Microorganisms CausingMicroorganisms CausingMicroorganisms Causing Microorganisms Causing Cardiac InfectionsCardiac InfectionsCardiac InfectionsCardiac Infections

Dr. Edhie Djohan Utama, SpMKDr. Edhie Djohan Utama, SpMKj , pj , pDep. Mikrobiologi FKUSUDep. Mikrobiologi FKUSU

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CARDITISCARDITISCARDITISCARDITISCarditis, or inflammation of the heart, , ,is most conveniently broken down into three categories: Pericarditis - Inflammation of the pericardium

Myocarditis - Inflammation of the heart muscleMyocarditis Inflammation of the heart muscle

Endocarditis - Inflammation of the endocardium

ClassificationClassificationClassificationClassification

• OLD• OLD– Subacute Bacterial Endocarditis

Death in 3 6 months• Death in 3-6 months– Acute Bacterial Endocarditis

• Death in < 6 weeks• Death in < 6 weeks

• NEWN ti V l E d diti– Native Valve Endocarditis

– Prosthetic Valve Endocarditis

INFEKSI PENYEBAB TERBANYAK DIAGNOSE LABORATORIUM

E d diti Streptococcus spp (60 80%) 3 l t k k lt d h di bilEndocarditis Streptococcus spp (60-80%) 3 sampel untuk kultur darah yang di-ambil pada 3 daerah berbeda dilakukan pengambilan 1 – 2 jam sebelum pemberian antimikroba

Staphylococcus spp (20-35%)

Batang Gram Neg. (2-13%) antimikroba.

Sampel darah diambil 1 sampel untuk anaerob dan satu untuk kultur aerobic

i 2 10 20 l

Bakteri lain2 (5%)

Jamur (2-4%) (Candida)

Kultur negatip (5-25%)masing2 10 – 20 ml

Myocarditis / PericarditisVirus Enterovirus Pemeriksaan serologic, jika perlu g , j p

dikombinasikan dengan kultur dan untuk PCR.

Adenovirus

Herpes virus

Influenzae virus

Parainfluenza virus

Bakteri Staphylococcus aureus Pemeriksaan mikroskopis dan kultur. Tes DNA jika perluStreptococcus pneumoniae

Enterobacteriaceae

Mycobacterium tuberculosis

Mycoplasma pneumoniae Tes serologik

INFEKSI PENYEBAB TERBANYAK DIAGNOSE LABORATORIUMBakteri Staphylococcus aureus Pemeriksaan mikroskopis dan kultur. Tes a e e e saa os op s da u u . es

DNA jika perluStreptococcus pneumoniae

Enterobacteriaceae

Mycobacterium tuberculosisy

Mycoplasma pneumoniae Tes serologikNeicceriae spp Kultur dan mikroskopisGram negative anaerobGram negative anaerob

Actinomyces & Nocardia

Rickettsia Tes serologikChl di t h tiChlamydia trachomatis

Fungi Candida spp Mikroskopik dan kultur jamurJikas perlu PCRAspergillus spp

C fCryptococcus neoformans

Protozoa Toxoplasma gondii Mikroskopik dan kultur jamurJikas perlu PCRTrypanosoma cruzi

Helminthes Tricinella spiralis Tes serologik

Kayser, Medical Microbiology, 2005

Infective EndocarditisInfective EndocarditisAd lt l ti• Adult population : – Rheumatic Heart Disease

• 20 – 25% of cases of IE in 1970’s & 80’s• 7 18% of cases in recent reported series• 7 – 18% of cases in recent reported series• Mitral site more common in women• Aortic site more common in men

– Congenital Heart Diseaseg• 10 – 20% of cases in young adults• 8% of cases in older adults• PDA, VSD, bicuspid aortic valve (esp. in men>60)

• Pediatric population– The vast majority (75-90%) of cases after the neonatal period

are associated with an underlying congenital abnormalityare associated with an underlying congenital abnormality• Aortic valve• VSD• Tetralogy of Fallot

Ri k f t i f ti i hild ith IE i 50%– Risk of post-op infection in children with IE is 50%

Infective EndocarditisInfective EndocarditisInfective EndocarditisInfective Endocarditis• Typically involves the valves :

– May involve all structures of the heart• Chordae tendinae• Sites of shunting• Mural lesions

I f ti f l h t b t i t– Infection of vascular shunts, by strict definition, is endarteritis, but lesion is the samesame

Infective EndocarditisInfective EndocarditisInfective EndocarditisInfective Endocarditis

• PathogenesisPathogenesis

Endothelial damageEndothelial damage

Platelet-fibrin thrombi

Microorganism adherence

Characteristics of Causative OrganismsCharacteristics of Causative Organismsgg

• Adherence factors critical for growth in the gvegetation– Can adhere to damaged valves (Staph, Strep and

Enterococci have adhesins that mediate attachment)Enterococci have adhesins that mediate attachment)– Staph adhesin binds fibrinogen and fibronectin– Bacteria trigger tissue-factor production from local gg p

monocytes and induce platelet aggregation so the organisms become enveloped in the vegetation

– Protection from immune clearance leads to largeProtection from immune clearance leads to large numbers of bacteria (109-1010 per g of tissue)

• In the vast majority of j ypatients, endocarditis can be effectively ytreated with medication and/or surgery. g y

• Nevertheless, endocarditis can cause serious damage or even death if left untreated.

