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Education : Dokter Umum, FK Universitas Sam Ratulangi 1987

Dokter Spesialis Penyakit Dalam FK Universitas Airlangga

1999

Konsultan Intensive Care FK Universitas Indonesia 2004

Position : Staff pengajar Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Tarumanegara Jakarta

Kepala ICU RS Royal Taruma JakartaKepala ICU RS MH Thamrin Salemba Jakarta

Organization : PERDICIPKGDI

dr. Frans Pangalila, SpPD-KICTempat/tanggal lahir : Surabaya, 31 Maret

The Potential Use of Fosfomycine for Management of Multidrug-Resistant in ICU

Frans JV Pangalila(Intensivist)

Case Report :31 years old - male with chronic steroid used due to lupusadmitted to ICU : restlessness - red frothy sputum

Chest X ray : bilateral infiltrate+ cardiomegali

Assessment- Lupus nephritis- Bronchopneumonia / Lung edema- Hyperglycemia- Severe sepsis

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....day 5 in HCU ( day 1 in ICU )developed : papule-vesicle started from the neck-facies and then entirely the whole bodyhemodynamic become unstable and hematemesis melena (+)

Chest x ray : infiltrate >>> + cardiomegali

Clinical Assesment Day 5 in ICU

Acute Respiratory Distress Syndrome (ARDS)-PaO2 / FiO2 ratio 125

Malignant Varicella (effloresence : vesicle/papule )GUT failure - hematemesis melenaFulminant Hepatitis + DIC

- AST 6780 ALT 7300 APTT >> dDimer 6400- Trombosit 88.000 Amoniak 235 Albumin 2.4

Acute Kidney Injury (on dialysis)Severe Sepsis

-Lekosit 22.700 Netrofil 93% procalcitonin 88 CRP 218

What is the Appropriate-Adequate Antimicrobial Chemotherapy ?

Discussion

• this case demonstrated :→ Severe Sepsis / Syok Septikmeans that :

• Bacterial load >> , MIC ↑ , MDR(+)• Macrofage dysfunction• Hipercatabolic / hipermetabolic

→ hipoalbumin→ increased volume distribution

Antibiotic appropriate-adequate- Hit hard (Big dose) and Fast -

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Major Bacterial Negative Nightmares in the Hospital Environment and ICU setting

Potensial Mechanisms of Resistance Gram Negative Bacteria

High Mortality Reaching 75% !!- How to Treat ?

CID 2009

The Result of Chaos.....

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Do You Know - What has been reported by Global Sepsis Alliance ( GSA)??

“ Every seconds someone dies of Sepsisacross the globe “

The Bacterial ChallengesECDC/EMEA joint technical report september 2009

each year, about 25.000 patients die in the EU from an infectioncaused by multidrug-resistant bacteriainfections due to these selected multidrug-resistant bacteria in the EU result in extra healthcare costs of > 900 million EUR andproductivity losses of at least EUR 1.5 billion each year

Appropriate :- the use of an antibiotic→ the etiologic of microorganism is sensitive andin a correct time

Adequate :- the correct dose for the

correct duration withadvantageous pk/pd parameter at the site of infection

- combination if possible

Appropriate- sensitivity and timing

Adequate - penetration

Best Outcome

Optimal(pk/pd driven)

We always required“ Early Appropriate-Adequate Antimicrobial Treatment “

The common reason of inappropriate Antimicrobial that trigger the MDR infection

lack of confidence to diagnose an infection and to identified highrisk of MDRpoor understanding of pk/pd parameterlack knowledge of local resistance antibiogram data

Population of patients not infected with MDR Infection

Subpopulation of patients infected

with MDR

Treatment of Infection

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(CHEST 2003)

“ Get it Right for the First Time“

Axiom : its really important for the physician to appreciate - what they entertained for the first time !!....sepsis – septic shock ?

not Critically Ill patients

Critically Ill patients

Baddour et al.AJRCCM 2004

Combination antibiotic therapy improved survival among critically ill patiens with bacteremic pneumococcal (but limit the duration of the combination to 3 - 5 days)

Pathogens associated with inappropriate initial therapy in VAP

Axiom : its important for the physician to identified an High Risk of MDR for the first time !!

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Pk/Pd parameter : dose optimization

Adequate Dose

Prolonged infusion increased free drug time > MIC and improved cell kill in an invitro of P.aeruginosa infection Louie et al AAC 2010

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Clinical and Economic Implications of an Extended -Infusion Dosing Strategy of Piperacillin-Tazobactam

for P.aeruginosaat Albany Medical Centre, investigators devised an alternative Pip-Tazodosing scheme that optimized pharmacodynamic (50% T > MIC) at atotal daily dose less than traditional dosing methodsidentified : P/T 3.375 g every 8 hours (4-h infusion) as an alternativemeans to traditional P/T dosing 3.375 g iv q4-6h (0.5 –hour infusion)

Lodise TP et al CID 2007

Known your local data

Local Data : sensitivity and antibiogram Royal Taruma Hospital

The recent case : Mr J 68 yrs (13 april 2012)Assessment : Chronic Subdural Hematom + Stroke NH + COPD+ NIDDM, after 3 weeks in ICU with tracheostomy - Culture : A.baumanii (+) Problem : difficult weaning !

