Streptococci & Enterococci: Classification, Pathogens & Treatment

1. Streptococci and Enterococci Thursday, September 26, 2013 John F. Love, MD, PhD Instructor, Section of Infectious Disease

2. Conflict of Interest • No financial conflicts to report • Admit to an academic partiality to group A Streptococcus

3. Classification of Streptococci • Strep: gram positive, catalase negative • Nutritionally fastidious • Facultative anaerobes but don’t use oxygen metabolically (create lactic acid) • Initial classification based on hemolysis on sheep blood agar plates • α (partial, reduction), β (complete), and γ (none) • 1930’s: Lancefield defines cell wall antigen groups • Concentrated on virulent, β-hemol species • Sherman: pyogenic, viridans, enterococci, lactic • 1980’s: Enterococci get own genus • Lactic acid Strep (Lancefield N): Lactobacillus • Nutritionally variant Strep (require pyridoxal): Abiotrophia and Granulicatella

4. Hemolysis Patterns of Streptococci

5. Classification of Strep from Humans

6. Zoonotic Strep Species

7. Case 1 • 12F • Developed fevers, sore throat, swollen cervical lymph nodes 3 days ago • Several kids at school sick recently • Today, developed an erythematous, blanching rash on torso, a redness on face sparing area around lips, and a coating on tongue. • She’s allergic to PCN. • Questions • What clinical condition? What pathogen? • How to diagnose? How to treat? • What complications to worry about?

8. Streptococcus pyogenes • Group A Strep, GAS; human-restricted pathogen • Cell-associated virulence factors • Hyaluronic acid capsule • Antiphagocytic • Not immunogenic • M protein (over 150 types); other genes with similar proteins • Antiphagocytic • Bind IgG, IgA • Iron transport • Resistance to antimicrobial peptides • Lipoteichoic acid (LTA) • Extracellular products • Streptolysin S (SLS): oxygen stabile • Streptolysin O (SLO): oxygen labile • DNases • Streptokinase: dissolves clots • SpeB (streptococcal pyogenic exotoxin): protease • SpeA and SpeC: scarlatinal toxins associated with scarlet fever • Superantigens

9. S. pyogenes • Asymptomatic colonization • Pharyngitis • Scarlet fever • Pyoderma, impetigo • Invasive SSTI: erysipelas, cellulitis, NF, myositis, peripartum sepsis • Strep TSS • Bacteremia • Sequelae: rheumatic fever, glomerulonephritis

10. Antibiotic Options for GAS • Try to use PCN or β-lactam if at all possible! • Cephalosporins, carbapenems have great activity • Clinda generally active; sporadic resistance • Increasing resistance to azithro, quinolones • Common resistance to tetracycline family • TMP/SMX questionable (assume inactive) • Vanco, dapto, linezolid

11. Streptococcal Pharyngitis • Ages 5-15 highest incidence; adults also infected (e.g., military recruits) • Person-to-person transmission via droplets or secretions; proximity and crowding worsen! • Food- and water-borne outbreaks occur • Acute onset sore throat, fever, malaise, HA • Look for GI sx in kids • Enlarged, hypermic tonsils, exudates • Tender cervical LAD • Cough, coryza, conjunctivitis should suggest alternative dx. • Self-limiting in about one week • Treat to hasten resolution, stop spread, reduce sequelae • Dx by cx or rapid antigen testing • Oral PCN-V, IM PCN-G, oral amox; cephalexin, azithro, clinda

12. Strep Pharyngitis (con’t) • Remember that 10% of kids asymptomatically colonized (lower in adults) • Cultures or rapid antigen test may remain positive after tx; don’t retreat unless sx have recurred. • Watch for suppurative complications: peritonsillar abscess, retropharyngeal abscess, lymphadenitis, mastoiditis, meningitis, brain abscess, thrombosis of intracranial venous sinuses

13. Scarlet Fever • Classically associated with pharyngitis, but may occur after infxns at other sites • Recent outbreak in China and Hong Kong • Requires GAS strain with erythrogenic toxins • Rash typically on 2nd day • Face flushed except for circumoral pallor • Enanthem: small, hemorrhagic spots on hard and soft palate • Exanthem: upper chest to torso, extremities; face, palms, soles spared; diffuse blush with points of deeper red that blanch; Pastia’s lines (skin folds deeper red) • Tongue: coated to red strawberry tongue

14. Scarlet Fever Pictures

15. Acute Rheumatic Fever (ARF) • Non-suppurative inflammatory lesions of heart, joints, subcutaneous tissues, CNS • Follows an upper respiratory GAS infection • Molecular mimicry?: Ig’s to M protein react with cardiac myosin, synovium, and articular cartilage • Occurs in 0.4 to 3% of untreated GAS pharyngitis cases • More recent ECHO studies suggest rate may be 10x higher than thought • Worldwide: 500,000 ARF per year, with 300,000 developing rheumatic heart disease • Recurrence rate higher with subsequent GAS infection

