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Microorganisms Causing Cardiac Infections

Dr. Edhie Djj,pohan Utama, SpMK Dep. Mikrobiologi FKUSU MedanM e d a n CARDITIS

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

Myocarditis - Inflammation of the heart muscle - Inflammation of the Classification

• OLD – Subacute Bacterial Endocarditis • Deathin3Death in 3-6 months – Acute Bacterial Endocarditis • Death in < 6 weeks • NEW – Na tive Va lve En docar ditis – Prosthetic Valve Endocarditis INFEKSI PENYEBAB TERBANYAK DIAGNOSE LABORATORIUM

EdEndocarditi s Streptococcus spp (60 -80%) 3ltkkltdhdi3 sampel untuk kultur darah yang di-ambil Staphylococcus spp (20- pada 3 daerah berbeda dilakukan 35%) pengambilan 1 – 2 jam sebelum pemberian Batang Gram Neg. (2-13%) antimikroba. Bakteri lain2 (5%) Jamur (2-4%) (Candida) Sampel darah diambil 1 sampel Kultur negatip (5-25%) untuk anaerob dan satu untuk kultur aerobic masi210ing2 10 – 20 m l / Pericarditis Virus Enterovirus Pemeriksaan serologg,jic, jika p erlu Adenovirus dikombinasikan dengan kultur dan untuk Herpes virus PCR. Influenzae virus Parainfluenza virus Bakteri Staphylococcus aureus Pemeriksaan mikroskopis dan kultur. Tes Streptococcus pneumoniae DNA jika perlu Mycobacterium tuberculosis Mycoplasma pneumoniae Tes serologik INFEKSI PENYEBAB TERBANYAK DIAGNOSE LABORATORIUM Baaekteri Staphylococcus aureus Peeemeriksaa n mikros osopsdauu.eskopis dan kultur. Tes Streptococcus pneumoniae DNA jika perlu Enterobacteriaceae Mycobacterium tuberculosis Mycoplasma pneumoniae Tes serologik Neicceriae spp Kultur dan mikroskopis Gram negative anaerob Actinomyces & Nocardia Rickettsia Tes serologik Chlamydi a t rach omati s Fungi Candida spp Mikroskopik dan kultur jamur Aspergillus spp Jikas perlu PCR CfCryptococcus neoformans Protozoa Toxoplasma gondii Mikroskopik dan kultur jamur Trypanosoma cruzi Jikas perlu PCR Helminthes Tricinella spiralis Tes serologik

Kayser, Medical Microbiology, 2005 • Adu lt popu la tion : – Rheumatic Heart Disease • 20 – 25% of cases of IE in 1970’s & 80’s • 7 – 18% of cases in recent reported series • Mitral site more common in women • Aortic site more common in men – Congenital Heart Disease • 10 – 20% of cases in young adults • 8% of cases in older adults • PDA, VSD, bicuspid (esp. in men>60)

• Pediatric population – The vast majority (75-90%) of cases after the neonatal period are associated with an underlying congenital abnormality • Aortic valve • VSD • Tetralogy of Fallot – Ris k o f pos t-op in fec tion in c hildren w ith IE is 50% Infective Endocarditis • Typically involves the valves : – May involve all structures of the heart • Chordae tendinae • Sites of shunting • Mural lesions – IfInfecti on of vascul ar sh unt s, b y st titrict definition, is endarteritis, but lesion is the same Infective Endocarditis

• Pathogenesis

Endothelial damage

Platelet-fibrin thrombi

Microorganism adherence Characteristics of Causative Organisms

• Adherence factors critical for growth in the vegetation – Can adhere to damaged valves (Staph, Strep and Enterococci have adhesins that mediate attachment) – Staph adhesin binds fibrinogen and fibronectin – trigger tissue-factor production from local monocytes and induce platelet aggregation so the organisms become enveloped in the vegetation – Protection from immune clearance leads to large numbers of bacteria (109-1010 per g of tissue) • In the vast majjyority of patients, endocarditis can be effectively treated with medication and/or surggyery. • Nevertheless, endocarditis can cause serious damage or even death if left untreated.

