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Curriculum Vitae
Nama : Dr Fauzar, SpPD-KP, FINASIM
Tempat/tgl lahir : Bukittinggi, 4 Juli 1965
Pendidikan:
o Dokter Umum/S1 : FK - Unand th 1992
o Dokter Spesialis Penyakit Dalam : FK - Unand th 2005
o Konsultan Pulmonologi : FK - UI/ RSCM th 2014

Jabatan sekarang:
Ka Sub Bagian Paru, Bagian Ilmu Penyakit Dalam FK-Unand/RS M Djamil

Antibiotic Choice in
Pneumonia Management

FAUZAR

Subbagian Pulmonologi Bagian Ilmu Penyakit Dalam

FK-Unand/RSUP Dr M Djamil Padang

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Definisi

Pneumonia : suatu peradangan parenkim

paru, distal dari bronkiolus terminal yang
mencakup bronkiolus respiratorius dan alveoli
yang disebabkan oleh mikroorganisme
(bakteri, virus, jamur, parasit).

KLASIFIKASI PNEUMONIA

CAP HCAP Membantu

pemilihan
antibiotik
empiris
awal yang
HAP VAP lebih tepat

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Terminologi HCAP dihapuskan

• IDSA/ATS 2005  HCAP
Pneumonia pada pasien non hospitalisasi yang
memiliki kontak signifikan dengan sistem
pelayanan kesehatan.

Dianggap memiliki risiko tinggi terinfeksi bakteri

MDR

Namun, banyak pasien HCAP tidak terinfeksi

bakteri MDR.
IDSA/ATS 2016  istilah HCAP dihapuskan. 5
Kalil AC, Matersky ML, Klompas M, Musceder J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired pneumonia and ventilator-associated pneumonia:
2016 Clinical practice guidelines by Infectius Disease Society of America and the American Thoracic Society .Clinical Infectius Diseases 2016; 1-50.

Pengobatan Pneumonia
Antibiotik
Idealnya berdasarkan:
• Pola resistensi kuman
setempat
• Tes sensitifitas

Suportif

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Antibiotik Empiris
Karena beberapa alasan yaitu :
Penyakit yang berat dapat mengancam jiwa

•Bakteri patogen yang berhasil diisolasi

belum tentu sebagai penyebab pneumonia

•Hasil pembiakan bakteri memerlukan

waktu

•Keterlambatan pemberian antibiotik

meningkatkan mortalitas

Pemilihan Antibiotik

IDSA & ATS 2016 merekomendasikan

seluruh rumah sakit memiliki antibiogram
lokal

Sehingga pemberian antibiotik empiris

berdasarkan distribusi lokal patogen
yang berhubungan dengan pneumonia
dan kepekaannya terhadap antimikroba

Antibiogram digunakan untuk meminimalisir

paparan terhadap antibiotik yang tidak perlu
dan menurunkan tingkat resistensi antibiotik

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Antibiogram memerlukan pembaruan dimana frekuensinya tergantung masing-masing rumah sakit.

Di RSUP M. Djamil Padang, pembaruan dilakukan satu tahun sekali.
Terdapat perbedaan yang signifikan terhadap frekuensi resistensi antimikroba antara satu rumah sakit
dengan rumah sakit lainnya

Pugh R, Grant C, Cooke RP, Dempsey G. Short-course versus prolonged course antibiotic therapy for hospital-acquired pneumonia in critically ill adults.
Cochrane Database Syst Rev 2015; 8:Cd007577. 9

Dasar pemilihan antibiotik empiris :

Jenis Pneumoninya

Keadaan klinis pasien

Pola kuman setempat

Data antibiogram setempat

Adanya faktor risiko kuman MDR dan mortalitas

Faktor lain seperti biaya, ketersediaan dan formularium

setempat

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Pemilihan Antibiotik Pada

Community Acquired Pneumonia

Site of Care Decision

Menentukan terapi dan arah diagnostik selanjutnya :

