Bloodstream Infection and Infective Endocarditis

Bloodstream infection types/common organisms involved

• Bacterial → Bacteremia

  • Staphylococci

  • Streptococci

  • Enterococci

  • Gram-negative bacilli: E. coli, Klebsiella spp.

  • Pseudomonas

  • Most likely organism(s) causing BSI can often be deduced based on patient’s risk factors, community-vs healthcare- acquired, site of primary infection

• Fungal → Fungemia

  • Candidemia if Candida spp. involved 

• Viral → Viremia

• BSI = Bloodstream infections

  • BSI typically involves only one organism

• CRBSI or CLABSI = Catheter-related or Central line-associated BSI

BSI RIsk Factors

• Sources of BSI

  • Primary sites of infection examples:

    • Pneumonia, SSTI, Intra-abdominal infections, UTI

  • Poor oral hygiene - transiently introduces bacteria to blood thru brushing of gums

  • IV drug use

  • IV catheters

  • Other risk factors include:

    • Immunocompromised, diabetes, indwelling prosthesis, recent surgery

How the pathogen gains entry into bloodstream

• Insertion site

  • Primary source for BSO with short-term catheters

    • Skin organisms - endogenous (skin flora) extrinsic (HCW hands, contaminated disinfectant)

• Catheter hub/lumen:

  • Primary source for BSI with long-term

    • Contaminated catheter hub - catheters endogenous and extrinsic

  • Infusate/IV fluid:

    • Rare cause of BSI

      • Contaminated infusate - extrinsic (fluid, medication) Intrinsic (manufacturer)

Proper strategy for obtaining blood cultures for diagnosis of BSI

• Draw 2 sets blood cultures BEFORE antibiotics started

  • 1 set = 1 pair → 2 bottle

  • 2 sets = 2 pairs → 4 bottles

  • Each “set” = 1 aerobic bottle + 1 anaerobic bottle

    • There should be 2 aerobic bottles and 2 anaerobic bottles

  • Each “set” should be drawn from difference sites 

    • Central line + percutaneous/peripheral site

• Identification methods

  • Gram stain

  • Culture

  • Rapid diagnostic tests

    • PCR

What should be done in order to minimize the likelihood of getting false-positive cultures that represent contamination rather than true BSI?

• If a blood culture is positive, it is NOT always a real infection - sometimes it is just contamination

• How do we tell?

  • How many bottles are positive?

    • 1 out of 4 bottles are positive → likely contamination

    • Multiple bottle or sets positive → likely true infection

  • The more bottles that grow the same organism, the more believable it is

• Which sets are positive?

  • If bacteria show up in different sets from different sites → real infection more likely

  • If only one set is positive → suspicious for contamination

• Organisms

  • Staphylococcus epidermidis is often considered contamination especially if only 1 bottle

  • Staphylococcus aureus, or other microbes other than S. epidermis, almost always treated as a real infection, even if only one bottle is positive

• Clinical setting: Patient s/sx, risk factors for BSI is also considered to determine if real infection:

  • Fever, low BP, signs of infection, risk factors (IV lines, immunosuppression)

Exam Question: Given a scenario, is this likely a contaminant or infection, and would you treat it with antibiotics?

• Be sure to take a look at the number of bottles that are positive and the type of organism

  • S. epidermis that is 1 out 4 bottle positive = contaminant, do not treat

  • Everything else = infection, treat

Understand the purpose for using antibiotic lock therapy for catheter-related/central line  associated bloodstream infection (CRBSI/CLABSI)

• For patients where catheter salvage (keeping the line) is attempted, consider antibiotic lock therapy

  • Primarily for patients with long-term caths, dialysis caths

  • Must use in conjunction with systemic IV antibiotics

• Refers to filling a catheter with a high-concentration antibiotic solution and letting it “lock”/soak inside the line to kill bacteria

  • A small amount of antibiotic solutions is injected into the catheter lumen, the solutions stays inside the catheter for several hours 

  • This targets bacteria living in biofilms inside the line

• CLABSI/CRBSI Management

  • Aside from initiating antimicrobial therapy, removal of IV catheter may be needed

  • Removal recommended if:

    • Short term cath with

      • G– bacilli, S. aureus, Enterococci, Fungi, Myobacteria

    • Long term cath with:

      • Severe sepsis

      • Endocarditis

      • Thrombophlebitis

      • Blood culture still + despite > 72 hours appropriate antimicrobial

      • S. aureus, Fungi, or Mycobacteria

Short term catheters

defined as < 10 days

• Complicated infection

  • Remove catheter and treat with systemic antibiotic for 4-6 weeks; 6-8 weeks for osteomyelitis in adults