S. Aureus vegetation, antiterior lea fltflet Risk Factors

• Structural heart disease – Rheumati c, congenit a l, ag ing – Prosthetic heart valves • IjInject tdded drug use • Invasive procedures (?) • Indwelling vascular devices • Other infection with bacteremia (e.g. , meningitis) • History of infective endocarditis Infective Endocarditis

• Intravenous Drug Abuse – Risk is 2 – 5% per pt./year – Tendency to involve right-sided valves • Distribution in clinical series – 46 – 78% tricuspid – 24 – 32% mitral – 8 – 19% aortic – Underlying valve normal in 75 – 93% – S. aureus predominant organism (>50%, 60- 70% of tricuspid cases) Infective Endocarditis Microbiology – Neonates : S. aureus, coag – staph, group B strep – Older children : 40% strep, S. aureus • Majority of cases caused by (Adult Cases) : – streptococcus, – stappyhylococcus, – enterococcus, or – fastidious gram negative cocco-bacillary forms : Gram negative organisms : • P. aeruginosa most common • HACEK - slow growing, fastidious organisms that may need 3 weeks to grow out of culture – sp. – – – Eikenella – INFECTIVE ENDOCARDITIS • Staphylococcus aureus (30-40%) • Viridans gg()roup streptococci (18%) • 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 : = Oral, skin, URI : S. viridans, Staphylococci, HACEK =GI= GI : S . bovis (ass. Polyps & colonic tumors) : G –ve (Enterobacteriacae) = GU : Enterococci = Nosocomial : intravascular catheters : S.aureus

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

• Gram negative organisms – 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

• Like o ther ora l v ir idans s trep tococc i, SiS. sanguis commonly enters the bloodstream following dental procedures Prosthetic valve : 2mo , NI : Intraoperative contamination : Bacteremic postoperative : S.coag.-ve, S. aureus, G-ve rod, diphtheroids, fungi : >12mo. = Community-acquired native valve :>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 - Lt side : varied etiology & abnormal valve : P.aeruginosa, Candida spp., : Bacillus , Lactobacillus, : Corynebacterium -Polymicrobial Causative organisms of infective endditidocarditis

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

*most common organisms associated with native valve endocarditis Native Valve IE • Viridans Streptococci and S. bovis – Aqueous 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 2 g q24 PLUS for the first 2 weeks • for synergy – Low concentrations are adequate (1-3 mcg/ml) – 3 mg/kg divided q12 or q8 – Little data for q24 dosing • Enterococci, sensitive – High rates of failure – 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,,p ampicillin resistant – Vancomycin plus gentamicin • Enterococci, vancomycin resistant – Linezolid or daptomycin – Penicillin + vancomycin + gentamicin ? DIAGNOSIS IE:

Because the clinical features of the disease can be quite variable and often nonspecific , diagnosis is mainly based on laboratory tests. Blood culture and serologggic testing are the most im portant. Always use venous blood to isolate the organism. A positive blood culture with some or all of the symptoms listed is needed to obtain the diagnosis. • Blood is normally considered sterile • Means of delivery for many microbial agents • Primary viremia/bacteremia clinically inapparent • Secondary viremia/bacteremia have clinical signs due to activation of inflammatory process Detection of Bacteremia

• Specimen collection • Specimen volume • NbNumber o fbldltf blood culture • Miscellaneous • Universal precautions • Aseptic techniques Blood Cultures (Microbiology Diagnostic)

3 sampel untuk kultur darah yang di-ambil pada 3 daerah berbeda Dilakukan pengambilan 1 – 2 jam sebelum pemberian antimikroba Sampel d ara h diam bil 1 sampe l un tu k anaero b dan sa tu un tuk k ult ur aerobic masing2 10 – 20 ml (Kayser, Medical Microbiology, 2005)

Literatur lain : MULTIPLE BLOOD CULTURES BEFORE EMPIRIC THERAPY : • If not critically ill – 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 blood cult ures • Bacteremia in adults have a number of CFU < 30 CFU/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 spppace an hour apart)

