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Streptococci and Enterococci

Streptococci and Enterococci. Thursday, September 26, 2013 John F. Love, MD, PhD Instructor, Section of Infectious Disease. Conflict of Interest. No financial conflicts to report Admit to an academic partiality to group A Streptococcus. Classification of Streptococci.

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Streptococci and Enterococci

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  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

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