S. Aureus mitral valve vegetation, t i l fl tanterior leaflet

Risk FactorsRisk Factors• Structural heart disease

Rh ti it l i– Rheumatic, congenital, aging– Prosthetic heart valves

I j t d d• Injected drug use• Invasive procedures (?)• Indwelling vascular devices• Other infection with bacteremia (e.g.

pneumonia, meningitis)• History of infective endocarditis

Infective EndocarditisInfective EndocarditisInfective EndocarditisInfective Endocarditis

• Intravenous Drug AbuseIntravenous Drug Abuse– Risk is 2 – 5% per pt./year– Tendency to involve right-sided valvesTendency to involve right sided valves

• Distribution in clinical series– 46 – 78% tricuspid

24 32% mitral– 24 – 32% mitral– 8 – 19% aortic

– Underlying valve normal in 75 – 93%– S. aureus predominant organism (>50%, 60-

70% of tricuspid cases)

Infective EndocarditisInfective EndocarditisMicrobiology

– Neonates : S. aureus, coag – staph, group B strep– Older children : 40% strep, S. aureusp,

• Majority of cases caused by (Adult Cases) :– streptococcus, – staphylococcus, p y– enterococcus, or – fastidious gram negative cocco-bacillary forms :

Gram negative organisms :• P aeruginosa most common• P. aeruginosa most common• HACEK - slow growing, fastidious organisms that may need 3 weeks to grow out of

culture– Haemophilus sp.– Actinobacillus– Cardiobacterium– Eikenella– Kingella

INFECTIVE ENDOCARDITISINFECTIVE ENDOCARDITIS• Staphylococcus aureus (30-40%)• Viridans group streptococci (18%)g ( )• Enterococci (11%)• Coagulase-negative staphylococci (11%)• Streptococcus bovis (7%)• Other streptococci (5%)• Non-HACEK Gram negatives (2%)• HACEK Organisms (2%)• Fungi (2%)• “Culture negative” (2-20%)

• Portals of entry :Portals of entry := Oral, skin, URI : S. viridans, Staphylococci, HACEK= GI : S bovis (ass Polyps & colonic tumors)= GI : S. bovis (ass. Polyps & colonic tumors)

: G –ve (Enterobacteriacae)= GU : Enterococci GU : Enterococci= Nosocomial : intravascular catheters : S.aureus

Like other oral viridans streptococci, S. sanguis commonly enters the bloodstream following dental procedures

Infective EndocarditisInfective Endocarditis• Gram negative organisms

P aeruginosa most common– P. aeruginosa most common– HACEK - slow growing, fastidious organisms that

may need 3 weeks to grow out of culture• Haemophilus sp.• Actinobacillus• Cardiobacterium• Eikenella• Kingella

Lik th l i id t t i S i• Like other oral viridans streptococci, S. sanguis commonly enters the bloodstream following dental procedures

Prosthetic valve : 2mo , NI: Intraoperative contamination: Intraoperative contamination: Bacteremic postoperative : S.coag.-ve, S. aureus, G-ve rod, diphtheroids, fungi

: >12mo. = Community-acquired native valve:>85% S.coag-ve : MRSA: 85% S.coag ve : MRSA

Transvenous pacemaker and/or implanted defibrillator : NI , within weeks, S. aureus, S.coag –ve

Injection drug users- TV

S aureus strains : MRSA- S.aureus strains : MRSA- Lt side : varied etiology & abnormal valve

: P.aeruginosa, Candida spp.,: Bacillus Lactobacillus: Bacillus, Lactobacillus, : Corynebacterium

-Polymicrobial

Causative organismsCausative organisms of infective of infective d ditid ditiendocarditisendocarditis

• Enterococci*• Viridans streptococci*p• Staphylococcus aureus*• Coagulase-negative staphylococciCoagulase negative staphylococci• Enterobacteriace

*most common organisms associated with native valve endocarditisvalve endocarditis

Native Valve IENative Valve IE• Viridans Streptococci and S bovis• Viridans Streptococci and S. bovis

– Aqueous Penicillin G 12-20 million units/day continuously or divided q4 or q6 for 4 weeks– If intermediate susceptibility to penicillin, aqueous penicillin G 24 million units or

ceftriaxone 2 g q24 PLUS aminoglycoside for the first 2 weeks

• Aminoglycosides for synergy– Low concentrations are adequate (1-3 mcg/ml)– Gentamicin 3 mg/kg divided q12 or q8– Little data for q24 dosing– Little data for q24 dosing

• Enterococci, ampicillin sensitive– High rates of failureg– β-lactams are bacteriostatic, must combine with aminoglycoside for optimal therapy– High-level gentamicin resistance occurs in 35%

• High-dose ampicillin for 8-12 weeks• Enterococci, ampicillin resistant, p

– Vancomycin plus gentamicin• Enterococci, vancomycin resistant

– Linezolid or daptomycin– Penicillin + vancomycin + gentamicin ?Penicillin vancomycin gentamicin ?

DIAGNOSIS IEDIAGNOSIS IE: : Because the clinical features of the disease can be quite variable and often nonspecific diagnosis is mainly basedvariable and often nonspecific, diagnosis is mainly based on laboratory tests.

Blood culture and serologic testing are the most important.g g pAlways use venous blood to isolate the organism. A positive blood culture with some or all of the symptoms listed is needed to obtain the diagnosislisted is needed to obtain the diagnosis.