• Uncomplicated infections

  • Coagulase-negative staphylococcus 

    • If the organism is a coagulase negative staphylococcus

      • Remove catheter and treat with systemic antibiotic for 5-7 days

      • If catheter is retained, treat with systemic antibiotic + antibiotic lock therapy for 10-14 days

  • For all other organisms: S. aureus, Enterococcus, Gram-negative bacilli, Candida

    • Remove catheter and treat with systemic antibiotic (antifungal for candida spp.) for 7-14 days (treat for 14 days after the first negative blood culture for candida spp.; ≥ 14 days for S. aureus)

Long term catheters

defined as ≥ 10 days

• Complicated infections

  • Remove CVC/P and treat with antibiotics for 7-10 days

  • Remove CVC/P and treat with antibiotics for 4-6 weeks; 6-8 weeks for osteomyelitis in adults

• Uncomplicated infections

  • …

Tunneled hemodialysis catheters

• Empiric antibiotics + antibiotic lock

MSSA Empiric/Definitive therapy options

• No renal dysfunction adult dosing

• Nafacillin 2 g IV q4h

• Cefazolin 2 g IV q8h

MRSA Empiric/Definitive therapy options

• No renal dysfunction adult dosing

• Vancomycin

  • target trough 15-20 mg/L or AUC/MIC 400-600 mg*hr/L

• Daptomycin 6 mg/kg IV q24h (some use 8-10 mg/kg per dose)

Enterococcus faecalis Empiric/Definitive therapy options

• No renal dysfunction adult dosing

• Vancomycin

  • Target trough 15-20 mg/L

• Ampicillin 2 g IV q4h (preferred b/c very narrow)

E. coli, Klebsiella spp. Empiric/Definitive therapy options

• No renal dysfunction adult dosing

• Ceftriaxone 2 g IV q24h

  • If EBSL: Ertapenem 1 g IV q24h (critically ill: Meropenem 1 g q8h)

• Ciprofloxacin 400 mg IV q12h or 500 mg PO q12h

• Levofloxacin 500 mg PO/IV q24h

• Definitive only and clinically stable: TMP/SXM PO 5 mg/kg/dose q8-12h

Pseudomonas Empiric/Definitive therapy options

• No renal dysfunction adult dosing

• Cefepime 2 g IV q8h

• Ceftazidine 2 g IV q8h

• Piperacillin/tazobactam

• Ciprofloxacin 400 mg IV q8h or 750 mg PO q12h

• Meropenem 1 g IV q8h

• Intermittent infusion (30 mins): 4.5 g IV q6h

• Extended infusion (4 h): 3.375 g - 4.5 g IV q8h

Empiric Therapy

If organism is unknown (or if organism known but no susceptibility  available), determine the most appropriate EMPIRIC therapy based on suspected  organism(s) in BSI

• This is the best educated guess before culture results

• Example: 

  • If worried about MRSA → Start Vancomycin

  • If believed infection is from urine, educated guess is likely E. coli → start Ceftriaxone

Definitive therapy

If organism is known (with susceptibilities), determine the most  appropriate DEFINITIVE therapy for this BSI

• Once lab identifies organisms + susceptibilities, switch to definitive therapy

• Example:

  • If the culture confirms MRSA → continue vancomycin

  • If you started ceftriaxone for E. coli BUT culture shows Pseudomonas aeruginosa, ceftriaxone does not cover this → must switch antibiotics to Cefepime, Zosyn, or Meropenem

Treatment approach to BSI

• Initiate empiric antimicrobial ASAP

  • Make sure spectrum covers suspected organisms

  • Narrow therapy as needed once ID and susceptibility available → switch to definitive therapy

• Dose at higher end of dose range - be aggressive 

  • IV route and “cidal” (bacteriacidal) drugs preferred

  • Once patient stable, potentially consider switch to PO therapy of equivalent spectrum antimicrobial with high bioavailability

    • Ex: For gram negative bacteremia, can potentially change from IV ceftriaxone to PO Ciprofloxacin

• Final treatment Duration:

  • 7 to 14 days typically

  • HOWEVER, final duration depends on organism(s), other concurrent infections, infectious source(s), and complications

Determine an appropriate start date for the course of therapy

• Day 1 of therapy refers to the first day the patient receives an antibiotic that actually works against the identified bacteria

• b/c E. coli is already susceptible to the antibiotic (Zosyn) started initially, the appropriate start date was 02/28

  • Remember E. coli is a G – bacteria, so its duration of therapy should be 7 days

• b/c pseudomonas is resistant to the initial therapy (Zosyn), which was started on 02/28, then the earlier date does NOT count as day 1

  • Day 1 is 03/03 when Cefepime was started b/c it covers Pseudomonas and its not resistant to the drug

• For S. aureus, treatment duration starts AFTER blood cultures become negative b/c you must confirm the bloodstream infection is cleared

  • Day 1 therapy was 03/06 b/c the cultures came back clear/negative from S. aureus

