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Curriculum VitaeCurriculum VitaeNamaNama : : Dr. Ronald Irwanto, SpPD Dr. Ronald Irwanto, SpPD -- KPTIKPTI

PendidikanPendidikan ::

SMA SMA : Kolese KANISIUS, 1994: Kolese KANISIUS, 1994Dokter UmumDokter Umum : FK TRISAKTI, 2001: FK TRISAKTI, 2001Spesialis Penyakit Dalam (Internist)Spesialis Penyakit Dalam (Internist) : FKUI, 2009: FKUI, 2009Konsultan Penyakit Tropik & InfeksiKonsultan Penyakit Tropik & Infeksi : FKUI, 2013: FKUI, 2013

PekerjaanPekerjaan ::

Anggota PETRI (Perhimpunan Peneliti Penyakit Tropik & Infeksi Anggota PETRI (Perhimpunan Peneliti Penyakit Tropik & Infeksi Indonesia)Indonesia)

Staf Pengajar Bagian Ilmu Penyakit Dalam, FK TRISAKTI, JakartaStaf Pengajar Bagian Ilmu Penyakit Dalam, FK TRISAKTI, Jakarta

Dokter RS PONDOK INDAH Dokter RS PONDOK INDAH –– PURI INDAH, JakartaPURI INDAH, Jakarta

Emerging cSSTIs Problem : Emerging cSSTIs Problem : Focus on MRSA Treatment Focus on MRSA Treatment

Ronald IrwantoRonald IrwantoDivision of Tropical Medicine and Infectious DiseaseDivision of Tropical Medicine and Infectious Disease

Department of Internal MedicineDepartment of Internal MedicineFaculty of Medicine University of IndonesiaFaculty of Medicine University of Indonesia

Staphylococci Associated Staphylococci Associated with Human Diseasewith Human Disease

S. aureusS. aureusS. epidermidisS. epidermidisS.saprophyticusS.saprophyticus

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Gram (+)ve BacteriaGram (+)ve Bacteria

OrganismOrganism CarrierCarrier InfectionsInfectionsCoagulatedCoagulated--positivepositivestaphylococci staphylococci ((S. aureusS. aureus))

Skin Skin Nasopharynx Nasopharynx VaginaVagina

SkinSkin : folliculitis, impetigo, furuncles, cellulitis, : folliculitis, impetigo, furuncles, cellulitis, carbuncles, postoperative wound infectionscarbuncles, postoperative wound infections

Deep InfectionsDeep Infections : endocarditis, meningitis, : endocarditis, meningitis, arthritis, pneumonia, osteomyelitis, pyomyositis, arthritis, pneumonia, osteomyelitis, pyomyositis, sepsis, and multiple organ failure.sepsis, and multiple organ failure.

ToxinToxin--mediated diseasemediated disease : food poisoning, : food poisoning, scalded skin syndrome, toxic shock syndrome.scalded skin syndrome, toxic shock syndrome.

CoagulaseCoagulase--negative negative staphylococcistaphylococci((S. epidermidisS. epidermidisand others)and others)

Skin Ear canal Skin Ear canal Genitourinary tractGenitourinary tract

§§ Indwelling foreign bodies infectionsIndwelling foreign bodies infections : prosthetic cardiac : prosthetic cardiac valves, permanent pacemaker wires and electrodes, valves, permanent pacemaker wires and electrodes, vascular grafts, cerebrospinal fluid shunts, peritoneal vascular grafts, cerebrospinal fluid shunts, peritoneal dialysis catheters, prosthetic joints, intravenous dialysis catheters, prosthetic joints, intravenous catheter.catheter.

Mucosal Mucosal membranesmembranes

§§ Urinary tract infectionUrinary tract infection : : nosocomialnosocomial ((S.epidermidisS.epidermidis); ); outpatient women (outpatient women (S. S. saprophyticussaprophyticus).).

§§ OtherOther : postoperative : postoperative endophthalmitisendophthalmitis, , native valve native valve endocarditisendocarditis, , osteomyelitisosteomyelitis..

Gates RH, Infectious Diseases Secret 2nd edition, 2003

What is MRSA?What is MRSA?