16. ARF • Major manifestations • Carditis: murmur, CHF, pericardial friction rubs or effusions; chronic mitral > aortic valves • Polyarthritis: knees, ankles, elbows, wrists • Chorea: Syndenham’s chorea (St Vitus dance); emotional lability, weakness, involuntary purposeless movements • Subcutaneous nodules: firm, painless; few mm to 2cm • Erythema marginatum: non-pruritic, non-painful eruption on trunk; evanescent, serpiginous. • Minor: fever, arthralgia, heart block, acute-phase reaction in blood labs • 1-5 weeks after GAS infxn; avg 19 days. Lasts 3 months. • Carditis in 40-50% first ARF, only sx posing long-term disability or death • Dx using criteria above, plus evidence of GAS infection by either culture or rising GAS antibody titer (ASO or DNaseB). • Tx: depends on severity, analgesics to aspirin to steroids

17. ARF Pictures

18. Chorea http://youtu.be/RsIQFeYOkAg

19. ARF Treatment: Secondary Prevention • Prevention of recurrence • IM benzathine PCN-G q3-4 weeks • Oral PCN-V or sulfasalazine 2nd line • Erythro for allergic • Duration depends on severity

20. Poststreptococcal Acute Glomerulonephritis • GAS, but also group C (S. equisubspzooepidemicus); certain M-types and groups associated • Occurs after either pharyngitis or pyoderma; up to 15% untreated cases • Recurrences less frequent than with ARF • Believed to be immunologic etiology: cross-reaction vs. deposition of Ab-Ag complexes • Worldwide: 470,000 cases/year, with 5000 deaths

21. PS-AGN • S/Sx (10-21 days latent): HTN, edema, discolored urine; malaise, HA, anorexia. Fever very uncommon. • Facial, periorbital swelling common • CHF-like respiratory sx • Labs: anemia; ESR up; low serum protein; BUN, Cr up; total complement and C3 down • Urine: mild hematuria, mild proteinuria • Dx: clinical hx, physical findings, evidence of recent Strep infection; maybe bx • Tx: fluid management; treat Strep (PCN); check contacts • Secondary prophylaxis is unnecessary (b/c recurrences very rare).

22. Case 2 • 39M, no pmhx • Pulled calf exercising at gym 4 days ago, took ibuprofen • 2 days later, developed pain, redness near site • ED: low grade temp; erythema on calf, warm, traced; dx cellulitis, started IV vanco. • Overnight, redness expands, becomes more tender, spiking fevers • Noon: febrile, tachycardic, soft BP; erythema deeper, no pain. WBC 15. • Questions • FIRST intervention? • Change in treatments?

23. Necrotizing Fasciitis • Erysipelas or cellulitis progresses from excessive pain to loss of pain sensation, hemorrhagic bullae, rapidly advancing border • Commonly very ill • Dx: need to think of it; pathologic dx • Laboratory Risk Indicator for NF (LRINEC): combines WBC, Hgb, CRP, Na, glucose, Cr • Tx: • Debridement (often multiple times) • Antibiotics: PCN and clindamycin • Consider toxic shock syndrome • Remember: not all NF is GAS

24. Streptococcal Toxic Shock Syndrome • Any Strep infxn with sudden onset of shock and organ failure (most common with skin site) • At least 11 toxins with superantigen activity, but likely many factors contribute • Activates 1 in 5 T cells (compare to 1 in 10,000 to 100,000 in normal infections) (Mueller-Alouf et al., 1994). • Result is cytokine Armageddon TNF-α, IL-1β, IL-6, TNF-β, IL-2, IFN-γ

25. Strep TSS • Sx: • Phase 1: fevers, chills, myalgias, GI sx, confusion, combative • Phase 2: tachycardia, tachypnea, fevers • Phase 3: shock and organ failure • If skin focus, sx evolve at site • Tx: • Source control! • ICU (ARDS in 55% cases) • RRT (renal failure in 50% cases) • Abx: PCN and clinda(high dose) (A-II rec) • Vanco, dapto, linezolid, Synercid for PCN-allergic • Maybe IVIg (B-II rec)

26. Why clinda? • Protein synthesis inhibitor: shuts down toxin production • PCN has Eagle effect: less active against stationary phase GAS • May be due to change in PBP expression • No such issue for clinda • Clinda 600-900mg IV q8h • Limited clinical data • Zimbelmanet al., 1999 (looked at NF)

27. So what about IVIg? • IVIg: some Abs to GAS toxins; improve immune milieu • Clinical data is incomplete • Darenberg et al., 2003 • PCN (12 g/day), clindamycin (600 IV TID), +/- IVIG (1 g/kg day 1, 0.5 g/kg days 2 and 3) • 10 IVIg, 11 placebo • IVIg had trend towards decreased mortality at 28 days (p=0.3), faster resolution of shock, faster improvement in end-organ failure; slower resolution of NF • No adverse events from IVIg. • Cost: about $75-100/gram…so this study regimen would add between $10,500 and $14,000 for 70kg adult.