• Blood is normally considered sterile• Means of delivery for many microbial agentsMeans of delivery for many microbial agents• Primary viremia/bacteremia clinically inapparent• Secondary viremia/bacteremia have clinical signs due to

activation of inflammatory processactivation of inflammatory process

Detection of BacteremiaDetection of BacteremiaDetection of BacteremiaDetection of Bacteremia

• Specimen collectionSpecimen collection• Specimen volume

N b f bl d lt• Number of blood culture• Miscellaneous • Universal precautions • Aseptic techniquesAseptic techniques

Blood Cultures Blood Cultures (Microbiology Diagnostic)(Microbiology Diagnostic)

3 sampel untuk kultur darah yang di-ambil pada 3 daerah berbeda Dilakukan pengambilan 1 – 2 jam sebelum pemberian antimikroba

S l d h di bil 1 l t k b d t t k k ltSampel darah diambil 1 sampel untuk anaerob dan satu untuk kultur aerobic masing2 10 – 20 ml (Kayser, Medical Microbiology, 2005)

Literatur lain :MULTIPLE BLOOD CULTURES BEFORE EMPIRIC THERAPY :• If not critically illy

– 3 blood cultures over 12-24 hour period– ? Delay therapy until diagnosis confirmed

• If critically ill– 3 blood cultures over one hour

• No more than 2 from same venipuncture• Relatively constant bacteremia

Specimen volume & number of Specimen volume & number of bl d ltbl d lt

Specimen volume & number of Specimen volume & number of bl d ltbl d ltblood culturesblood culturesblood culturesblood cultures

• Bacteremia in adults have a number ofBacteremia in adults have a number of CFU < 30 CFU/ml

• Adults 10 20 ml minimal 10 ml• Adults 10-20 ml, minimal 10 ml• Children 1-5 ml • Number of blood cultures

– 1 bottles 80-92%– 2 bottles 90-99%– 3 bottles 99.6% (be space an hour apart)( p p )

Lecturer: Kanya Preechasuth : Clinical microbiology, Faculty of Associated Medical Sciences, CMU, Jan 12, 2006

Timing of collection> 1 hr

influx of bacteria fever, chill

l h d f h inormal host defense mechanisms

bacteria was cleared

Ideal 30 min. before peak temperature

MiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneous• Blood culture media

– Trypticase soy broth or Brain heart infusion broth

– Thio broth or thioglycolate broth – Blood : culture media = 1:10 (5:50)

• neutralized bactericidal property of blood• high ratio : prolonged detection time• low ratio : inhibit by serum factorsy

MiscellaneousMiscellaneousMiscellaneousMiscellaneous• Anticoagulant

– 0.025-0.05% Sodium polyanetol sulphonate (SPS)

• Inactivate neutrophils• Inactivate antimicrobial (amonoglycosides,

polymixin)• Inhibit phagocytosis• Inhibit phagocytosis• Inhibit growth of Neisseria gonorrhoea, N.

meningitidis• Prevent by add 1-1.2% gelatin

Heparin EDTA and citrate inhibit numerous organismsHeparin, EDTA, and citrate inhibit numerous organisms

MiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneousMiscellaneous• Additives

– 10-20% Hypertonic sucrose or sorbitol– Penicillinase– Antimicrobial-adsorbing (resin): nonspecific

adsorbtion

• Incubation at 35-370C and 5% CO2

• Ventilation for strictly aerobe (Pseudomonsa, and fungi)

Conventional cultureConventional cultureConventional cultureConventional cultureConventional cultureConventional cultureConventional cultureConventional culture• Culture media

– TSB 50 ml, 10 ml = Conventional culture– 0.025% SPS– 1-1.2% gelatin– 5% CO2

• Blood sample

= Lysis centrifugation= Automated blood culture system

• Blood sample– Adults 5 ml, 3 bottles– Children 1 ml, 2 bottles

• Blind subculture– Blind aerobic subculture : after 24 hrs– Blind anaerobic subculture : after 48 hrs

Earl blind s bc lt re after 6 18 hrs– Early blind subculture : after 6- 18 hrs– Final subculture : after 5-7 days (bacteria) or 14 days (fungal)

• Chocolate agar at 35-370C and 5% CO2

Conventional cultureConventional cultureConventional cultureConventional culture

• Microscopic examinationMicroscopic examination• Gram’s stain (105 CFU/ml)

Conventional cultureConventional cultureConventional cultureConventional culture

• Macroscopic examinationMacroscopic examination• Sign of growth (106-107CFU/ml)

Turbidity– Turbidity– Gas bubbles in the medium

H l i f RBC– Hemolysis of RBCs– The appearance of small aggregates of

bacterial or fungal growth on the surface ofbacterial or fungal growth on the surface of sedimented RBC

Growth detection :Growth detection :• Preliminary report : by phone or report• Isolated on an appropriated medium• Identification & susceptibility test• Identification & susceptibility test

Probable contamination :Probable contamination :• 2-3 % contamination• Bacillus spp., Corynebacterium spp., or coagulase-negative

staphylococci in only one of several cultures• Multiple organisms from only one of several cultures• Multiple organisms from only one of several cultures• The organisms causing the infection at a primary site of infection is

not the same as the isolated from the blood culture (physician-based)

• Growth of the same organism in repeated cultures• Growth of certain organisms such as member of Enterobacteriaceae,

St i ti b d St

Probable pathogen :Probable pathogen :

Strep pneumoniae, gram-negative anaerobe, and Strep pyogenes

Automated blood culture systemAutomated blood culture systemAutomated blood culture systemAutomated blood culture system• BecT/Alert® (Organon Teknika)• BACTEC® 9240 (Becton Dickinson)• Detection unit• Detection unit

- 120, 240 cells- agitate continuously

it d 144 ti /d (10 i i t l)- monitored 144 times/days (10 min. interval)

• Computer system• Culture medium

- 20, 30, 40 ml. Trypticase soy broth- up to 4 ml. blood (pediatric) p (p )- up to 10 ml. blood (adult)- anticoagulant = SPS

supplements with BHI solids and activated charcoal- supplements with BHI solids and activated charcoal

“Culture Negative” IE“Culture Negative” IE• Less common with improved blood culture

methodsmethods• Special media required :

– Brucella, Mycoplasma, Chlamydia, Histoplasma, Legionella, Bartonella

• Longer incubation may be required– HACEK

• Coxiella burnetii (Q Fever), Trophyrema whipplei will not grow in cell-free mediapp g