    • Must continue therapy for total duration even after culture comes back negative

For the antimicrobial therapies recommended, list the side effects and monitoring parameters  appropriate for each therapy

• Monitor for resolution of symptoms (fever, WBC), effectiveness of antimicrobial therapy

• Follow up on culture and micro susceptibilities

• Screen for drug interaction and monitor for drug toxicities

• Adjust antimicrobial doses PRN

  • Optimize pharmacodynamics (consider drug PK as well as organisms and MIC)

  • Monitor renal function; Keep in mind of need renal dosing adjustments, including those on dialysis

• Ensure appropriate treatment duration

Distinguish between uncomplicated versus complicated Staphylococcus aureus bacteremia (i.e.  what factors should be evaluated?) 

o Given a patient case, determine the most appropriate duration of therapy for  Staphylococcus aureus bacteremia 

▪ Duration for uncomplicated Staphylococcus aureus bacteremia, and how to determine  an appropriate start date for the course of therapy 

▪ Generally recommended duration of antibiotic therapy for complicated Staphylococcus  aureus bacteremia

• S. aureus Bacteremia

  • Duration of therapy dependent on uncomplicated vs. complicated bacteremia

    • Uncomplicated if meets all of the following:

      • NO endocarditis

      • NO implanted prostheses

      • NO evidence of metastatic sites of infection

      • Follow-up blood cultures 2 - 4 days after initial positive cultures are negative

      • Afebrile within 72 hours of starting effective treatment

    • Treatment duration

      • Uncomplicated: 14 days

      • Complicated: 4 to 6 weeks, depending on extent of infection and complication(s) (source control)

    • Exam question:

      • Given a scenario, do you think this is a complicated or uncomplicated infection and what would be the duration of therapy?

Infective Endocarditis (IE) - What is it/Pathophysiology

• Inflammation of endocardium

• Most commonly involves the heart valve

  • But can involve ventricular septal defect, damaged endocardium, or intracardiac devices

• Pathophysiology

  • Bacteria enters bloodstream and finds “refuge” and attaches to damaged areas of cardiac tissue or foreign material in heart

  • Fibrin and platelet recruitment → clot formation, growth → bacterial growth → more fibrin/platelet recruitment → etc

• Complications

  • Valvular abscess

  • Valve prolapse, aortic insufficiency → HF

  • Septic emboli → stroke, PE

IE Risk Factors

• Prior IE

• Prosthetic heart valve

• Congenital heart disease

• Rheumatic heart disease

• IV drug use

• Presence of intravascular device

• Others

  • > 60 y/o

  • Male

  • Poor dentition/dental infection

  • Uncontrolled DM

Recognize signs/symptoms of IE, including major/minor Modified Duke’s Criteria

• Definite IE

  • Pathological

    • Culture positive, evidence embolized vegetation or intra-cardiac abscess

  • Clinical

    • Two major criteria 

    • 1 major criteria + 3 minor criteria

    • 5 minor criteria

• Possible IE

  • 1 major criteria + 1 minor criteria or 3 minor criteria

• Rejected/Rule-out

  • Does not meet above criteria and alternative diagnosis found

• Major

  • Blood culture positive for typical organisms consistent with IE on 2 separate blood cultures

  • Single positive blood culture for Coxiella burnetii

  • Evidence endocardial involvement, + ECHO results

• Minor

  • Predisposition, predisposing heart condition, IVDU

  • Fever (temp > 38*C or 100.4*F)

  • Vascular phenomena: arterial emboli, pulmonary infarcts, myotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions

  • Immunologic phenomena:Osler nodes

  • Micro evidence: positive blood cultures for organism not typically associated with IE

Describe the advantages and disadvantages between transthoracic and transesophageal  echocardiograms (TTE vs TEE)

• Used for IE diagnosis (echocardiogram) - helps visualize heart

  • Transthoracic (TTE) 

    • Echo over the thorax 

  • Transesophageal (TEE)

    • this is more invasive, probes down the esophagus

    • But helps visualize heart better (preferred)

    • Need to put patient to sleep

Identify the most common bacterial (gram-positive organisms) causes of IE

• Bacterial

  • Staphylococci (G+)

  • Streptococci (G+)

  • Enterococci (G+)

  • G– bacilli

HACEK - will not be on exam

Streptococcal Endocarditis Native Valve (NVE) Regimen

Note: PCN MIC is 0.12 mcg/mL or less

• Pen G 2 to 3 mil units IV q4h x4w

OR

• Ceftriaxone 2 g IV q24h x4w

  • “easier” to administer

This is a 4 week regimen, not two, because dealing with heart infection

Streptococcal Endocarditis Native Valve (NVE) Regimen

Note: PCN MIC is 0.12 mcg/mL or less

• Pen G 2 to 3 mil units IV q4h x2w

OR

• Ceftriaxone 2 g IV q24h x2w

PLUS

• Gentamicin 3 mg/kg per 24 h IV or IM in 1 dose

This is a 2 week regimen (decrease from 4 weeks) because of the addition og gentamicin