Site of
Care

Rawat Rawat
Jalan Inap

Non ICU ICU

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Site of Care Decision

Pengambilan keputusan untuk site of care
dapat dinilai dengan cara:
a) Obyektif: dengan menggunakan scoring
system (CURB 65, PSI)
b) Subyektif: penilaian klinisi mengenai keadaan
secara umum dari pasien

Bacterial Causes of CAP

• Streptococcus pneumoniae 16-60%

• Haemophilus influenzae 3-38%
• Legionella spp 2-30%
• Mycoplasma pneumoniae 1-20%
• Other aerobic Gram-neg 7-18%
• Chlamydophila pneumoniae 6-12%
• Staphylococcus aureus 2-5%

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Antibiotik Empirik CAP

 Antibiotik empiris
didasarkan atas
prediksi kuman
patogen
terbanyak
penyebab CAP
dan pengetahuan
mengenai
suseptibilitas di
tempat tersebut

Rekomendasi terapi empirik pada CAP

rawat jalan

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Rekomendasi terapi empirik pada CAP

rawat inap

Rekomendasi terapi empirik pada CAP

dengan kondisi khusus

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Pemilihan Antibiotik Pada

Hospital Acquired Pneumonia

Presentation Title

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Guideline Pemilihan Antibiotik

Empiris untuk HAP

Fakor Risiko Kuman MDR

• Pemakaian Antibiotik IV dalam 90 hari terakhir

• Dirawat difaskes dengan isolat S. aureus positif
MRSA > 20% ( risiko MRSA)

Risiko Tinggi Mortalitas

• Pasien HAP yang butuh ventilator
• HAP dengan shock sepsis
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Patogen MDR

• Pseudomonas aeruginosa
• Klebsiella pneumoniae
• Acinetobacter sp
• Escherichia coli dan
• Methicillin-resistent Staphylococcus
aureus (MRSA).

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Guideline Pemilihan Antibiotik

Empiris Pada HAP

Faktor Risiko Risiko Tinggi

MRSA Mortalitas

Antibiotik IV
dalam 90 hari
terakhir Ventilator

Dirawat di HAP dengan

faskes dengan syok sepsis
isolat S.aureus
MRSA > 20%

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Not at High Risk of Mortality and no Factors Increasing the

Likelihood of MRSA

Piperacillin-tazobactam 4,5 g IV q6h

OR
Cefepim 2 g IV q8h
OR
Levofloxacin 750 mg IV daily
OR
Imipenem 500 mg IV q6h
Meropenem 1 g IV q8h

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Not at High Risk of Mortality but With Factors Increasing The

Likelihood of MRSA
Piperacillin-tazobactam 4,5 g IV q6h
OR
Cefepim or ceftazidime 2 g IV q8h
OR
Levofloxacin 750 mg IV daily
Ciprofloxacin 400 mg IV q8h
OR
Imipenem 500 mg IV q6h
Meropenem 1 g IV q6h
OR
Aztreonam
Plus :
Vancomisin 15 mg/kgBB IV q8-12h with goal to target 15-20 mg/ml trough level
consider a laoding dose of 25-30/kg for several ill
OR
Linezolid 600 mg IV q12h

High Risk of Mortality or Receip of Intravenous Antibiotics During th Prior 90d

Two of the following , avoid two 2 β lactam

peracillin-tazobactam 4,5 g IV q6h
OR
Cefepim or ceftazidime 2 g IV q8h
OR
Levofloxacin 750 mg IV daily
Ciprofloxacin 400 mg IV q8h
OR
Imipenem 500 mg IV q6h
Meropenem 1 g IV q6h
OR
Amikasin, Gentamicin,Tobramicin
OR
Aztreonam
Plus :
Vancomisin 15 mg/kgBB IV q8-12h with goal to target 15-20 mg/ml trough level
consider a laoding dose of 25-30/kg for several ill
OR
Linezolid 600 mg IV q12h

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Pemilihan Antibiotik Pada

Ventilator Associated Pneumonia

Rekomendasi Pemberian Antiobiotik Empirik pada Pasien dengan VAP

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Rekomendasi Pemberian Antiobiotik Empirik pada Pasien dengan VAP