Other microbiologic methodsOther microbiologic methods• PCR

– Coxiella burnetii– Tropheryma whipplei– Bartonella henselae

• Serology– Coxiella burnetii– Bartonella– Brucella

Legionella– Legionella– Chlamydophila psittaci

Treatment of IETreatment of IE• Native vs. Prosthetic Valve• Bactericidal therapy is necessary• Eradication of bacteria in the vegetationg

– May be metabolically inactive (stationary phase)p )

– May need higher concentrations of antimicrobial agents

Antimicrobial TherapyAntimicrobial Therapy• Most patients are afebrile in 3-5 days• Long duration of therapy (4-6 weeks or more)Long duration of therapy (4 6 weeks or more)• Combination therapy most important for

– Shorter course regimens– Enterococcal endocarditis– Prosthetic valve infections

• Viridans Streptococci and S. bovis– Aqueous Penicillin G 12-20 million units/day

continuously or divided q4 or q6 for 4 weekscontinuously or divided q4 or q6 for 4 weeks– If intermediate susceptibility to penicillin, aqueous

penicillin G 24 million units or ceftriaxone 2 g q24 PLUS aminoglycoside for the first 2 weeksPLUS aminoglycoside for the first 2 weeks

Antimicrobial TherapyAntimicrobial Therapy• Antibiotics are usually administered

intravenously for 2-6 weeks. Duration depends on the virulence of the pathogenon the virulence of the pathogen.

• The drug of choice for most cases of viridians streptococcal endocarditis is penicillinstreptococcal endocarditis is penicillin.– The cure rate for viridans streptococcal endocarditis

is above 90%.– Without treatment, VSE is typically fatal within six

months.

• Antifungals alone are not enough to cure fungal• Antifungals alone are not enough to cure fungal IE, although Amphotericin B is often administered in conjunction with surgery.

Infective Endocarditis: TreatmentInfective Endocarditis: TreatmentProlonged, parenteral, bactericidal antibiotics= Highly sensitive streptococci (MIC<0.1 mcg/mL) g y p ( g )

· Penicillin G or Ceftriaxone 4 weeks· Penicillin G and Gentamicin 2 weeks· Vancomycin (for Pen-allergic) 4 weeks Vancomycin (for Pen-allergic) 4 weeks

= Relatively resistant streptococci (MIC >0.1, < 0.5) · Penicillin G 4 weeks and Gentamicin 2 weeks Penicillin G 4 weeks and Gentamicin 2 weeks· Vancomycin (for Pen-allergic) 4 weeks

= Enterococci Enterococci · Pen G or Ampicillin and Gentamicin 4-6 weeks· Vancomycin (for Pen-allergic) 4-6 weeks and Gentamicin

(Department of Internal Medicine, Tokyo Metropolitan Geriatric Hospital)

Treatment of IETreatment of IE= Antibiotic therapy must persist for at least 14 days, even if symptoms

disappear prior to that time.= A combination of antibiotics, rather than a single antibiotic, is always

used. If no organism has been isolated after repeated attempts the recommended therapy is:

Ampicillin, given IV every 4 hours + Gentamycin, given every 8 hours.

= If an organism has been isolated then the antibiotic regimen is based on If an organism has been isolated, then the antibiotic regimen is based onthe species of the etiologic agent, the age of the patient and the extent of the disease.

If tibi ti th i t f l i l l f i f t d= If antibiotic therapy is not successful surgical removal of infected endocardium may be necessary. This is especially true with fungal infections and when the patient has an intracardiovascular prosthesis. Nonspecific therapy includes:Nonspecific therapy includes:

ChemoprophylaxisChemoprophylaxisChemoprophylaxisChemoprophylaxisAdult Prophylaxis: Dental, Oral, Respiratory, Esophageal

Standard RegimenStandard Regimen

Amoxicillin 2g PO 1h before procedure or A i illi 2 IM/IV 30 b f dAmpicillin 2g IM/IV 30m before procedure

Penicillin Allergic Clindamyciny

600 mg PO 1h before procedure or 600 mg IV 30m before

Cephalexin OR Cefadroxil 2g PO 1 hour beforeCephalexin OR Cefadroxil 2g PO 1 hour before Cefazolin 1.0g IM/IV 30 min before procedure Azithromycin or Clarithromycin 500mg PO 1h before

Native Valve IENative Valve IES• S. aureus– Penicillinase-resistant semi-synthetic penicillin (oxacillin or nafcillin) 1.5-

2 g IV q4 or cephalosporin (cefazolin 1-2 g IV q8) for 4-6 weeksAminoglycoside synergistic but does not affect survival not– Aminoglycoside synergistic but does not affect survival, not recommended

– Short course in right-sided IE• 2 weeks of semi-synthetic penicillin and aminoglycoside

• MRSA (Methicillin-resistant S. aureus)– Vancomycin is bacteriostatic– Vancomycin plus aminoglycoside or rifampin– Daptomycin– Linezolid

• HACEK– Ceftriaxone 2 g IV q 24 x 4-6 weeks

Prosthetic Valve IEProsthetic Valve IE

• Staphylococci most commonStaphylococci most common– Coagulase negative staphylococci

Enterococcus• Enterococcus• Nutritonally variant streptococci• Fungi

Candidal EndocarditisCandidal EndocarditisCandidal EndocarditisCandidal Endocarditis• Candidal endocarditis is a severe condition that has been traditionally

associated with an exceptional high mortality and recurrence rates. Both nati e and prosthetic al es ma be affected Combining medical ithnative and prosthetic valves may be affected. Combining medical with surgical interventions, the hospital survival rates have been commonly below 50%. The highest long term survival rate is 67%

Open heart surgery is one of the most frequent risk factors for fungal• Open heart surgery is one of the most frequent risk factors for fungal endocarditis, with a rate of 0.23% to 1% of all cardiac surgeries.

• Fungal prosthetic valve endocarditis has been reported to be 9.6% and 4 3% respectively4.3%, respectively.