Lecturer: Kanya Preechasuth : Clinical microbiology, Faculty of Associated Medical Sciences, CMU, Jan 12, 2006 Timing of collection > 1 hr influx of bacteria fever, chill

normalhl host d ef ense mech ani sms

bacteria was cleared

Ideal 30 min. before peak temperature Miscellaneous • 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 factors Miscellaneous • Anticoagulant – 0.025-0.05% Sodium polyanetol sulphonate (SPS) • Inactivate neutrophils • Inactivate antimicrobial (amonoglycosides, polymixin) • Inhibit phagocytosis • Inhibit growth of Neisseria gonorrhoea, N. meningitidis • Prevent by add 1-1.2% gelatin

Heparin, EDTA , and citrate inhibit numerous organisms Miscellaneous • Additives – 10-20% Hypertonic sucrose or sorbitol – Penicillinase – Antimicrobial-adsorbing (resin): nonspecific adsorbtion

0 • Incubation at 35-37 C and 5% CO2 • Ventilation for strictly aerobe (Pseudomonsa, and fungi) Conventional culture

• Culture media – TSB 50 ml, 10 ml = Conventional culture – 0.025% SPS = Lysis centrifugation – 1-1.2% gelatin = Automated blood culture system –5% CO2 • 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 – Early blind su bcu ltu re : after 6- 18 hrs – Final subculture : after 5-7 days (bacteria) or 14 days (fungal) 0 • Chocolate agar at 35-37 C and 5% CO2 Conventional culture

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

• Macroscopic examination • Sign of growth (106-107CFU/ml) – Turbidity – Gas bubbles in the medium – HlifRBCHemolysis of RBCs – The appearance of small aggregates of bacterial or fungal growth on the surface of sedimented RBC Growth detection :

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

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 • The organisms causing the infection at a primary site of infection is not the same as the isolated from the blood culture (physician-based) Probable pathogen : • Growth of the same organism in repeated cultures • Growth of certain organisms such as member of Enterobacteriaceae, Strep pneumoni ae, gram-negative anaero be, an d Strep pyogenes Automated blood culture system • BecT/Alert® (Organon Teknika) • BACTEC® 9240 (Becton Dickinson) • Detection unit - 120, 240 cells - agitate continuously -monitored 144 times /days (10 miitin. interva l)

• Computer system • Culture medium - 20, 30, 40 ml. Trypticase soy broth -up to 4 ml. blood (pediatric ) - up to 10 ml. blood (adult) - anticoagulant = SPS - supplements with BHI solids and activated charcoal “Culture Negative” IE • Less common with improved blood culture methods • Special media required : – Brucella, Mycoplasma, Chlamydia, Histoplasma, Legionella, • Longer incubation may be required – HACEK • (), Trophyrema whipplei will not grow in cell-free media Other microbiologic methods • PCR – Coxiella burnetii – Tropheryma whipplei – • Serology – Coxiella burnetii – Bartonella – Brucella – Legionella – Chlamydophila psittaci Treatment of IE

• Native vs. Prosthetic Valve • Bactericidal therapy is necessary • Eradication of bacteria in the vegetation – May be metabolically inactive (stationary pp)hase) – May need higher concentrations of antimicrobial agents Antimicrobial Therapy • Most patients are afebrile in 3-5 days • 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 weeks – If intermediate susceptibility to penicillin, aqueous penicillin G 24 million units or ceftriaxone 2 g q24 PLUS aminoglycoside for the first 2 weeks Antimicrobial Therapy • Antibiotics are usually administered intravenously for 2-6 weeks. Duration depends on the virulence of the pathogen. • The drug of choice for most cases of viridians streptococcal 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 IE, although Amphotericin B is often administered in conjunction with surgery. Infective Endocarditis: Treatment

Prolonged, parenteral, bactericidal antibiotics = Higgyhly sensitive strepp(tococci (MIC<0.1 mcgg)/mL) · Penicillin G or Ceftriaxone 4 weeks · Penicillin G and Gentamicin 2 weeks · Vancomycin (for Pen-allergic) 4 weeks = Relatively resistant streptococci (MIC >0.1, < 0.5) · Penicillin G 4 weeks and Gentamicin 2 weeks · Vancomycin (for Pen-allergic) 4 weeks = 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 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 the species of the etiologic agent, the age of the patient and the extent of the disease. = If an tibioti c th erapy i s no t successf ul surgi ca l remova l o f in fec te d endocardium may be necessary. This is especially true with fungal infections and when the patient has an intracardiovascular prosthesis. Nonspecific therapy includes: Chemoprophylaxis

