Rational use of antibiotic in community-acquired pulmonary ... use of ATB, Wipa 23 May 2007.pdfRational use of antibiotic in community-acquired pulmonary infection รศ.พญ.วิภา

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

2

Common cold Bronchitis Pneumonia Sepsis

Respiratory tract infection

No antibiotic Need early antibiotic

Viral Bacterial

Do you OK?


Respiratory tract infection

Over use of antibiotics

Increased costSide effectInduced drug resistance

Under use of antibiotics

Sepsis, septic shockComplication (empyema)Increased cost


Lower respiratory tract infection (LRTI)

Acute bronchitis

Acute exacerbation of asthma

Acute exacerbation of COPD (AECB)

Community-acquired pneumonia (CAP)


Rational antibiotic use in LRTI

Viral vs BacterialNo antibiotic vs Need antibioticWhich antibiotic (s)Oral vs ParenteralDose and Duration

6

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


Bacterial or viral infection

Symptoms?

Signs?

Chest X-ray?Leukocytosis?

C-reactive protein?

Procalcitonin?


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

11

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.)


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


Chest X-ray

Diagnosed pneumonia Severity Complication


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


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%


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

*

*

24

Sputum Gram’s stainSputum Gram’s stain

S.aureus B.pseudomallei

High specificity

High specificity

Nocardia Strongyloidiasis

Special organismsSpecial

organisms


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.)


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%


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.)


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)


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




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


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


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


Switch parenteral to oral formSwitch เมื่อ1. อาการทางคลินิกไอ เหนื่อยหอบ เสมหะดีขึน้

ไขลงเปนเวลาอยางนอย 8 hr.2. CBC พบ WBC ลดลง หรือเปลี่ยนแปลงในทางที่ดีขึน้3. ไมมีอาการคลื่นไส อาเจียน รับประทานอาหารและยา

ทางปากได

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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


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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THANK YOU

Documents

Rational use of antibiotic in community-acquired pulmonary ... use of ATB, Wipa 23 May 2007.pdfRational use of antibiotic in community-acquired pulmonary infection รศ.พญ.วิภา