มีฤทธิฆ์าเชื้อ B.pseudomallei โดย
3rd cephalosporin ควรพิจารณาใหเปน ceftazidime 2 กรัม
ฉีดเขาเสนเลือดดําทุก 8 ชั่วโมง
มโีรคปอดอยูเดิม เชน bronchiectasis หรือ โรคปอดอุดกั้นเรื้อรังระดับรุนแรง
ควรพิจารณาใหยาที่มีฤทธิฆ์าเชื้อ P.aeruginosa
Reechaipichitkul W. 23 May 2007 48
ทั้งนี้มีขอพิจารณาเพิ่มเติมในผูปวยบางราย คือ
มีลักษณะทางคลินิกของกลามเนื้ออักเสบเฉพาะที่ หรือมีประวัติคลายไขหวัดใหญ
นํามากอนหรือ ติดยาเสพติด ควรพิจารณาใหยาที่มีฤทธิ์ฆาเชื้อ S.aureus
มีลักษณะทางคลินิกสงสัยเชื้อริคเกตเซียและเลปโตสไปรา เลือกใช doxycycline
แทน macrolide
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Respond to management Site of careInitial antibiotic within 4 hrEmpirical therapy
ตอบสนองตอการรักษาดีตั้งแตระยะแรกๆอาการทางคลินิกดีขึ้นภายใน 24-48 hr
ไมตอบสนองตอการรักษาหลังการรักษาผานไป72 hr
อาการทรุดลง หลังเริ่มการรักษา 24-48 hr
Early switch to oralEarly discharge
Re-evaluate:diagnosis, causative agentshost, complication
Reechaipichitkul W. 23 May 2007 50
Switch parenteral to oral formSwitch เมื่อ1. อาการทางคลินิกไอ เหนื่อยหอบ เสมหะดีขึน้
ไขลงเปนเวลาอยางนอย 8 hr.2. CBC พบ WBC ลดลง หรือเปลี่ยนแปลงในทางที่ดีขึน้3. ไมมีอาการคลื่นไส อาเจียน รับประทานอาหารและยา
ทางปากได
51
No response or delayed responce1. เลือกยาปฏิชีวนะไมเหมาะสม (indequate antibiotis selection)2. Unusal pathogen : Leptospira spp, Nocardia spp,
Histoplasmosis spp.Endemic pathogen : B.pseudomallei, Rickettsial tsutsugamushi
3. Complication : empyema thorasis, meningitis, arthritis, endocarditis
4. ติดเชื้อที่วินิจฉยัไดเฉพาะการตรวจพิเศษเทานั้น เชน bronchosiopy:PCP, fungus, TB (เชื้อนอย)
5. ไมใช CAP : CA lung, alveolar hemorrhage, BOOP, PE, CHF ARDS, hypersensitivity pneumonitis, acute interstitial pneumonia
Reechaipichitkul W. 23 May 2007 52
ATB and durationNarrow if known pathogenF/U 1-2 wk at OPD
- ถาอาการดีขึน้ชดัเจน ไมตอง CXR- ถาอาการดีขึน้ไมชัดเจน เชน ยังมีอาการไอ ไข เบือ่อาหาร ควรตรวจ CXR, sputum ซ้ําDuration ประมาณ 7-14 วันS.pneumoniae 7-10 วันAtypical pathogen 10-14 วัน
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New trend antibiotic use for CAPNewNew trendtrend antibiotic use antibiotic use for CAPfor CAPShort course high dose regimen
Improve compliance
Decrease problem of drug resistance
Levofloxacin 750 mg x 5 days vs
Azithromycin microsphere 2 g single dose
(D’ Ignazio J, et al. Antimicrob Agent Chemother 2005; 49: 4035-41.)
(Dunbar LM, et al. CID 2003; 37: 752-60.)
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Conclusion Do not use antibiotic in case of viral infection(dcreased resistance problem, side effect and cost)If equivocal, follow up symptoms & signs (+CXR) within 3 days are an importantEarly antibiotic in case of bacterial infection (within 4hr. in CAP) will improve outcomeAppropriate antibiotic -Which one, dose, duration (compliance)-Initial board spectrum antibiotic (cover likely organisms)
and then pathogen directed antibiotic (if identified etiology)-Awareness of resistance, side effect and cost effectiveness
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