Adult Prophylaxis: Dental, Oral, Respiratory, Esophageal Standard Regimen

Amoxicillin 2g PO 1h before procedure or Ampi c illin 2g IM/IV 30m bfbefore proce dure Penicillin Allergic Clindamycin 600 mg PO 1h before procedure or 600 mg IV 30m before Cephalexin OR Cefadroxil 2gPOg PO 1 hour before Cefazolin 1.0g IM/IV 30 min before procedure Azithromycin or Clarithromycin 500mg PO 1h before Native Valve IE • S. aureus – Penicillinase-resistant semi-synthetic penicillin (oxacillin or nafcillin) 1.5- 2 g IV q4 or (cefazolin 1-2 g IV q8) for 4-6 weeks – 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 IE

• Staphylococci most common – Coagulase negative staphylococci • Enterococcus • Nutritonally variant streptococci • Fungi Candidal Endocarditis

• Candidal endocarditis is a severe condition that has been traditionally associated with an exceptional high mortality and recurrence rates. Both nativ e and prosthetic v alv es may be affected. Combining medical w ith 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 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%, 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 Pericarditis

• Candida pericarditis is a rare but serious condition that can lead to severe sepsis, and death if not diagnosed and treated pppy[romptly [1863]]p. Candidal pericarditis may 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 byyy Rabinovici et al. only 18 had species identification. Of these 78% of them were caused by Candida albicans. Candidal Endocarditis

1. Blood cultures. The sensitivity of blood cultures to detect invasive candidiasis is generally low. However, the intravascular 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 Candida spp. have been reported in reviews of fungal endocarditis [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 blood cultures for this group were 7 and 5 respectively [1640]. Antifungal therapy

Very 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. 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.

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

• Azoles. The ava ila bility o f ora l an tifunga l agen ts has a dde d a very impor tan t too l 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 Candida endocarditis. Candida species and Candida Pericarditis

Candida 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 Strategies To make the diagnosis of Candida pericarditis, one should : • 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 • Ideall y, have a his topa tho log ic con firma tion o f yeas t forms in per icar dia l tissue. Therapies • TtiTreating CdidCandida periditiiicarditis requires an aggress ive approac hthth that combines surgical and medical treatment. • prolonged courses of amphotericin B but the precise length of therapy is not defined Less prevalent causative agents include • Other bacteria – The HACEK Group • Haemophilus species, Actinobacillus actinomycetemcomitans, , , and Kingella species – Usual bacterial causes • Bacillus cereus, Clostridium perfringens, Mycobacterium tuberculosis, Nocardia asteroides, Coxiella burnetii, etc. • Fungi – Candida and Asppgergillis species Drugs (usually causing hypersensitivity myocarditis)

– Chemotherappgeutic drugs - Doxorubicin and anthracyclines, streptomycin, cyclophosphamide, interleukin-2, anti-HER-2 receptor antibody/Herceptin – Antibiotics - Penicillin, chloramphenicol, sulfonamides – Antihypertensive drugs - Methyldopa, spironolactone – Antiseizure drugs - Phenytoin, carbamazepine – Amphetamines, cocaine, catecholamines Pericarditis

• Also called: Adhesive Pericarditis, Postmyocardial Pericarditis, , Bacterial Pericarditis, Polyserositis, Chronic Pericarditis, Constrictive Pericarditis. • Pericarditis 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 with pericarditis also have some fluidinthefluid in the pericardial sac. Myocarditis • Also called: Fulminant Myocarditis, Acute Myocarditis • Myocarditis is an uncommon inflammation of the heart muscle ((ymyocardium ). This inflammation can be caused by infectious agents, toxins, drugs or for unknown reasons. It may be localized to one area of the heart, or it may affect the entire heart. • Approximatel y 50% of the time,,y myocarditis is classified as idiopathic although a viral etiology is often suspected but unproved. Myocarditis

• Despite three decades of study, the diagnosis andtitild management remain controversial. • The exact incidence and prevalence remain unknown. • Clinical presentation varies • Most patients are asymptomatic and recover without treatment Etiology Agents of Myocarditis