Definition: oxacillin minimum inhibitory Definition: oxacillin minimum inhibitory concentration (MIC) >= 4microgram/mlconcentration (MIC) >= 4microgram/mlResistant to Resistant to methicillinmethicillin..Resistant to Resistant to betalactambetalactam ::

Penicillin, cephalosporin, Penicillin, cephalosporin, carbapenem and betalactamase carbapenem and betalactamase inhibitor/betalactam combinations inhibitor/betalactam combinations

Staphylococcus Character ChangesStaphylococcus Character Changes

The mecA gene encodes for a 78-kDa penicillin-binding protein (PBP) 2A, which has unusually low affinity for all β-lactam antibiotics—a property that translates to the virtually complete resistance of MRSA strains to the entire β-lactam family ofantimicrobial agents

Pinho MG, Lencastre H, Tomasz A, An acquired and a native penicillin binding protein cooperate in building the cell wall of drug resistance staphylococci,2001

Model for the cooperative functioning of the TGase domain of PBP2 and the TPase activity of PBP2A in methicillin-resistant S. aureus.

Pinho M G et al. PNAS 2001;98:10886-10891

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Skin and Soft Tissue InfectionsMajor pathogens*

Rank order USA France Germany Italy Spain

1 Enterococcus (24.9%)

S. aureus(29.2)

S.aureus(18.8)

S. aureus(24.2)

Enterococcus(18.1)

22S. aureus

(23.7)CoNS(13.5)

Enterococcus(16)

Enterococcus(19.7)

S. aureus(17)

33CoNS (11.1)

Enterococcus(10.3)

E.coli(14.5)

P. aeruginosa(16.1)

CoNS (13.1)

44E. coli(8.8)

E. coli(9.9)

CoNS(11.8)

CoNS(12.6)

E.coli(12.7)

55 P. aeruginosa(8.7)

P. aeruginosa(8.9)

P. aeruginosa(5.3)

E.coli(7.8)

P. aeruginosa(8.4)

* TSN (The Surveillance Network) study in 2001

Jones ME, et al. Int J Antimicrob Agents. 2003;22:406.

Diabetic Foot Infections:Diabetic Foot Infections:MicrobiologyMicrobiology

Predominant pathogensPredominant pathogens–– Aerobic gramAerobic gram--positive cocci positive cocci Staph.aureusStaph.aureus

and and ββ hemolytic strep (esp GBS)hemolytic strep (esp GBS)Chronic woundsChronic wounds–– Complex flora: Enterobacteriaceae, Complex flora: Enterobacteriaceae,

enterococci, obligate anaerobes, enterococci, obligate anaerobes, Pseudomonas aeruginosaPseudomonas aeruginosa

Resistant pathogens: MRSA, VREResistant pathogens: MRSA, VRE

Lipsky BA, et al. Clin Infect Dis. 2004;39:885-910.

MRSA Risk FactorMRSA Risk Factor

Davis JP, Fox BC CA-MRSA Guidelines for Clinical Management and Control of Transmission,University of Wisconsin Hospital and Clinics,2005

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1.Available at: http://www.cdc.gov/ncidod/hip/Aresist/mrsafaq.htm.2.Adapted from Tambyah PA et al. Infect Control Hosp Epidemiol. 2003;24:436-438.

3.Campbell AL, et al. Infect Control Hosp Epidemiol. 2003;24:427-430.

Staphylococcus aureusStaphylococcus aureus commonly commonly carriedcarried on skin or on skin or in nose (25%in nose (25%--30%)30%)11

Most MRSA infection Most MRSA infection arisesarises in the hospital or in the hospital or healthcare setting,healthcare setting,11--33 particularly among elderly or particularly among elderly or sick patientssick patients11

MRSA infections MRSA infections includeinclude : skin infections, bone : skin infections, bone infections, pneumonia, and bloodstream infectionsinfections, pneumonia, and bloodstream infections11

MRSA is almost alwaysMRSA is almost always spreadspread by direct or indirect by direct or indirect physical contact with MRSA patientsphysical contact with MRSA patients11

EPIDEMIOLOGY OF MRSAEPIDEMIOLOGY OF MRSA

1.Available at: http://www.cdc.gov/ncidod/hip/Aresist/mrsafaq.htm.2.Adapted from Tambyah PA et al. Infect Control Hosp Epidemiol. 2003;24:436-438.

3.Campbell AL, et al. Infect Control Hosp Epidemiol. 2003;24:427-430.