Gentamicin Synergy

• 3 mg/kg q24h: ONLY target trough <1mg/L

• 1mg/kg q8h: target peak 3-5 mg/L, target trough <1mg/L

Synergy: Beta-lactam + Gentamicin

Without beta-lactam

• gentamicin has trouble getting inside the bacteria

• especially true for gram-positive cocci (thick cell wall)

• so its effect is limited

With the beta-lactam

• Beta-lactam damages the bacterial cell wall by binding to penicillin binding proteins, prevents peptidoglycan cross linkage

• this creates holes/weak spots

• Now gentamicin can enter the bacteria more easily, reach its target (30S ribosome), and shut down protein production

• results in much stronger bacterial killing especially for endocarditis infections and gram-positive organisms

The downside

• gentamicin is toxic:

  • Nephrotoxicity

  • Ototoxicity

• So reserved for serious infection only

Easy analogy

• Beta-lactam = breaks the wall

• Gentamicin = goes inside and shuts down the factory

Streptococcal Endocarditis Native Valve (NVE) Regimen

• Vancomycin 15 mg/kg IV q12h

• In practice, usually 15-20 mg/L or AUC/MIC 400-600 mg*hr/L - for exam, will be tested on in practice/clinical parameters

Streptococcal Endocarditis Native Valve (NVE) Regimen

Note: PCN MIC > 12 mcg/mL to < 0.5 mch/mL

• Pen G 4 mil units IV q4h x4w

PLUS

• Gentamicin 3 mg/kg per 24 IV or IM in 1 dose x2w

  • Ceftriatone reasonable alternative for VGS isolates S to Cef

    • 2g IV q24h

OR

• Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses

  • Vanco is allergy to beta-lactam

    • target AUC 400-600

    • target trough 15-20

Streptococcal Endocarditis Prosthetic Valve Regimen

• Pen G 4 mil units IV q4h x6w

OR

• Ceftriaxone 2 g IV q24h x6w

With or Without

• Gentamicin 30 mg/kg per 24 h IV or IM in one dose x2w

Streptococcal Endocarditis Prosthetic Valve Regimen

• Pen G 4 mil units IV q4h x6w

OR

• Ceftriaxone 2 g IV q24h x6w

PLUS

Gentamicin 3 mg/kg per 24 h IV or IM in one dose x6w

Staphylococcal Endocarditis Native Valve Regimen

MSSA

• Nafcillin or Oxacillin 2 g IV q4h x6w

• Cefazolin 2g IV q8h x6w

  • more commonly used

Staphylococcal Endocarditis Native Valve Regimen

MRSA

• Vancomycin 15 mg/kf IV q12h x6w

  • In practice, this regimen is used: 15-20 mg/L or AUC/MIC 400-600 mg*hr/L

• Daptomycin 8-10 mg/kg IV q24h x6w

  • use total BW

Staphylococcal Endocarditis Prosthetic Valve Regimen

MSSA

• Nafcillin or Oxacillin 2 g IV q4h ≥6w

  • Cefazolin 2 g IV q8h alternative in pts w non-immediate-type hypersensitivity reactions to penicillins

PLUS

• Rifampin 300 mg PO q8h ≥6w

PLUS

• Gentamicin 1 mg/kg IV q8h x2w

  • use IBW

If we're doing divided doses, usually we're doing 1mg per kilogram every 8 hours, using ideal body weight, and so you need the peak and trough.

• Gentamicin synergy:

  • target peak 3-5 mg/L

  • target trough <1 mg/L

Staphylococcal Endocarditis Prosthetic Valve Regimen

MRSA

• Vancomycin 15 mg/kg IV q12h ≥6w

PLUS

• Rifampin 300 mg PO q8h ≥6w

PLUS

• Gentamicin 1 mg/kg IV q8h x2w - use IBW

Recall Vancomycin target trough or AUC/MIC and Gentamicin Synergy target peak and trough

Enterococcal Endocarditis - If susceptible to penicillin/ampicillin + gentamicin NVE or Prosthetic Valve

Recommended for patients with a CrCl > 50 mL/min

• Ampicillin 2 g IV q4h x4-6w

OR

• Pen G x4-6w

PLUS

• Gentamicin 1 mg/kg IV q8h x4-6w - use IBW

Enterococcal Endocarditis - If susceptible to penicillin/ampicillin + gentamicin - NVE AND Prosthetic Valve

CrCl > 50 mL/min

• Double beta-lactam ampicillin 2 g IV q4h x6w

PLUS

• Ceftriaxone 2 g IV q12h x6w