• 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 • Rickettsial - Scrub , Rocky Mountain , Q fever • BtilBacterial - Diphth er ia, tu bercu los is, s trep tococc i, men ingococc i, , clostridia, staphylococci, , Mycoplasma pneumoniae, psittacosis • Spirochetal - Syphilis, leptospirosis / Weil disease, relapsing fever/Borrelia, Lyme disease • Fungal - Candidiasis, aspergillosis, cryptococcosis, histoplasmosis, actinomycosis, blastomycosis , coccidioidomycosis, mucormycosis • Protozoal - , toxoplasmosis, trypanosomiasis, malaria, leishmaniasis, balantidiasis, sarcosporidiosis • Helminthic - Trichinosis, echinococcosis, schistosomiasis, heterophyiasis, cysticercosis, visceral larva migrans, filariasis Etiology Agents of Myocarditis Viruses : Enteroviruses Influenza A and B Adenovirus Herpes HIV Bacteria : Beta-hemolytic Streptococcus Corynebacterium diphtheria BlibdfiBorrelia burgdorferi Enterococcus spp Chlamyypdia psittaci Mycoplasma pneumonia Staphylococcus aureus

• pto Protozoa : Trypanosoma cruzii Toxoplasma gondi Helminths : Trichinella spiralis Echinococcus Autoimmunity : Infection associated Autouto--immuneimmune disease associated Primary autoimmunity Hypersensitivity: Methyldopa Sulfamethoxazole TiiToxicity: ChliCatecholamines Cocaine Ethanol Viral Myocarditis

• Coxsackievirus A9 is a self-limiting myocarditis, whereas coxsackievirus B3 causes severe myocarditis resulting in a 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 disrupti on of met ab oli sm and pert urb ati on o f i n flamma tion an d 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 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, yy,ellow fever virus, rabies Viral Infection of Heart (Myocarditis)

Viral myocarditis results when the muscles in the walls of heart become infected with a virus. Entereoviruses and adenoviruses are the ppyrimary causative agents of viral myocarditis.

Symptoms • Fever • Cough • Nausea • Vomiting • Myalgia • Arthralgia • Palpitation • (in severe cases) Candidal Myocarditis

• Hematogenous seeding of Candida into the myocardium was frequently found in the early autopsy reviews of patients dying with systemic invasive candidiasis. • The lack of inflammatory response is most notable in immunosuppressed patients Medical 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 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 sm all seri es h av e demo nst rated t he ir e fficacy (t he e fficacy of in terf er on-aaplph a will be 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 . Glu costeroids and other immunosuppressive drugs are CONTRAINDICATED. Chlamydia pneumoniae as an emerging risk factor in . • Seroepidemiologic studies have associated C. pneumoniae antibody with , , carotid artery disease, and cerebrovascular disease. The association of C. pneumoniae with atheroscl eros is is corro bora te d by the presence o f the organ ism 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 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 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 a causative role of C. pneumoniae in the disease process. Infection, inflammation and atherosclerosis • C. pneumoniae, H. pylori, Porphyromonas gingivalis, Cytomegalovirus, Herpes simplex virus, Hepatitis A, B, and C virus linked with an increased risk of cardiovascular diseases • Proinflammatory effects of infection – increased CRP, cytokines MYOCARDIAL INFARCTION • Myocardial infarction can occur in the absence of the common risk factors such as hyperc ho lestero lem ia, dia betes me llitus or cigarette smoking. The sequence of events that leads to acute myocardial infarction includes atherosclerotic plaque formation, plaque rupture, coronary artery thrombosis and coronary occl usi on. An ythin g th at l eads to pl aque r uptur e can result in myocardial infarction.

ETIOLOGY: • Chylamydia pneumoniae, a Gram-, pleomorphic, obligate intracellular parasite. DIAGNOSIS MYOCARDIAL 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) b. Lactic dehydrogeinase (LDH) 4. Cardiac imaging 5. Presence of chlamidia in the plaque 6. Presence of antibiodies to C. pneumoniae TREATMENT: MYOCARDIAL INFARCTION

= Treatment for the infection is administration of one of these compounds (listed in order from most effective to least efficatious): = Macrolid e an tibio tics (ery thromyc in, az ithromyc in, clarithromycin) Tetracyclines Fluoroquinolones (ciprofloxacin, norfloxacin and ofloxacin) Infectious 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 bacteraemia, such as , 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 performed.