Staphylococcus aureusStaphylococcus aureus commonly commonly carriedcarried on skin on skin or in nose (25%or in nose (25%--30%)30%)11

Most MRSA infection Most MRSA infection arisesarises in the hospital or in the hospital or healthcare setting,healthcare setting,11--33 particularly among elderly or particularly among elderly or sick patientssick patients11

MRSA infections MRSA infections includeinclude : skin infections, bone : skin infections, bone infections, pneumonia, and bloodstream infections, pneumonia, and bloodstream infectionsinfections11

MRSA is almost alwaysMRSA is almost always spreadspread by direct or by direct or indirect physical contact with MRSA patientsindirect physical contact with MRSA patients11

EPIDEMIOLOGY OF MRSA

The Prevalence of MethicillinThe Prevalence of Methicillin--Resistant Resistant Staphylococcus aureus Staphylococcus aureus ( MRSA ) is Rising in ( MRSA ) is Rising in

Many European CountriesMany European Countries

1. Voss A et al. Eur J Clin Microbiol Infect Dis. 1994;13:50-55.2. Speller DCE et al. Lancet. 1997;350:323-325.

3. EARSS newsletter, December 2000. Available at: www.earss.rivm.nl. Accessed 8 December 2001.

MRSA PrevalenceMRSA Prevalence Key countries Key countries (blood isolates)(blood isolates)1990 1990 --199119911,21,2

(%)(%)2000200033

(%)(%)

11.911.9 4242 ItalyItaly1.51.5 3737 UKUK10.110.1 3636 SpainSpain

55 2222 AustriaAustria4.14.1 2222 BelgiumBelgium4.54.5 99 GermanyGermany00 00 NetherlandsNetherlands

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MRSA Isolates in RSCMMRSA Isolates in RSCMRangeRange Isolates Isolates % OXA resist% OXA resistJul Jul –– Sept 2007Sept 2007 3030 39.339.3Oct Oct –– Dec 2007Dec 2007 4343 39.539.5Jan Jan –– Mar 2008Mar 2008 4646 28.328.3Apr Apr –– Jun 2008Jun 2008 1717 50.050.0Jul Jul –– Sept 2008Sept 2008 5252 19.219.2Oct Oct –– Dec 2008Dec 2008 5050 36.036.0Jan Jan –– Mar 2009Mar 2009 3535 37.137.1Mar Mar –– Jun 2009Jun 2009 5858 27.627.6

Loho T, Astrawinata DAW. 2009

Methicillin-resistant Staphylococcus aureus

Type of Infection

Population-based surveillance in 3 communities in USA (2001-2002)

Total No. of MRSA cases : 12,553Nosocomial MRSA : 10,906 (86.9 %)Community-acquired MRSA : 1,647 (13.1 %)

Higher incidence in young children (< 2 YO)

Type of infection : SSTI (77 %), Wound infection (10%), UTI (4%), Bacteremia (3%), Pneumonia (2%), Osteomyelitis (1%)

Fridkin SK, et al. N Engl J Med. 2005;352:1436.

How to Diagnose How to Diagnose cSSTIs by MRSA?cSSTIs by MRSA?

Risk Factor +Risk Factor +Clinical Appearance :Clinical Appearance :PVL+PVL+

Severe, frequently SSTIsSevere, frequently SSTIsProgressiveProgressive

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Laboratory Diagnostic Laboratory Diagnostic

Direct gram smear Direct gram smear CultureCulturePCRPCRAntibody to staphylococcusAntibody to staphylococcus

Microbiologic Diagnosis ofMicrobiologic Diagnosis ofMRSA Infection MRSA Infection

§§ InadequateInadequate susceptibility to susceptibility to betalactambetalactam ABAB

Definite Diagnosis Mec A Gene +

MRSA, is it Colonization or Infection?MRSA, is it Colonization or Infection?

COLONIZATION :COLONIZATION :Culture Culture :: ++Symptom Symptom : : ––

MRSA decolonizationMRSA decolonization therapy can be defined as the administration oftherapy can be defined as the administration oftopical antimicrobial or antiseptic agents, with or without systemictopical antimicrobial or antiseptic agents, with or without systemicantimicrobial therapyantimicrobial therapy, to MRSA, to MRSA--colonized persons for the purpose ofcolonized persons for the purpose oferadicating or suppressing the carrier stateeradicating or suppressing the carrier state

INFECTION :INFECTION :CultureCulture :: +/+/--SymptomSymptom : : ++++ ++++

(Severe, progressive)(Severe, progressive)

MRSADe-Colonization :-Mupirocin-Chlorhexidin

Alvares A, Labarca J, Salles M, Prevention Strategies for MRSA in Latin America, Brazilian J Infect Dis, vol.14, 2010

MRSAAB-TREATMENT

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Rodrigues-Bano et al, Inf Microbiol Clin 2008 ; 26(5):285-98

AREA, POPULATION AND REGIMEN

MRSA De-Colonization

When to Start the MRSA Empirical When to Start the MRSA Empirical Treatment in cSSTI?Treatment in cSSTI?