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Gram-Positive Antibiotics with MRSA Activity

• Glycopeptides
• Vancomycin 15 mg/kg IV q8-12h (consider
a loading dose of 25-30 mg/kg x 1 for
severe illness
• OR
• Oxazolidinones
• Linezolid 600mg IV q12h

Gram-Negative Antibiotics with Antipseudomonal Activity:

β-Lactam-Based Agents

• Antipseudomonal penicillins
• Piperacillin-tazobactam 4.5g IV q6h
• OR
• Cephalosporins
• Cefepime 2 g IV q8h
• Ceftazidime 2 g IV q8h
• OR
• Carbapenems
• Imipenem 500 mg IV q6h
• Meropenem 1 g IV q8h
• OR
• Monobactams
• Aztreonam 2 g IV q8h

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Gram-Negative Antibiotics with Antipseudomonal Activity:

Non-β-Lactam-Based Agents

• Fluoroquinolones
• Ciprofloxacin 400 mg IV q8h
• Levofloxacin 750 mg IV q24h
• OR
• Aminoglycosides
• Amikacin 15-20 mg/kg IV q24h
• Gentamicin 5-7 mg/kg IV q24h
• Tobramycin 5-7 mg/kg IV q24h
• OR
• Polymyxins
• Colistin 5 mg/kg IV x 1 (loading dose) followed by 2.5 mg
x (1.5xCrCl + 30) IV q12h (maintenance dose). Polymyxin B
2.5-3.0 mg/kg/d divided in 2 daily IV doses

Rubinstein et al., 2001; Wunderinket al., 2003

Linezolid versus vancomycin in

NP: clinical cure rates
• Similar clinical cure rates across treatment groups

Linezolid 600mg i.v . Vancomy cin 1g i.v . q12h

Vancomy cin 1 g i.v . q12h Linezolid 600 mg i.v .
q12h
q12h p=ns
80 80 p=ns
70 66.4 68.1 70 67.9
p=ns 114/168 64.9
Clinical cure rate (%)

p=ns
Clinical cure rate (%)

53.4 52.1 60
111/171
52.7 52.2
50 50

40 40

30 30

20 20

135/256
0 128/245
0
ITT C linic ally e valuab le p atie nts ITT Clinica lly e valuable p a tients

Clinical cure defined as: resolution or improvement of baseline symptoms

Clinical cure defined as: resolution or improvement in baseline symptoms and and symptoms of pneumonia, with improvement or lack of progression of
radiograph, with no further requirement for antimicrobial therapy radiographic findings

Adapted from Rubinstein E, et al. Clin Infect Dis 2001;32:402–12 Adapted from Wunderink RG, et al. Clin Ther 2003;25:980–92

ns, not significant

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Rubinstein et al., 2001; Wunderinket al., 2003

Linezolid versus vancomycin in NP:

microbiological success rates

• Similar microbiological success rates were seen in between treatment groups in

both studies
Study 1: pathogen eradication rates (%)1 Study 2: pathogen eradication rates (%)2
Linezolid Vancomycin Linezolid Vancomycin

S. aureus 61.0 65.1 S. aureus 53.8 43.5

MRSA 65.2 77.8 MRSA 63.2 43.5
S. pneumoniae 100 100 S. pneumoniae 77.8 92.3

Study 11
• 67.9% of patients treated with linezolid
• 71.8% of patients treated with vancomycin (p=ns)
Study 22
• 61.8% of patients treated with linezolid
• 53.2% of patients treated with vancomycin (p=ns)

1. Rubinstein E, et al. Clin Infect Dis 2001;32:402–12; 2. Wunderink RG, et al. Clin Ther 2003;25:980–92

Rubinstein et al., 2001; Wunderinket al., 2003

Linezolid versus vancomycin in NP:

safety and tolerability

• Both linezolid and vancomycin were well tolerated

Study 11 Study 22
3
Linezolid 600mg i.v. q12h 30 Linezolid 600mg i.v. q12h

vancomycin 1g i.v. q12h

Vancomycin 1g i.v. q12h
19.9 20.2
20
14.0 14.0

10
9/1
143 0 4 /1 3 0 9 36/2 3 9 193
0
Treatment discontinuation Death during study
due to AEs

AE, adverse event

1.Rubinstein E, et al. Clin Infect Dis 2001;32:402–12 2. Wunderink RG, et al. Clin Ther 2003;25:980–92.