• Intravenous drug abusers have the highest rates of fungal endocarditis. Candida spp. account for between 50 and 60% of cases [1982].

• Neonates may develop endocarditis as part of the picture of disseminated neonatal candidiasis. Candida spp. causes all of the infections.

Candidal PericarditisCandidal PericarditisCandidal PericarditisCandidal Pericarditis• Candida pericarditis is a rare but serious p

condition that can lead to severe sepsis, cardiac tamponade and death if not diagnosed and treated promptly [1863]. Candidal pericarditis p p y [ ] pmay occur in relation to obvious hematogenous seeding from invasive candidiasis

• Candida albicans is the most frequent species, followed by C. tropicalis. Of the 26 cases reviewed by Rabinovici et al. only 18 had y yspecies identification. Of these 78% of them were caused by Candida albicans.

Candidal EndocarditisCandidal Endocarditis1. Blood cultures. The sensitivity of blood cultures to detect

invasive candidiasis is generally low. However, the intravascular site of this infection changes that rule Indeedintravascular site of this infection changes that rule. Indeed, when compared with other fungal agents able to cause endocarditis, Candida is the most frequently cultured [1981].

1. Rates of 83 to 95% of positive blood cultures for Candidaspp. have been reported in reviews of fungal endocarditis [1499 1640] In the review by Nguyen et al of 18[1499, 1640]. In the review by Nguyen et al. of 18 prospectively identified cases of candidal prosthetic valve endocarditis, all patients had several positive blood cultures The mean and median number of positive bloodcultures. The mean and median number of positive blood cultures for this group were 7 and 5 respectively [1640].

Antifungal therapyAntifungal therapyVery few authors have reported successful treatment with a non-surgical approach for this condition. Indeed, the chronic nature of Candida makes eradication of this infection difficult and long-term antifungal therapy is usually necessary.

• Amphotericin B. Despite being the agent recommended by experts, amphotericin B has two disadvantages when treating this candidal endocarditis.

– First, its penetration into the vegetation has been shown to be poor. Second its toxicity profile frequently limits therapy– Second, its toxicity profile frequently limits therapy.

Nevertheless, amphotericin B, alone or in combination with flucytosine, is still considered the gold standard for the initial phase of therapy.Daily doses should be the maximum tolerated dose in the range of 0.5 to 1 mg/kg/day, until a total dose of ~ 2 grams has been given.mg/kg/day, until a total dose of 2 grams has been given.

• Flucytosine. Because of the previously mentioned difficulty on curing Candidaendocarditis, the synergism between amphotericin B and flucytosine is attractive.

Azoles Th il bilit f l tif l t h dd d i t t t l• Azoles. The availability of oral antifungal agents has added a very important tool for the long term treatment of a condition with a very high relapsing rate. Likewise, there are no useful data on the potential role of itraconazole. The characteristics of fluconazole make it attractive for the treatment of Candidaendocarditis.

Candida species and Candida species and CandidaCandida PericarditisPericarditisCandida albicans is the most frequent species, followed by C. tropicalis. Of the 26 cases reviewed by Rabinovici et al. only 18 had species identification.Of these 78% of them were caused by Candida albicans.

Specific Diagnostic StrategiesTo make the diagnosis of Candida pericarditis, one should : • Recognize the patient populations at risk,Recognize the patient populations at risk, • Perform an echocardiogram when suspecting the picture, • Perform a pericardiocentesis, • Isolate Candida from the pericardial fluid or tissue, and

Id ll h hi t th l i fi ti f t f i i di l• Ideally, have a histopathologic confirmation of yeast forms in pericardial tissue.

TherapiesT ti C did i diti i i h th t• Treating Candida pericarditis requires an aggressive approach that combines surgical and medical treatment.

• prolonged courses of amphotericin B but the precise length of therapy is not definednot defined

Less prevalent causative agents includeLess prevalent causative agents include• Other bacteria

– The HACEK Group• Haemophilus species, Actinobacillus

actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella, , gspecies

– Usual bacterial causes• Bacillus cereus, Clostridium perfringens,

Mycobacterium tuberculosis, Nocardiaasteroides, Coxiella burnetii, etc., ,

• Fungi– Candida and Aspergillis speciesp g p

DrugsDrugs (usually causing hypersensitivity (usually causing hypersensitivity ))myocarditis)myocarditis)

– Chemotherapeutic drugs - Doxorubicin and p ganthracyclines, streptomycin, cyclophosphamide, interleukin-2, anti-HER-2 receptor antibody/Herceptinreceptor antibody/Herceptin

– Antibiotics - Penicillin, chloramphenicol, sulfonamidessulfonamides

– Antihypertensive drugs - Methyldopa, spironolactone

– Antiseizure drugs - Phenytoin, carbamazepine – Amphetamines, cocaine, catecholamines

PericarditisPericarditisPericarditisPericarditis

• Also called: Adhesive Pericarditis,Also called: Adhesive Pericarditis, Postmyocardial Pericarditis, Acute Pericarditis, Bacterial Pericarditis, Polyserositis, Chronic Pericarditis, Constrictive Pericarditis.

• Pericarditis is an inflammation of thePericarditis is an inflammation of the pericardium, the thin, fluid-filled sac surrounding the heart. It can cause severe chest pain (especially upon taking a deep breath) and shortness of breath.

• Most patients pwith pericarditis also have some fluid in thefluid in the pericardial sac.

MyocarditisMyocarditis• Also called: Fulminant Myocarditis, Acute

Myocarditis

• Myocarditis is an uncommon inflammation of the heart muscle (myocardium). This inflammation ( y )can be caused by infectious agents, toxins, drugs or for unknown reasons. It may be localized to one area of the heart or it maylocalized to one area of the heart, or it may affect the entire heart.

• Approximately 50% of the time, myocarditis is pp y , yclassified as idiopathic although a viral etiology is often suspected but unproved.

