Streptococci and Enterococci

Thursday, September 26, 2013

John F. Love, MD, PhDInstructor, Section of Infectious Disease

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

Streptococcus

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

Hemolysis Patterns of Streptococci

Classification of Strep from HumansSpecies Lancefield Hemolytic Comments

S. pyogenes A β

S. agalactiae B β, γ Group B Strep

S. dysgalactiae subsp. equisimilis

C, G β Formerly S. equisimilis; pyogenic; respiratory, SSTI

S. pneumoniae None α

S. bovis species group

D α, γ Viridans; associated with colon cancer; IE

S. mutans group not useful α, γ, rarely β Viridans; dental caries and IE

S. salivarius group not useful α, γ Viridans; opportunistic

S. mitis group not useful α Viridans; IE, opportunistic

S. anginosus group A, C, F, G, or no detectable

α, β, γ Viridans; formerly known as S. milleri; 3 species S. anginosus, S. constellatus, and S. intermedius; purulent infxns

Zoonotic Strep SpeciesSpecies Lancefield Hemolysis Comments

S. dysgalactiae subsp dysgalactiae

C, L α, β, γ Domesticated animals

S. equi subsp equi C β Equine strangles; limited documentation of human infxn

S. equi subsp zooepidemicus

C β Bovine mastitis; outbreaks of human nephritis

S. pornicus E, P, U, V β Swine; human female genital tract; may cross react w/ GBS antigen testing

S. canis G β Dogs; infrequent human pathogen

S. suis R, S, T α, β Swine; infrequent human meningitis

S. iniae None detectable

β Fish; SSTI, sepsis

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?

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

S. pyogenes

• Asymptomatic colonization• Pharyngitis– Scarlet fever

• Pyoderma, impetigo• Invasive SSTI: erysipelas, cellulitis, NF, myositis,

peripartum sepsis• Strep TSS• Bacteremia• Sequelae: rheumatic fever, glomerulonephritis

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

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

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

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

Scarlet Fever Pictures

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

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

ARF Pictures

Chorea

http://youtu.be/RsIQFeYOkAg

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

Category Duration after last attack

RF w/o carditis 5 years or age 21 (whichever longer)

RF w/ carditis but no residual heart (valvular) disease

10 years or age 21 (whichever longer)

RF w/ carditis and residual heart (valvular) disease

10 years or age 40 (whichever longer); maybe lifelong

Poststreptococcal Acute Glomerulonephritis

• GAS, but also group C (S. equi subsp zooepidemicus); 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

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).

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?

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

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

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)

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

– Zimbelman et al., 1999 (looked at NF)

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.

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?

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.

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)

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

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.

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.

Antibiotic Susceptible Intermediate Resistant

PCN (oral) ≤0.06 0.12-1 ≥2

PCN (IV), non-CNS ≤2 4 ≥8

PCN (IV), CNS ≤0.06 n/a ≥0.12

Amox (oral), non-CNS ≤2 4 ≥8

CTX, non-CNS ≤1 2 ≥4

CTX, CNS ≤0.5 1 ≥2

Resistance to Other AntibioticsAntibiotic % Suscept.

PCN (IV), non-CNS 95%

PCN (IV), CNS 49%

CTX, non-CNS 95%

CTX, CNS 90%

Ery 56%

Levo 97%

Bactrim 66%

Vanco 100%

Linezolid 98%

Tetracycline 61%

BMC Antibiogram, all adult inpatient pneumococcus, 2011 (N=67)

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

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!

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.

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

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

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

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)• Intrapartum abx 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 intrapartum abx for planned C-section in absence of

labor or membrane rupture.• PCN; cefazolin or vanco for allergies

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?

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

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)

Treatment of Native Valve Endocarditis from Strep viridans and

OthersOrganism Antibiotic Regimen

PCN-sens Strep viridans (MIC ≤0.12) PCN-G (12-18 million U daily, divided) or CTX (2g q24h) x 4 weeks

PCN-G or CTX plus gentamicin (3 mg/kg qday) x 2 weeks

Vancomycin x 4 weeks

PCN-intermed Strep viridans (>0.12 but ≤0.5)

PCN-G (24 million U) or CTX (4 weeks) plus gentamicin (2 weeks)

Vancomycin x 4 weeks

PCN-resistant Strep viridans (>0.5), Abiotrophia, Granulicatella, Gemella

PCN (18-30 million U) or amp (12g/day, divided) plus gentamicin x 4-6 weeks

Vancomycin x 6 weeks

At BMC in 2011, 20% of Strep viridans were intermediate MIC vs. 80% sensitive.

Treatment of Prosthetic Valve IE with Strep viridans

Organism Regimen

PCN-susceptible (MIC ≤0.12) PCN-G (24 million U) or CTX (2g q24h) x 6 weeks +/- gentamicin (3 mg/kg q24) x 2 weeks

Vancomycin x 6 weeks

PCN-resistant (MIC>0.12) PCN-G (24 million U) or CTX (2g q24h) plus gentamicin x 6 weeks

Vancomycin x 6 weeks

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

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

Streptococcus anginosus group• Formerly called Strep milleri group• 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

Streptococcus dysgalactiae subsp equisimilis

• 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

Streptococcus bovis group

• Complex phylogeny, but S. gallolyticus subsp gallolyticus is one associated w/ IE and bacteremia

• Causes 11-27% of all IE, and 24% Streptococcal IE• High association with colonic malignancy and

hepatobilliary disease (77% of bacteremias found to have CA in one series)