What is the Appropriate AntimicrobialChemotherapy should be given to this case ??

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The Available Antibiotics for MDR Microorganisms

P.aeruginosa(IMP, MBL, KPC)

colistinfosfomycine

carbapenem /doripenem

K.pneumoniae(ESBL, MBL, KPC)

colistintigecyclin

fosfomycine

A.baumanii(AmpC, ESBL, MBL,

OXA-48)

colistintigecyclin

sulbactam (high dose)

MRSA (VRA)

neoglycoside ?ACHN-490 ?

all gram (-) MDR(except NDM-1)

linezolideteicoplanin

• 8 patients with HAP• MIC to doripenem 4 - 8 ụ/ml• clinical cure 60% microbial cure 72%,respectively• with doripenem 1g 4 hour infusion target attaintmentfor P.aeruginosa with MIC = 4ụ/ml , 97.2%

Clinical Characteristic and Outcomes of 18 patients with Carbapenem-Resistant P.aeruginosa and A.baumanii VAP

Treated with Combination Carbapenem-FosfomycineInternal File Data : ICU Royal Taruma Hospital

• 18 patients with Ventilator Associated Pneumonia after at least 10 - 12 days hospitalized ( consist of 15 patientsPseudomonas (83%) and 3 patients Acinetobacter (17%)

• Treatment arm : meropenem 3 x 1 gr or doripenem 3x1gr(4 hour infusion) with fosfomycine 3 x 2gr (1.5 - 2 hourinfusion)

• Time to receipt of combination regimen : 5 - 6 days• Results :

- P.aeruginosa : clinical improvement 73.3%- A.baumanii : all failure ( 2 patients death and 1 patien change toanother antibiotic )

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patient sex Age,yrs Comorbid Microorganism Clinical outcome

1 M 64 Stroke NH, NIDDM P.aeruginosa Improved

2 M 62 NIDDM, CAD, COPD P.aeruginosa Failure (death)

3 F 66 NIDDM, Alzheimers P.aeruginosa Improved

4 M 49 Stroke H, AKI P.aeruginosa Improved

5 F 58 Stroke NH, NIDDM, AKI P.aeruginosa Improved

6 M 38 Severe Head Injury P.aeruginosa Improve

7 M 65 Post hemicolectomy, NIDDM, AKI

P.aeruginosa Failure (death)

8 F 70 NIDDM, CAD, COPD, AKI A.baumanii Failure (death)

9 M 59 Liver cirrhosis, COPD P.aeruginosa Improved

Clinical Characteristic and Outcomes of 18 patients with Carbapenem-Resistant P.aeruginosa and A.baumanii VAP Treated

with Combination Carbapenem-Fosfomycine

NIDDM : non insulin depedent diabetes mellitus CAD: coronary artery disease AKI : Acute Kidney InjuryCOPD : chronic obstructive pulmonary disease Stroke NH/H : stroke non hemorragic / hemorrhagic

Patient Sex Age,yrs Comorbid Microorganism Clinical outcome

10 M 61 Stroke NH, NIDDM, CAD A.baumanii Failure*11 M 30 Severe Head Injury P.aeruginosa Improved

12 F 37 Meningitis, TB pulmonar A.baumanii Failure (death)

13 M 46 NIDDM, HIV P.aeruginosa Failure (death)

14 M 78 Stroke H P.aeruginosa Improved

15 F 52 NIDDM, CKD P.aeruginosa Improved

16 M 72 NIDDM, BPH P.aeruginosa Improved

17 F 67 Stroke NH, NIDDM, CHF P.aeruginosa Failure *18 F 33 Preeclampsi, AKI P.aeruginosa Improved

* Failure : changes with another antibiotic CHF : congestive heart failureCKD : chronic kidney disease BPH : benigna prostat hypertrophy

Internal Data File : ICU Royal Taruma Hospital

Clinical success / cure rate: > 92%

Lancet Infect Dis 2010

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Known your local dataLocal Data : ESBL 2012 ( Royal Taruma Hospital )

Internal Data File : ICU Royal Taruma Hospital

Key Issues

Early appropriate-adequate antimicrobial therapy ( within1 hour after diagnosis ) should be administration in severe infection (combination if possible) Host characteristic, source of infection and local ecologyare determinants of choice empirical antimicrobial therapyUse of pk/pd principles to optimize dosing in order tominimize risk of failure and emerge of bacterial resistanteven with limited data : Fosfomycine could be provide asalternative combination antimicrobial in severe infectiondue to MDR pathogen