28. Case 3 • 23F IVDU admitted with septic arthritis • No hx recurrent infxns as child • Aspirated fluid shows GPC diplococci • Blood cultures later grow same, α hemolytic • Questions • Antibiotic tx? • Other testing?

29. Streptococcus pneumoniae • Micro lab identifies by α hemolysis, catalase negative, susceptible to Optochin, and dissolved by bile acids. • Polysaccharide capsule: 91 serogroups and counting • Naturally competent (can take up DNA) • Doesn’t make highly toxic, tissue-damaging products • Niche is human nasopharynx: 5-10% healthy adults and 20-40% healthy kids colonized • Very young and very old most susceptible to invasive disease, but epidemiology changing with vaccination.

30. Factors that Predispose to Pneumococcal Disease • Extremes of age • Defective Ab formation • HIV • Complement defects • Few or ineffective PMNs (steroids, EtOH, DM) • Asplenia (incl sickle cell) • Excess exposure (daycare, prison, shelter) • Prior respiratory infxn, esp flu • Pulmonary inflammatory (smoking, COPD)

31. Pneumococcal Pneumonia • Often multiple risk factors • Cough, fatigue, fever, chills, SOB • Lung exam abnormal • CXR: usually infiltrate; air bronchograms correlate with bacteremia; frequent effusion, and rare empyema. • Labs: leukocytosis, but rare leukopenia • Dx: sputum cx +/- blood cx (can have neg sputum but pos blood cx). Ag test positive in 80% of cases, 10% w/o pneumococcus; can pick up colonization in kids so don’t use in pediatrics. • Complications: empyema; cardiac events

32. Other Clinical Syndromes of Pneumococcus • Otitis media • Usually #1 or #2 to H. flu. • Sinusitis • Usually #1 or #2 to H. flu. • Meningitis • Most common bacterial meningitis in adults; also in kids >6 mos in countries w/ Hib vaccine • Direct extension or bacteremia • Exacerbation of chronic bronchitis • 2nd to H. flu. • Conjunctivitis • Endocarditis (uncommon) • Purulent pericarditis (rare) • Septic arthritis • Osteomyelitis (esp of vertebrae) • SSTI • If an uncommon pneumo infection in young person…check HIV.

33. Treating Pneumococcus • In 2008, MIC breakpoints for pneumococcus differentiated CNS from all other sites • Came from observation that you can’t get PCN into CSF at high concentrations, but good levels in lung and other sites. • Also picking up genes for altered PBPs.

34. Resistance to Other Antibiotics BMC Antibiogram, all adult inpatient pneumococcus, 2011 (N=67)

35. Treatment Recommendations • Otits media: amox; amox/clav, quinolone, or CTX if fails • Sinusitis: amox, amox/clav, quinolone…if truly bacterial (see recent guidelines) • PNA: quinolone, macrolide, doxy, amox +/- clav for outpatient; PCN, amp, CTX, vanco, quinolone; typically 7-8 days total. • Meningitis: vanco plus CTX, plus steroids; narrow abx when MICs known

36. Pneumococcal Vaccinations • Two flavors of vaccine: • Pneumovax: capsular polysaccharide of 23 serotypes; PPS23 • Prevnar: capsular polysaccharide conjugated to protein (improves humoral response), 7 serotypes originally, now up to 13; PCV13 • Recommendations • Use PCV13 for kids; multiple shot protocol • Adults with immunocompromise, asplenia, etc…get one dose of PCV13, then one PPS23 at least 8 weeks later, and 5 years thereafter. • Adults over 65: PPS23 once • These guidelines change frequently!

37. Changes in Capsule Type after Vaccination Introduced • May have replacement in colonization types. • Other countries found invasive diseases increasing from non-vaccine strains. • Herd protection. Invasive pnuemo infections in kids <5. From CDC.