MyocarditisMyocarditisyy• Despite three decades of study, the diagnosis

d t i t i land management remain controversial.• The exact incidence and prevalence remain

unknown.• Clinical presentation variesp• Most patients are asymptomatic and recover

without treatmentwithout treatment

EtiologyEtiology Agents ofAgents of MyocarditisMyocarditis• Viral - Enterovirus, coxsackie B, adenovirus, influenza, cytomegalovirus,

poliomyelitis, Epstein-Barr virus, HIV-1, viral hepatitis, mumps, rubeola, varicella variola/vaccinia arbovirus respiratory syncytial virus herpesvaricella, variola/vaccinia, arbovirus, respiratory syncytial virus, herpes simplex virus, yellow fever virus, rabies

• Rickettsial - Scrub typhus, Rocky Mountain spotted fever, Q feverB t i l Di hth i t b l i t t i i i• Bacterial - Diphtheria, tuberculosis, streptococci, meningococci, brucellosis, clostridia, staphylococci, melioidosis, Mycoplasma pneumoniae, psittacosis

• Spirochetal Syphilis leptospirosis / Weil disease relapsing• Spirochetal - Syphilis, leptospirosis / Weil disease, relapsing fever/Borrelia, Lyme disease

• Fungal - Candidiasis, aspergillosis, cryptococcosis, histoplasmosis, actinomycosis blastomycosis coccidioidomycosis mucormycosisactinomycosis, blastomycosis, coccidioidomycosis, mucormycosis

• Protozoal - Chagas disease, toxoplasmosis, trypanosomiasis, malaria, leishmaniasis, balantidiasis, sarcosporidiosis

• Helminthic - Trichinosis, echinococcosis, schistosomiasis, heterophyiasis, cysticercosis, visceral larva migrans, filariasis

EtiologyEtiology Agents ofAgents of MyocarditisMyocarditisViruses : Enteroviruses

Influenza A and BAdenovirusAdenovirusHerpes HIV

Bacteria : Beta-hemolytic StreptococcusCorynebacterium diphtheriaB li b d f iBorrelia burgdorferiEnterococcus sppChlamydia psittaciy pNeisseria meningitidisMycoplasma pneumoniaStaphylococcus aureusStaphylococcus aureus

• pto

ProtozoaProtozoa : : Trypanosoma cruziiTrypanosoma cruziiToxoplasma gondiToxoplasma gondiToxoplasma gondiToxoplasma gondi

HelminthsHelminths : : Trichinella spiralisTrichinella spiralisEchinococcusEchinococcusEchinococcusEchinococcus

Autoimmunity Autoimmunity : Infection associated: Infection associatedAutoAuto--immune disease associatedimmune disease associatedPrimary autoimmunityPrimary autoimmunity

HypersensitivityHypersensitivity: Penicillins: PenicillinsMethyldopaMethyldopaSulfamethoxazoleSulfamethoxazole

T i iT i i C h l iC h l iToxicity:Toxicity: CatecholaminesCatecholaminesCocaineCocaineEthanolEthanol

Viral MyocarditisViral Myocarditis• Coxsackievirus A9 is a self-limiting myocarditis, whereas

coxsackievirus B3 causes severe myocarditis resulting in a high mortality ratea high mortality rate.

– The induction of the coxsackie-adenovirus receptor (CAR) and the complement deflecting protein decay accelerating factor (DAF, CD55) may allow efficient internationalization of the viral genome. Viral replication may lead to further di ti f t b li d t b ti f i fl ti d itdisruption of metabolism and perturbation of inflammation and its response. Vasospasm induced by endothelial cell viral infection may also contribute to further damage. New evidence of dystrophin disruption by expression of enteroviral protease 2A points to yet another unique pathogenic mechanism.

• Approximately 50% of the time, myocarditis is classified as idiopathic, although a viral etiology is often suspected but unprovedbut unproved

– Viral - Enterovirus, coxsackie B, adenovirus, influenza, cytomegalovirus, poliomyelitis, Epstein-Barr virus, HIV-1, viral hepatitis, mumps, rubeola, varicella, variola/vaccinia, arbovirus, respiratory syncytial virus, herpes simplex virus, yellow fever virus, rabies y ,

Viral Infection of HeartViral Infection of Heart (Myocarditis)(Myocarditis)Viral Infection of Heart Viral Infection of Heart (Myocarditis)(Myocarditis)Viral myocarditis results when the muscles in the walls of heart become infected with a virus. Entereoviruses and adenoviruses are the primaryp ycausative agents of viral myocarditis.

Symptoms• Fever• Fever • Cough • Nausea • Vomiting • MyalgiaMyalgia • Arthralgia • Palpitation • Heart failure (in severe cases)

Candidal MyocarditisCandidal MyocarditisCandidal MyocarditisCandidal Myocarditis

• Hematogenous seeding of Candida intoHematogenous seeding of Candida into the myocardium was frequently found in the early autopsy reviews of patients dyingthe early autopsy reviews of patients dying with systemic invasive candidiasis.

• The lack of inflammatory response is most notable in immunosuppressed patients

Medical CareMedical Care• Treatment of myocarditis includes supportive therapy for symptoms

of acute heart failure with use of diuretics, nitrates/sodium nitroprusside, and angiotensin-converting enzyme (ACE) inhibitors.

– Inotropic drugs (eg, dobutamine, milrinone) may be necessary for severe decompensation, although they are highly arrhythmogenic.

– Long-term treatment follows the same medical regimen, including ACE inhibitors, beta-blockers and aldosterone receptor antagonists However in somebeta blockers, and aldosterone receptor antagonists. However, in some instances, some of these drugs cannot be implemented initially because of hemodynamic instability.