Clinical Microbiology and Infection 12 (4), Volume 12 Issue 4, Page 309 – 314, April 2006 Rheumatoid arthritis • An inflammatory joint disorder primarily characterised by symmetrical polyarticular synovitis. • *ff* Affects 1-3%f% of population. • * F 2-3x > M. • * Onset any age – more common 25 to 50 years (peak age of onset is 35-45 years). • * Associated with reduced life expectancy and increased disability. • * Generally considered as a systemic disease – but, in the early stages it is only an articular disease, with the systitemic ex tra-articu lar man ifes ta tions no t d eve lop ing until late in the disease Aetiology:

• Unknown – probably multifactorial - inappropriate inflammatory response. • Genetic predisposition (HLA-DR4 antigen increases risk by 5x) – localised to a pentapeptide in HLA-DRB1. • Environmental, infectious (parvovirus), diet, trauma or psychological factors may play a role in initiating immune response. • Pathogenesis Pathogenesis • Inciting agent activates immune system --> immunological reactions --> immune complexes in synovial fluid activate complement --> inflammatory response --> joint destruction. • Earliest change is inflammation and oedema of synovium with increased vascularity and increased production of synovial fluid – shidfCDhows evidence of CD4+ ThT he lper ce lls m igra ting in to the joint. • Next the synovial villi hypertrophy, synovial cells proliferation , increased vascularisation (angiogenesis) and pannus form (granulation tissue that grows across surface of articular cartilaggjy)e from adjacent synovium). • This is followed by destruction of cartilage by pannus – mediated by pro-inflammatory cytokines (eg TNF-alpha, interleukin-1-beta, interferon-gamma) and metalloproteases (eg collagenases). Lab tests are not diagnostic Blood – 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 positive for rheumatoid factor have a poorer prognosis. Higher prevalence of other autoantibodies are also seen (antikeratin antibodies, antiperinuclear antibodies, anti-RA 33 antibodies) Cardiovascular 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 years after infection. – 1 Aortic aneurysm – 2 Aortic Valve Disease – 3 Coronary Artery Disease Treatment of syphilis

Early: • Benzathine Penicillin, 2.4 MU intramuscularly, (1.2 MU into each buttock.) 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).

Late, neurosyphilis or eye involvement or any stage with coincident HIV infection: • Procaine penicillin IM (1.8-2.4g) plus oral probenecid 500mg qid for 17 days (or doxycycline 200mg bd for 28 days). Diagnosis

• Acute myocarditis is defined histologically as inflammation of the m yocardi um with associated m yocell ular necrosis. • Gold Standard is endomyocardial biopsy. • Previously Dallas criteria were used, now WHO/ ItInternati onal lS Soci itety and dFd Federati on of fCdil Cardiology Tas k Force define: - Active myocarditis: > 14 leucocytes/mm with necrosis anddd degenera tion - 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 other Valvular endothelium colonized tissue trauma turbulence metabolic Platelet-fibrin deposition Trauma

Nonbacterial thrombotic Bacteremia endocarditis (NBTE) Complement Ab Adherence

Colonization bacterial division fibrin depositon platelet aggregation extracellular proteases neutrophils protection mature vegetation Candidal 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 recommendd[ded [1915]N]. Non-surgilical can didthdidates have been trea tdithted 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 alone were 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, ideally using biologic tissue [1513, 1593 Pathways involved in inflammation and destruction in the rheumatoid joint The five key factors of intracellular signaling and proliferation, adhesion, inflammation, angiogenesis, and matrix degradation are linked by various inflammatory effector cells, such as tumor necrosis factor, interleukin-1 and interleukin-6, and matrix- degrading enzymes, including matrix metalloproteinases and cathepsins, finally resulting in a persisting vicious circle. IL, interleukin; MMPs, matrix metalloproteinases; TNF, tumor necrosis factor. From: Muller –Ladner et al., Na ture Clin. Prac tice Rheumatol. 1:102, 2005