38. Streptococcus agalactiae (Group B Streptococcus) • Capsule is most significant virulence factor • Colonizes genital and lower GI tracts of 10-40% of women; also found in oropharynx, upper GI • Pass to baby peripartum by ascension or during birth

39. Neonatal Infections • Early-Onset • 12 hours of age average • Bacteremia (85%), pneumonia (10%), meningitis (5-10%) • Heavy maternal carriage (untreated), delivery at less than 37 weeks, intra-partum fever, intra-amniotic infection, ROM >18 hours • Late-Onset • Median 36 days (7-89) • Bacteremia (65%) and meningitis (25-30%) • Treatment involves ampicillin plus aminoglycoside initially, before move to PCN-G

40. Infections in Adults • Found with predisposing factors, incl DM, liver disease, malignancy, renal failure • Puerperal infection of mother • Upper genital tract; amniotic fluid, bacteremia, endometritis • Primary bacteremia • Pneumonia • Endocarditis • Large, friable vegetations; rapid valve destructions • Arthritis • Osteomyelitis • SSTI • Recurrent GBS infection • 4% of cases will have another invasive GBS infection • Treat: PCN-G (or vanco); add gent for endocarditis

41. Prevention • Screening pregnant women led to 65% drop in early-onset GBS illness in newborns. • Lower vaginal and rectal swab at 35-37 weeks (unless going to treat already b/c of hx) • Intrapartumabx for: • Positive screening • Previous infant w/ invasive GBS • GBS bacteriuria during current pregnancy • GBS status unknown, plus delivery <37 weeks or ROM >18 hours or fever • No intrapartumabx for planned C-section in absence of labor or membrane rupture. • PCN; cefazolin or vanco for allergies

42. Case 4 • 67M with HTN, DM, COPD, CAD admitted w cough, SOB, LE edema; afebrile; CXR fluid vs multifocal PNA • Given dose of levoflox in ED • One blood cx drawn at admit: GPC pairs and chains  Strep viridans • Questions: • How do we interpret the blood cx?

43. Strep viridans • Made up of 5 groups • anginosus group • mitis group • mutans group • salivarius group • sanguinis group • Normal flora of animals and humans • Low virulence; no toxins

44. Strep viridans: Endocarditis • Often with previous valvular pathology • Proportion increases with time after valve replacement • Subacute: often weeks • Fever, malaise, anorexia • Low-grade bacteremia (1-30 CFU per mL blood)

45. Treatment of Native Valve Endocarditis from Strep viridans and Others At BMC in 2011, 20% of Strep viridans were intermediate MIC vs. 80% sensitive.

46. Treatment of Prosthetic Valve IE with Strep viridans

47. Other Manifestations of Strep viridans • Bacteremia • Account for 2.6% of all positive blood cultures • After toothbrushing, 25-50% of people have bacteremia • If transient, may consider limited clinical significance. • More common and profound in ONC patients, esp BMT. Bad outcomes (maybe just marker of bad mucosal barriers?) • Meningitis • Rare: 0.3 to 5% of culture-positive meningitis • However, concern about contamination • Pneumonia • Very rarely the sole, instigating pathogen

48. IE Prophylaxis: IDSA Guidelines • “bacteremia resulting from daily activities is much more likely to cause IE than bacteremia associated with dental procedures” • Only people with certain conditions get ppx: • Prosthetic valves or perivalvular material • Previous IE • Congenital heard disease, only cyanotic CHD, repaired CHD with prosthetic materials within last 6 mos, repaired CHD with defect • Cardiac transplant w/ cardiac valvulopathy • Procedures warranting ppx: • Dental procedures manipulating gingiva or cutting mucosa • Respiratory tract • Infected skin, skin structures, or musculoskeletal tissue • NOT needed for GI or GU procedures, vaginal delivery, hysterectomy, tattooing. • Regimens • Amoxicillin 2g PO x 1, 30-60 min before procedure • Keflex (2g), clinda (600mg) or azithro (500mg) PO x 1

49. Streptococcus anginosus group • Formerly called Strep millerigroup • S. intermedius, S. constellatus, S. anginosus • Viridans strep, but cause pyogenic infections • Caramel-like odor of colonies • Commensals of oropharyngeal, urogenital, and GI • Synergize with other bacteria, esp anaerobes • More toxins than other viridans • Clinical conditions • Dental abscess, CNS abscess, liver abscess, empyema • IE: high myocardial abscess, metastatic abscesses • Sensitive to PCN, CTX generally; vanco, clinda for allergy; resistant to AG’s although still synergy; macrolides poor

50. Streptococcus dysgalactiaesubspequisimilis • Group C or G by Lancefield; had several older species rolled into it. • Common flora of oropharynx, skin • Infxns often mimic GAS or GBS infections • Pharyngitis • Get ASO bump • PS-AGN has been documented, but not ARF • SSTI • Pyoderma, erysipelas, impetigo • May be more common cause of cellulitis than GAS • Arthritis, often polyarticular • Osteomyelitis • Endocarditis: acute to subacute; poor response to β-lactam monotherapy; frequent emboli • Tx • PCN; amox, vanco, linezolid, cefazolin • Naf, ox not effective; high rates of tetra, clinda, ery resistance • Very good synergy b/w PCN and gent