No culture resultsSevere infection (sepsis)Clinical profile, prior treatment of antibiotic, disease progressivism Risk factorsPresence of MRSA colonization

Graffunder EM et al. J Antimicrob Chemother. 2002;49:999-1005.

Antimicrobial Treatment for MRSAAntimicrobial Treatment for MRSA

Glycopeptide Vancomycin (500 mg q6h OR 1 g q12h) (500 mg q6h OR 1 g q12h) Teicoplanin (400 mg IV, then 200 mg/d IV/IM)Teicoplanin (400 mg IV, then 200 mg/d IV/IM)

Oxazolidinones Linezolid (600 mg q12h IV/PO)(600 mg q12h IV/PO)

Streptogramin QuinopristinQuinopristin--DalfopristinDalfopristin

Glycylcycline Tigecycline (100 mg IV, then 50 mg IV q12h)Tigecycline (100 mg IV, then 50 mg IV q12h)

Alternative Cotrimoxazole, Minocycline, Fluoroquinolones, Cotrimoxazole, Minocycline, Fluoroquinolones, RifampicinRifampicin

Combination Cotrimoxazole + RifampicinCotrimoxazole + RifampicinMinocyclin + RifampicinMinocyclin + Rifampicin

CDC Guidelines 2005

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Treatment of MRSATreatment of MRSA

Based on Microbiological and susceptibility test Staph.Aureus Based on Microbiological and susceptibility test Staph.Aureus resistant to methicilin or oxacillin (resistant to methicilin or oxacillin (MIC > 4 ug/mlMIC > 4 ug/ml))Antibiotic for MRSA :Antibiotic for MRSA :

GlycopeptideGlycopeptide : Vancomycin, Teicoplanin: Vancomycin, TeicoplaninOxazolidinonesOxazolidinones : Linezolid: LinezolidStreptograminStreptogramin : Quinopristin: Quinopristin--DalfopristinDalfopristinGycylcyclineGycylcycline : Tigecycline: TigecyclineAlternative Alternative : Cotrimoxazole, Minocycline, Clindamycine: Cotrimoxazole, Minocycline, Clindamycine

Fluoroquinolones, Rifampicin, TetracyclineFluoroquinolones, Rifampicin, TetracyclineCombination treatmentCombination treatment : :

Cotrimoxazole + RifampicinCotrimoxazole + RifampicinMinocyclin + RifampicinMinocyclin + Rifampicin

Journal of Antimicrobial Chemotherapy (2006) 57, 589-608

Treatment of MRSATreatment of MRSA

Susceptibility First choice AlternativeSusceptibility First choice Alternative

Methicillin(oxacillin)Methicillin(oxacillin) VancomysinVancomysin 1g bid iv1g bid iv CotrimoxazoleCotrimoxazole 60 mg/kg/day60 mg/kg/dayresistantresistant TeicoplaninTeicoplanin 3 mg/kg (mild infection) in divide dose 23 mg/kg (mild infection) in divide dose 2--4x iv4x iv

6 mg/kg (severe infection) (960 mg bid oral)6 mg/kg (severe infection) (960 mg bid oral)12 mg/kg (endocarditis) bid iv12 mg/kg (endocarditis) bid iv Minocyclin Minocyclin (or doxycyclin)(or doxycyclin)for the first 2for the first 2--5 day followed by 100 mg bid iv or oral5 day followed by 100 mg bid iv or oral33--12 mg/kg qd12 mg/kg qd CiprofloxacinCiprofloxacin 400 mg bid iv400 mg bid iv

LinezolidLinezolid 600 mg bid iv or oral or 500 mg bid oral600 mg bid iv or oral or 500 mg bid oralQuinopristinQuinopristin--DalfopristinDalfopristin Levofloxacin Levofloxacin 500 mg qd iv500 mg qd iv

7,5 mg/kg bid or tid iv or oral7,5 mg/kg bid or tid iv or oral

Oxacillin resistantOxacillin resistant QuinopristinQuinopristin--Dalfopristin Dalfopristin Vancomycin intermediate 7,5 mg/kg bid or tidVancomycin intermediate 7,5 mg/kg bid or tid