• No benefit has been established for the use of antiviral agents, although some small series have demonstrated their efficacy (the efficacy of interferon-alpha will s a se es a e de o st ated t e e cacy (t e e cacy o te e o a p abe evaluated in the ongoing ESETCID).

• Viral myocarditis is typically a mild disease and responds well to bed rest. Bacterial, fungal and protozoan myocarditis can be treated with the appropriate antibiotics Gl costeroids and otherthe appropriate antibiotics. Glucosteroids and other immunosuppressive drugs are CONTRAINDICATED.

Chlamydia pneumoniae as an emerging risk factor Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease.in cardiovascular disease.

• Seroepidemiologic studies have associated C. pneumoniae antibody with coronary artery disease, myocardial infarction, carotid artery disease, and cerebrovascular disease. The association of C. pneumoniae with th l i i b t d b th f th i iatherosclerosis is corroborated by the presence of the organism in

atherosclerotic lesions throughout the arterial tree and the near absence of the organism in healthy arterial tissue. C. pneumoniae has also been isolated from coronary and carotid atheromatous plaques.

• Compelling evidence of the association between C. pneumoniae and atherosclerosis has been obtained by polymerase chain reaction (PCR), immunocytochemical (ICC) staining, and electron microscopy, which haveimmunocytochemical (ICC) staining, and electron microscopy, which have detected C. pneumoniae in atherosclerotic lesions

• A causative role of C. pneumoniae infection in cardiovascular disease has not yet been firmly established However the high frequency of infectionnot yet been firmly established. However, the high frequency of infection found in human atherosclerotic tissue in comparison to normal tissue, the induction and progression of atherosclerotic-like inflammatory changes in infected animal models of atherosclerosis, and the early results from antichlamydial intervention studies in humans are consistent with aantichlamydial intervention studies in humans are consistent with a causative role of C. pneumoniae in the disease process.

Infection, inflammation and Infection, inflammation and atherosclerosisatherosclerosis

• C. pneumoniae, H. pylori, Porphyromonas gingivalis, Cytomegalovirus, Herpes simplex virus, Hepatitis A, B, and C viruslinked with an increased risk of cardiovascular diseases

• Proinflammatory effects of infection –increased CRP, cytokines

MYOCARDIAL INFARCTIONMYOCARDIAL INFARCTION• Myocardial infarction can occur in the absence

of the common risk factors such as h h l l i di b llihypercholesterolemia, diabetes mellitus or cigarette smoking. The sequence of events that leads to acute myocardial infarction includes yatherosclerotic plaque formation, plaque rupture, coronary artery thrombosis and coronary occlusion. Anything that leads to plaque rupture occ us o yt g t at eads to p aque uptu ecan result in myocardial infarction.

ETIOLOGYETIOLOGY:• Chylamydia pneumoniae, a Gram-, pleomorphic,

obligate intracellular parasite.obligate intracellular parasite.

DIAGNOSIS DIAGNOSIS MYOCARDIAL INFARCTIONMYOCARDIAL INFARCTION ::

1. Non-specific indices of tissue necrosis and inflammation a. Polymorphonuclear leukocytosis b. Erythrocyte sedimentation rate that rises more slowly

than the WBC count

2. The electrocardiogram 3. Serum enzyme changes

a Creatine phosphokinase (CK)a. Creatine phosphokinase (CK) b. Lactic dehydrogeinase (LDH)

4 Cardiac imaging4. Cardiac imaging 5. Presence of chlamidia in the plaque 6. Presence of antibiodies to C. pneumoniae

TREATMENT:TREATMENT: MYOCARDIAL INFARCTIONMYOCARDIAL INFARCTION

= Treatment for the infection is administration of one of these compounds (listed in order from mostof these compounds (listed in order from most effective to least efficatious):M lid tibi ti ( th i ith i= Macrolide antibiotics (erythromycin, azithromycin, clarithromycin) TetracyclinesTetracyclines Fluoroquinolones (ciprofloxacin, norfloxacin and ofloxacin)

Infectious arthritisInfectious arthritis• An infection of native joints leads generally to suppurative arthritis, which

may be of one joint (monarticular) or several joints (oligoarticular).

• Bacteria that produce symptoms in multiple joints during bacteraemiaBacteria that produce symptoms in multiple joints during bacteraemia, such as Neisseria gonorrhoeae, may also induce inflammation in the neighbouring tendon sheaths. Viral infections frequently involve multiple joints and produce inflammation without suppuration.

• Chronic granulomatous monarticular arthritis may occur because of infection with either mycobacteria or fungi, which must be differentiated from other causes of chronic monarticular arthritis.

• A sterile arthritis may occur early in infection (as with hepatitis B), or later (as with a post-infectious arthritis). Any patient presenting with an inflamed joint should have infection as a diagnostic possibility and appropriate cultures must be performedappropriate cultures must be performed.

Clinical Microbiology and Infection 12 (4), Volume 12 Issue 4, Page 309 –314 April 2006314, April 2006

Rheumatoid arthritisRheumatoid arthritis• An inflammatory joint disorder primarily characterised by

symmetrical polyarticular synovitis. * ff % f• * Affects 1-3% of population.

• * F 2-3x > M. • * Onset any age – more common 25 to 50 years (peak Onset any age more common 25 to 50 years (peak

age of onset is 35-45 years). • * Associated with reduced life expectancy and increased

disabilitydisability. • * Generally considered as a systemic disease – but, in

the early stages it is only an articular disease, with the t i t ti l if t ti t d l isystemic extra-articular manifestations not developing

until late in the disease

Aetiology:Aetiology:• Unknown – probably multifactorial -

inappropriate inflammatory responseinappropriate inflammatory response. • Genetic predisposition (HLA-DR4 antigen

increases risk by 5x) localised to aincreases risk by 5x) – localised to a pentapeptide in HLA-DRB1.