• Aortic valve most common• Follows Strep viridans treatment guidelines• Rare vancomycin resistance (probably acquired from

VRE)

Nutritionally Variant (Deficient) Strep: Abiotrophia and Granulicatella

• Originally called Streptococcus mitior• Require pyridoxal or cysteine for growth• Small colonies; often satellites around other species; somewhat

difficult to culture• Normal flora of upper respiratory, GI, UG tracts• In vitro MICs don’t correlate well with clinical responses

– Less susceptible to PCN (33-67% relatively resistant)– Vancomycin active– PCN or vanco have synergy with gentamicin– Decr susceptibility to 3rd gen cephs, azithro, clinda

• Cause IE (esp Abiotrophia): 5% of bacterial IE, majority of culture-negative IE (although cultures more sens now)– Compared to other bacterial IE: more complications, more

embolization, more CHF, more surgery needed, more relapses despite appropriate tx

Streptococcus iniae

• β hemolytic; no Lancefield antigen• May be misidentified as a viridans by

automated systems• Cellulitis of hand(s) with accompanying

bacteremia• Handling live or dead fish (especially tilapia)• Good response to β-lactam abx

Case 5

• 49M admitted 2 week ago with ICH, complicated ICU post-op course incl MRSA VAP, today day 5 of 7 vancomycin

• Fever today, tachycardic; WBC up• Blood cx drawn from CVC growing GPC pairs

and short chains• Questions:– What organism(s) do you worry about?– What is your next step?

Enterococcus

• Part of Streptococcus until 1984.• Can grow in 6.5% NaCl and from 10°-45°C;

hydrolyze esculin in presence of 40% bile salts• Most infections from E. faecalis or E. faecium;

leading cause of nosocomial infxns• Colonize GI tract; selected for by abx

Enterococcus: Clinical Manifestations

• Bacteremia +/- IE (1-32%)– Frequent comorbidities– IE subacute; fever, constitutional sx; 50% CHF; emboli 27-43%;

death 11-35%• UTI• Meningitis

– 0.3 to 4% of cases; usu severe comorbidities• Abd Infxn

– Unclear contribution to pathology in polymicrobial collections– Nosocomial peritonitis, PD-related infxn

• Neonatal• SSTI

Enterococci: Challenges of Treatment

• Intrinsically resistant to many abx, with acquisition of additional resistance

• Looking for bactericidal tx for IE• β-lactams not regularly bactericidal as

monotherapy, requiring AG as synergy

β-lactams and Enterococci• MICs 10-100x higher than Streptococci; ampicillin retains

highest potency, followed by PCN-G and carbapenems.• E. faecium is usually resistant

– Overexpress pbp5, decreasing affinity• E. faecalis rarely resistant, but may express a β-lactamase

(not readily detected without specific testing)– For faecaLis, β-Lactams still work.

• Ceftaroline has good in vitro activity against E. faecalis (but not amp-resistant E. faecium).

• Ceftriaxone or cefotaxime in combination with high-dose ampicillin for E. faecalis IE with resistance to AGs

Vancomycin

• Resistance develops through acquisition of genes that alter cell wall biochemistry– VanA most common; VanB, VanC also clinically

found– Changes D-ala-D-ala to D-ala-D-lactate, leading to

1000-fold decrease in affinity

• Televancin not very active against VRE

Other Drugs• Daptomycin

– May want to use higher dose, 8-10 mg/kg– Resistance rare

• Linezolid– Resistance may be increasing

• Tigecycline– Appears active against both VSE and VRE

• Synercid (quinupristin/dalfopristin)– Not active against E. faecalis

• Quinolones– Sometimes used in combination regimen for salvage

• Chloramphenicol

BMC Enterococcus Sensitivity PatternsDrug All Enterococcus E. faecalis* E. faecium*

Ampicillin 68% 96% 7%

Gent (synergy) 78% 71% 100%

Levoflox 52% 60% 0%

Linezolid 100% 100% 100%

Nitrofurantoin 67% 100% 0%

PCN 63% 83% 0%

Synercid 34% 0% 100%

Streptomycin (synergy)

73% 53% 83%

Tetracycline 19% 30% 14%

Vancomycin 71% 77% 0%

* Only speciated for certain cultures, like blood.

Treatment Guidelines for Enterococcal IE

Resistance Pattern

PCN AG Vanco Regimen

S S S Amp or PCN plus AG x 4-6 weeks(? Amp plus CTX if lose AG)Vanco plus AG x 6 weeks

R S S Amp/sulbact + AG x 6 weeks (only if β-lactamase producer)Vanco plus AG x 6 weeks

AG: use gent if sensitive; consider streptomycin if sensitive.

Worst-case Scenario: Pan-Resistant Enterococcus

Leuconostoc species• Catalase-negative, GPCs pairs or chains; plants and

dairy products; rare opportunistic pathogens• Intrinsically resistant to vancomycin• Bacteremia, IE, pulmonary infections, meningitis, brain

and liver abscesses• Must get MICs• Usually sensitive to PCN and Amp, although MIC’s

usually higher than for Strep• Dapto, carbapenems have good activity• Poor activity of trimethoprim, sulfonamide, fosfomycin

Ongoing Areas of Research• GAS

– Vaccine?– Linezolid instead of clinda?– Mechanisms of persistence and recurrence– Genetic plasticity and evolution of new strains

• Pneumococcus– Serotype replacement?– Non-capsule vaccine?

• GBS– Vaccine?

• Enterococcus– Management of MDR

Where to Look for Help?

• www.idsociety.org– IDSA website– Practice guidelines for SSTI, IE