LinezolidLinezolid 600 mg bid or oral600 mg bid or oral

Paradisi F, Med Clin North Am 2001;85(1):1-17

( MRSA )

( VISA )

Deep Seated Infections:Deep Seated Infections:bacteremiabacteremia, , osteomyelitis, abscesses, endocarditisosteomyelitis, abscesses, endocarditis

MRSA Treatment UK Guidelines 2008MRSA Treatment UK Guidelines 2008

Nathwani D et.al. Journal of Antimicrobial Chemotherapy (2008) 61, 976–994

First lineFirst line

VancomycinVancomycin (1 g i.v./ 12 hour) Teicoplanin (400–800 mg i.v./24h)PLUS gentamicin (5(5––7 g/kg i.v. once daily)/ rifampicin 7 g/kg i.v. once daily)/ rifampicin (300 mg po twice daily)/ Na(300 mg po twice daily)/ Na--fusidate (3x500 mg po)fusidate (3x500 mg po)

Second Second lineline

Linezolid (2x600 mg i.v./po)Linezolid (2x600 mg i.v./po)

AlternativeAlternative Daptomycin (1x4 mg/kg i.v.)Daptomycin (1x4 mg/kg i.v.)Tigecycline (100 mg loading dose followed by 50 mg i.v)Tigecycline (100 mg loading dose followed by 50 mg i.v)

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MRSAIn vitro susceptibility pattern

0

10

20

30

40

50

60

70

80

90

100

Fridkin SK, et al. N EnglJ Med. 2005;352:1436.

Sensitivity Pattern (%)Sensitivity Pattern (%)BacteriaBacteria VancomycinVancomycin TeicoplaninTeicoplanin LinezolidLinezolidMRSAMRSA 8585 8585 7070MSSAMSSA 95.595.5 88.688.6 88.888.8MRSEMRSE 8787 69.369.3 95.795.7MSSEMSSE 94.694.6 92.992.9 92.992.9Strep. Strep. pneumoniaepneumoniae

NDND 100100 100100

Strep. viridansStrep. viridans NDND 92.992.9 92.992.9Strep. Non Group Strep. Non Group AA

NDND 8080 NDND

Strep. Non Strep. Non hemolytichemolytic

NDND 89.789.7 71.171.1

Microbiology FKUI 2006

Cipto Mangunkusumo HospitalCipto Mangunkusumo HospitalJanJan--June 2007 (Sensitivity Pattern)June 2007 (Sensitivity Pattern)

Staph.Staph. aureusaureus : : 88 isolates88 isolates–– MRSA : 40%MRSA : 40%

Staph. Staph. epidermidisepidermidis :: 371 isolates371 isolates–– MRSE : 66%MRSE : 66%

BacteriaBacteria VancomycinVancomycin TeicoplaninTeicoplanin LinezolidLinezolid

Staph. Staph. aureusaureus

7272 5555 8686

Staph. Staph. epidermidisepidermidis

8686 5252 8787

Clinical Pathology Dept-Cipto Mangunkusumo Hospital. 2007

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CONCLUSIONCONCLUSIONMethicillin Resistant Staphylococcus aureus (MRSA) is a Methicillin Resistant Staphylococcus aureus (MRSA) is a Staphylococcus aureus with oxacillin Staphylococcus aureus with oxacillin minimum inhibitory minimum inhibitory concentration (MIC) >= 4microgram/mlconcentration (MIC) >= 4microgram/ml based on Clinical based on Clinical Laboratory Standart Institute (CLSI) criteria. This pathogens Laboratory Standart Institute (CLSI) criteria. This pathogens genotype is identified as a betalactam resistant.genotype is identified as a betalactam resistant.

MRSA infection arises both MRSA infection arises both in the hospital and community in the hospital and community setting. setting.

Complicated Skin and Soft Tissue Infections (cSSTIs) is the Complicated Skin and Soft Tissue Infections (cSSTIs) is the most frequent event of MRSA infectionsmost frequent event of MRSA infections and and usually has usually has severesevere and and progressiveprogressive clinical outcome.clinical outcome.

Proper narrow spectrum AB for GramProper narrow spectrum AB for Gram--positive bacteria is the positive bacteria is the first choice of therapy after bacterial culture is obtained. A few first choice of therapy after bacterial culture is obtained. A few kind of antibiotics such as : glycopeptide or oxazolindinone is kind of antibiotics such as : glycopeptide or oxazolindinone is the drug of choice of MRSA infectionthe drug of choice of MRSA infection