• Environmental infectious (parvovirus)• Environmental, infectious (parvovirus), diet, trauma or psychological factors may play a role in initiating immune responseplay a role in initiating immune response.

• Pathogenesis

PathogenesisPathogenesis• Inciting agent activates immune system --> immunological

reactions --> immune complexes in synovial fluid activate complement --> inflammatory response --> joint destructioncomplement > inflammatory response > joint destruction.

• Earliest change is inflammation and oedema of synovium with increased vascularity and increased production of synovial fl id h id f CD4 T h l ll i ti i tfluid – shows evidence of CD4+ T helper cells migrating into the joint.

• Next the synovial villi hypertrophy synovial cells proliferationNext the synovial villi hypertrophy, synovial cells proliferation, increased vascularisation (angiogenesis) and pannus form (granulation tissue that grows across surface of articular cartilage from adjacent synovium). g j y )

• This is followed by destruction of cartilage by pannus –mediated by pro-inflammatory cytokines (eg TNF-alpha, interleukin 1 beta interferon gamma) and metalloproteasesinterleukin-1-beta, interferon-gamma) and metalloproteases (eg collagenases).

Lab tests are not diagnosticLab tests are not diagnosticBlood – increased ESR in 90%; normochromic normocytic anaemia

Synovial fluid – during active joint inflammation --> cloudy, sterile, reduced viscosity, and increased white blood cells.

Rheumatoid factor – present in 75% of those with rheumatoid arthritis – higher prevalence in those with extrarticular manifestations good prognostic test as those who are positivemanifestations – good prognostic test, as those who are positive for rheumatoid factor have a poorer prognosis.

Higher prevalenceHigher prevalence of other autoantibodies are also seen (antikeratin antibodies, antiperinuclear antibodies, anti-RA 33 antibodies)

Cardiovascular SyphilisCardiovascular Syphilis• Although morphological involvement of the

cardiovascular system occurs in 80% of cases of.tertiary syphilis only about 10% of these are manifested clinically.

• The spirochetes evoke endarteritis in the vasa vasorum of the aorta and coronary ostia. Clinical manifestations occur in 15 30 yearsClinical manifestations occur in 15 - 30 years after infection.– 1 Aortic aneurysmy– 2 Aortic Valve Disease– 3 Coronary Artery Disease

Treatment of syphilisTreatment of syphilisEarly:• Benzathine Penicillin, 2.4 MU intramuscularly, (1.2 MU into each

buttock ) Two doses one week apartbuttock.) Two doses, one week apart. • Second line treatments (all oral) are: Doxycycline 100mgs b.d for 14

days. Or Erythromycin (oral) 500mgs qid for 14 days. Or Azithromycin 50 mg daily for 14 days.

Late, latent:• 3 doses of Benzathine penicillin 2.4 MU IM given at weekly intervals (or

doxycycline 100 200mg bd for 28 days)doxycycline 100-200mg bd for 28 days).

Late, neurosyphilis or eye involvement or any stage with coincident HIV infection:HIV infection:• Procaine penicillin IM (1.8-2.4g) plus oral probenecid 500mg qid for 17

days (or doxycycline 200mg bd for 28 days).

DiagnosisDiagnosis

• Acute myocarditis is defined histologically as inflammation of the m ocardi m ith associated m ocell lar necrosisof the myocardium with associated myocellular necrosis.

• Gold Standard is endomyocardial biopsy.• Previously Dallas criteria were used, now WHO/

I t ti l S i t d F d ti f C di l T kInternational Society and Federation of Cardiology Task Force define:

- Active myocarditis: > 14 leucocytes/mm with necrosis d d tiand degeneration

- Chronic myocarditis >14 leucocytes/mm but no necrosis or degeneration

• Further classified according to inflammatory infiltrate i.e. neutrophils, monocytes and macrophages in the acute stage, with lymphocytes and fibroblasts in the later stages.

Mucous membrane or otherValvular endothelium colonized tissue

traumaturbulencemetabolic

Platelet fibrin deposition TraumaPlatelet-fibrin deposition Trauma

Nonbacterial thrombotic Bacteremiaendocarditis (NBTE)

Complement AbAdherence

Colonizationbacterial divisionfibrin depositonplatelet aggregationextracellular proteasesneutrophils protection

mature vegetationmature vegetation

Candidal EndocarditisCandidal Endocarditis• Candida endocarditis carries a high rate of mortality. Medical treatment

alone usually fails. Surgical replacement of the infected valve as well as the administration of a prolonged antifungal regimen is strongly

d d [1915] N i l did t h b t t d ithrecommended [1915]. Non-surgical candidates have been treated with long-term suppressive oral therapy, but this approach should be used only in extreme cases as is considered non-curative [153].Attempts to treat Candida endocarditis with antifungal agents aloneAttempts to treat Candida endocarditis with antifungal agents alonewere invariably unsuccessful [1982]. The best ever reported survival rate of this fatal infection (more than 50% at 5 years) has been achieved by combining an aggressive perioperative antifungal regimen with radical surgical debridement of all infected tissue and valve replacement ideallysurgical debridement of all infected tissue and valve replacement, ideally using biologic tissue [1513, 1593

Pathways involved in inflammation and destruction in the rheumatoid jointThe five key factors ofThe five key factors of intracellular signaling and proliferation, adhesion, inflammation,angiogenesis, and matrix degradation are linked by various inflammatory effector cells such as tumor necrosiscells, such as tumor necrosis factor, interleukin-1 and interleukin-6, and matrix-degrading enzymes, including matrix metalloproteinases and cathepsins, finally resulting in apersisting vicious circle. IL, interleukin; MMPs matrixinterleukin; MMPs, matrix metalloproteinases; TNF, tumornecrosis factor. From: Muller –Ladner et al., N t Cli P tiNature Clin. Practice Rheumatol. 1:102, 2005