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Rubinstein et al., 2001; Wunderinket al., 2003

Linezolid versus vancomycin in NP:

study conclusions
Efficacy
• Clinical cure rates for Linezolid (plus aztreonam) were equivalent to those reported for
vancomycin (plus aztreonam) in both studies
• Pathogen eradication rates were similar for both treatment groups, irrespective of the
pathogen

Safety and tolerability

• Linezolid has a good safety profile, and is well tolerated in the treatment of NP
• Most AEs in both treatment groups were of mild-to-moderate intensity and of limited
duration
• In Study 2, overall survival was similar for Linezolid and vancomycin groups, with a
difference in favour of Linezolid in patients with baseline APACHE-II scores of 16–19
(p=0.011)

These studies demonstrate that Linezolid and vancomycin are equally effective in
treating NP, with respect to clinical and microbiological outcomes

AE, adverse event

1.Rubinstein E, et al. Clin Infect Dis 2001;32:402–12
2. Wunderink RG, et al. Clin Ther 2003;25:980–92.

Wunderink et al., 2012

Linezolid versus vancomycin in

NP proven to be due to MRSA

Study design: Nosocomial pneumonia patients

(n=1225)
1:1 randomization and start of
treatment for 7-14 days *

Linezolid 600 mg
Vancomycin 30 mg/kg IV q12h
IV or oral q12h

Culture
(+) MRSA results
av ailable
(-) MRSA (-) MRSA

Discontinued Continue Continue Discontinued

This study was a non-inferiority trial with a nested superiority hypothesis

•except in subj ects with documented bacteremia who can be treated for up to 21 days at the discretion of the investigator

Wunderink RG et al, Clin Infect Dis 2012; 54(5): p. 621-629

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Wunderink et al., 2012

ZEPHyR Primary End Point: Clinical Cure

at EOS (Per-Protocol Population)
Clinical Cure Rate Statistically Significantly Higher
With Linezolid than Vancomycin

P=.042 95% CI: 0.5, 21.6

Patients (%) With
Clinical Cure

95/165 81/174
Linezolid Vancomycin
9 indeterminate were
excluded from the analysis
600 mg IV q12h 15 mg/kg IV q12h
CI, confidence interval; IV,
intravenous.
Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629.

Wunderink et al., 2012

ZEPHyR Clinical Response at EOS and

EOT (Per-Protocol and mITT Populations)

95% CI: 4.9, 22.0

95% CI: 4.0, 20.7

P=.042
95% CI: .5, 21.6 95% CI: .1, 19.8
Clinical Response
Patients (%) With

95/165 81/174 102/186 92/205 150/180 130/186 161/201 145/214

PrimaryEnd Point SecondaryEnd Points

Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629

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Wunderink et al., 2012

ZEPHyR Secondary End Point: Microbiologic

Response Rates at EOS and EOT
Patients With Respiratory
Per-Protocol Population
Secretions for Culture
Documented eradication* Presumed eradication†
95% CI: 12.3, 30.2
100 82.6%
81.9%
(76/92)
Microbiologic Response

(149/182)
95% CI: .4, 21.5
Patients (%) With

80
61.4%
58.1% 60.6% (35/57) 54.1%
(97/167) 49.0% (114/188) (59/109)
50.0%
60 73/149
(26/52)
47.1%
(82/174) 48.2%
55/114
40 (62/97)
68.3%
56/82
51.0%
20 (76/149) 51.8%
36.1% (59/114
31.7%
(35/97)
(26/82)
0
Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin Linezolid Vancomycin
EOS EOT EOS EOT
† No microbiologic data, but confirmed clinical cure.
•Microbiologic data available, confirmed microbiologic eradication.

Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629

Wunderink et al., 2012

ZEPHyR Secondary End Point: Clinically

Important Investigator-Reported All-Cause
Adverse Events (ITT Population)
Linezolid Vancomycin
Adverse Event, n (%) (n=597) (n=587)
Anemia 30 (5.2) 42 (7.2)
Renal failure/impairment/azotemia* 22 (3.7) 43 (7.3)
Cardiac arrest 11 (1.8) 13 (2.2)
Thrombocytopenia 8 (1.3) 13 (2.2)
Pancreatitis 5 (0.8) 1 (0.2)
Polyneuropathy — 1 (0.2)
Pancytopenia/neutropenia 4 (0.6) 2 (0.4)
Paresthesia — 1 (0.2)

•Patient was reported to have at least 1 (or >1) of the following: renal failure, renal impairment, and/or azotemia.

Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629

41

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Wunderink et al., 2012

ZEPHyR Conclusions:
Efficacy
• For the primary end point, linezolid achieved a statistically
significantly higher success rate compared with vancomycin1
• Similar results observed for clinical and microbiologic
response at EOS and EOT in per-protocol and mITT populations1
• Microbiologic responses paralleled clinical outcomes1
• MRSA clearance at EOT was 30% greater with linezolid
than with vancomycin
• Results confirm pattern of clinical efficacy seen in prior
subgroup analyses of studies comparing linezolid with
vancomycin in MRSA nosocomial pneumonia2,3

1. Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629

2. Wunderink RG et al. Chest. 2003;124(5):1789- 1797.
3. Kollef MH et al. Intensive Care Med. 2004;30(3):388-394.

Wunderink et al., 2012

ZEPHyR Conclusions:
Adverse Events

• Although overall serious AEs and AEs were equivalent,

nephrotoxicity was nearly twice as common in the
vancomycin group1

• More frequent hematologic abnormalities (eg, anemia,

thrombocytopenia) previously reported with linezolid were
not observed in ZEPHyR2
• Possibly due to short duration of therapy

1. Wunderink RG et al, Clinical Infectious Diseases. 2012; 54(5): p. 621-629

2. Kalil AC et al. Crit Care Med. 2010;38(9):1802-1808.

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Clinical Efficacy of
Piperacillin/Tazobactam in HAP

An Evidence-based Review of Randomized

Control Studies

Piperacillin vs Imipenem
Jaccard C, Troillet N, Harbarth S, et al. Antimicrob Agents Chemother 1998 Nov;42(11):2966-2972.

Piperacillin/Tazobactam vs Ceftazadime
Joshi M, Bernstein J, Solomkin J, et al. J Antimicrob Chemother 1999;43:389-397.
Alvarez-Lerma F, Insausti-Ordenana J, Jorda-Marcos R, et al. Intensive Care Med 2001;27:493-502.
Brun-Buisson C, Sollet JP, Schweich H, et al. Clin Infect Dis 1998 Feb;26:346-354.
Fowler RA, Flavin KE, Barr J, et al. Chest 2003 Mar;123(3):835-844.

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Piperacillin/Tazobactam vs.
Imipenem in HAP
 Prospective, randomized, multicenter (Switzerland)
 Adult (≥72 h in hospital)
 Piperacillin/tazobactam – 4.5 g q8h IV
OR
 Imipenem/cilastatin – 500 mg/500 mg q6h IV

 HAP episodes: clinical and bacteriologic response

 Evaluable patients
 75 in piperacillin/tazobactam group
 79 in imipenem/cilastatin group

Jaccard C, Troillet N, Harbarth S, et al. Antimicrob Agents Chemother 1998 Nov;42(11):2966-2972.

Success Rates in Evaluable †

Patients
Piperacillin/ Imipenem/ P value
tazobactam cilastatin
Clinical 83% 71% 0.09
response (62/75) (56/79)
P. aeruginosa 91% 50% 0.004
response (19/21) (12/24)
†
Cure was defined as the resolution of symptoms of pneumonia and an improved chest radiograph.

• Pseudomonas pneumonia failure

Pip/tazo - 2/21 (10%)
Imipenem - 12/24 (50%); P = 0.004
• Resistance developed during therapy
Pip/tazo - 1 patient
Imipenem - 6 patients

Jaccard C, Troillet N, Harbarth S, et al. Antimicrob Agents Chemother 1998 Nov;42(11):2966-2972.

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Piperacillin/Tazobactam + Amikacin vs.

Ceftazidime + Amikacin
 Prospective, randomized, open, multicenter (Spain)
 Adult
 Piperacillin/tazobactam – 4.5 g q6h IV PLUS
OR Amikacin
 Ceftazidime – 2 g q8h IV 15 mg/kg/day,
divided
 HAP episodes
 Clinical response
 Cured, improved, relapse, or failure
 Bacteriologic response
 Eradication, presumed eradication, superinfection, relapse,
or failure

Alvarez-Lerma F, Insausti-Ordeñana J, Jordá-Marcos R, et al. Intensive Care Med 2001;27:493- 502.

Success Rates in Evaluable †

Patients
Pip/tazo Ceftazidime P-
+ Amikacin + Amikacin value
Clinical 63.9% 61.5% 0.831
response (53/83) (16/26)
Microbiologic 68.9% 65.0% 0.757
response (31/45) (13/20)
†Successful outcomes included a cured or improved clinical response, and an eradication
or presumed eradication of the baseline pathogen.

Alvarez-Lerma F, Insausti-Ordeñana J, Jordá-Marcos R, et al. Intensive Care Med 2001;27:493-502.

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Piperacillin/Tazobactam
Combination Therapy
Compared with ceftazidime + amikacin:
 Equivalent treatment efficacy
 Similar eradication rates of baseline pathogen
 Attributable mortality rate
 Not statistically significant

Alvarez-Lerma F, Insausti-Ordeñana J, Jordá-Marcos R, et al. Intensive Care Med 2001;27:493-502.

TERIMA KASIH

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Pathogen-specific Therapy (IDSA 2016)

Pathogen Recommendation
MRSA HAP/VAP Either vancomycin or linezolid rather than other antibiotics or
antibiotic combinations
P. aeruginosa Against aminoglycoside monotherapy
Antibiotic for definitive (not empiric) therapy be based upon the
results of antimicrobial susceptibility testing
Extended-Spectrum Choice of an antibiotic for definitive (not empiric) therapy be
β-Lactamase based upon the results of antimicrobial susceptibility testing and
(ESBL)–Producing patient-specific factors
Gram- Negative
Bacilli
Acinetobacter spp. Treatment with either a carbapenem or ampicillin/sulbactam if the
isolate is susceptible to these agents
Acinetobacter species that is sensitive only to polymyxins, we
recommend intravenous polymyxin (colistin or polymyxin B) and
we suggest adjunctive inhaled colistin
Carbapenem- Intravenous polymyxins (colistin or polymyxin B) and adjunctive
Resistant Pathogen inhaled colistin for pathogens sensitive only to polymyxins

Adapted from Kalil AC, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and
57
the American Thoracic Society. Clin Infect Dis.2016:ciw353.

Criteria for Severe Community-Acquired

Pneumonia

Minor Criteria
• Respiratory rate ≥30 breaths/min
• PaO 2/FiO2 ≤250
• M ultilobar infiltrates
• Co nsfusion/disorientation
• Uremia (BUN level, ≥20 mg/dL)
• Leukopenia (WBC count, <4000 cells/mm3)
• Thrombocytopenia (platelet count, <100.000 cells/mm3)
• Hypothermia (core temperature, < 36◦C)
• Hypotension requiring aggressive fluid resuscitation

Major Criteria
• Invasive mechanical ventilation
• S eptic shock with the need for vasopressors
Note : BUN, blood urea nitrogen; PaO2/FiO2, arterial oxygen pressure/fraction of
inspired oxygen; WBC, white bood cell.

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