Practice of blood culture:

Can we do better?

Dr Purva Mathur

Importance

Role of Microbiological

Cultures in ASP

IDSA Guideline;

April 13, 2016

ASP with a culture-guided de-escalation of antibiotics successfully reduces • Length of stay • Mortality • Cost of antimicrobials, • DDDs • Antimicrobial resistance rate Highly recommended for hospitals.

BSIs

• Morbidity & mortality

• > 30,000 deaths (U.S. hospitals)

• Mortality: 34 to 52%

• Septicemia affected nearly 1 out of every 23 hospitalized patients (4.2%) (2009)

• Aggregate cost: $15.4 billion or 4.3% of all hospital costs.

• Rapid identification: Multiple positive

impacts on patient outcomes

– Reductions in mortality

– Morbidity

– LOS

– Antibiotic use

– Cost of treatment

– AMR

Blood collection

Continued till etiological

agent is identified & AST results are available

Target (tailor)

therapy

Empirical & often

broad-spectrum antimicrobial therapy

Empirical & often

broad-spectrum antimicrobial therapy

Target (tailor)

therapy

Delay in microbial identification

• 50% BSIs

• Up to 70%

fungemia • Receive incorrect

therapy during the

empirical treatment

period before

culture results are

available

Efficient communication

• Gram staining

• Microorganism identification

• ASTs – Timely switches from

empirical therapy to targeted therapy

Essential for providing safe, effective, and efficient care of patients with BSIs

1

Updated Bundles in Response to New Evidence

The leadership of the Surviving Sepsis Campaign (SSC) has believed since its inception that both the SSC Guidelines and the SSC performance improvement indicators (1) will evolve as new evidence that improves our understanding of how best to care for patients with severe sepsis and septic shock becomes available. With publication of 3 trials (2,3,4) that do not demonstrate superiority of required use of a central venous catheter (CVC) to monitor central venous pressure (CVP) and central venous oxygen saturation (ScvO2) in all patients with septic shock who have received timely antibiotics and fluid resuscitation compared with controls or in all patients with lactate >4 mmol/L, the SSC Executive Committee has revised the improvement bundles as follows: TO BE COMPLETED WITHIN 3 HOURS OF TIME OF PRESENTATION*:

1. Measure lactate level 2. Obtain blood cultures prior to administration of antibiotics 3. Administer broad spectrum antibiotics 4. Administer  30ml/kg  crystalloid  for  hypotension  o

r

 la cta te  ≥4mmol/L * “Time  of  presentation”  is  defined  as  the  time  of  triage  in  the  emergency  department  or,  if  presenting  from  another  care  venue, from the earliest chart annotation consistent with all elements of severe sepsis or septic shock ascertained through chart review.

TO BE COMPLETED WITHIN 6 HOURS OF TIME OF PRESENTATION:

5. Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure  (M AP)  ≥65mmHg

6. In the event of persistent hypotension after initial fluid administration (MAP < 65 mm Hg) or  i

f  in

i

tial  la cta te  was  ≥4  mm ol/L,  re-assess volume status and tissue perfusion and document findings according to Table 1.

7. Re-measure lactate if initial lactate elevated.

Detection of microorganisms

by conventional method

• Blood-cultures – “Gold standard”

• Provides causal organism for further AST & optimization of antimicrobial therapy

Limitations

• 1 to 3 days

• Non-cultivable/fastidious

microorganisms

• Culture neg. if treatment

begun prior to blood

sampling

• Timing of blood-culture

collection

• Volume of blood cultures

An Ideal Platform

• Should identify a broad spectrum of pathogens (bacteria, fungi, viruses, and protozoa)

• Determine susceptibility to a battery of antibiotics

• Allow analysis of specimens in high or low throughput

• Low cost per sample

• Minimum hands-on time

• User friendly

• Generate timely results (6 hours or less).

???

BACTEC 9000 series (BD)

BacT/Alert 3D system (bio-Merieux)

Colorimetric or fluorimetric

detection of increased CO2 levels

due to growth

VersaTREK (TREK) Measures change in gas pressure

(production of CO2) in the headspace

Continuous monitoring systems

CO2: system signals positive; removed and sub-cultured

Identification of pathogens by advanced culture-based

methods

• Gram staining after positive signal

• Pathogen ID & AST from blood is

usually performed using microdilution

broth identification with automated

continuously-monitoring systems:

– Vitek 2 (bioMe’rieux),

– Phoenix (BD)

– Micro Scan Walk Away (Siemens)

• Or semi-automated systems

– Micronaut (Merlin)

• Continuously monitoring expert-based systems

have decreased turnaround time

– Mean of 6.75 h for complete ID of bacteria

– ~18 h for fungi

Including antibiotic susceptibility reporting (Vitek 2 data)

Rapid Assays

Based on 2 methodological groupings

Nucleic acid-based detection tests

Proteomic-based methods using mass

spectrometry (MS)

Rapid pathogen identification by

Mass spectrometry

• Notion of using mass spectrometry for

identification of bacteria was proposed in

1975

• Not possible to analyze intact proteins

(they would have fragmented in the process)

Mass spectrometry

• Technology for analysis of intact

macromolecules: invented in the

1980s

• In 1985, Koichi Tanaka described

a “soft desorption ionization”

method using ultrafine metal

powder & glycerol that enabled

mass spectrometric analysis of

biological macromolecules

• Awarded the Nobel Prize in

Chemistry

• Hillenkamp & Karas reported Soft desorption ionization using an organic compound matrix

• Term matrix-assisted laser desorption ionization (MALDI) was coined.

• Advances in IT

• Computer science

• Development of validated comprehensive databases of mass spectra representing diverse types of bacteria and fungi

Enabled automation of MALDI-TOF MS and associated data analysis

• An important tool for the Clinical Microbiology labs

MALDI-TOF MS

• Most common application of MALDI-TOF MS:

ID of pure microbial isolates grown by culture.

• Protein pattern matching by MALDI-TOF MS

– More accurate than conventional biochemical

phenotypic testing

– Faster and less expensive than 16S DNA sequencing

MALDI-TOF

• Two MALDI-TOF

instruments currently FDA

approved

• Microflex Biotyper

(Bruker)

• Vitek Mass Spectrometry System (bioMerieux)

• Particle sizes (mass spectrum) is unique to each

organism; identified by comparison with a

library of standard reference spectra.

• Allocation of a numerical score to each

identification

– log score ≥2.0: acceptable identification species

– >1.7 but <2.0: identification to the genus level

• Results: 10–30 minutes

• Can be applied to broth media from a positive BC

bottle (not FDA approved)

• Diagnostic yield ~ 80%; turnaround time of 20–60

minutes

• ID of yeast in positive BC broth: more challenging

than bacteria

• Polymicrobial BSIs: detects at least 1 of the

organisms, but it rarely (<10% of cases) detects all

organisms

• Relies on culture (median 12- 17 hour delay)

• They cannot directly detect AMR

• In order to accelerate diagnosis, it is desirable

to detect & identity pathogens directly from the

patient’s blood, avoiding the culture step.

Direct detection from blood:

Nucleic Acid Technology

• Molecular techniques applied directly to

whole blood samples

• Same-day identification of pathogens

• Early pathogen-specific targeting of antimicrobial therapy.

Identification using NAT

(1) Methods applied after

cultivation steps & using

positive BCs/ single colonies

(2) assays that can be

applied directly to drawn

blood or other primarily

sterile specimens, like CSF.

Two categories

Identification using NAT

(1) Pathogen-specific

methods

(2) multiplex assays

covering several different

pathogens typical for a

certain infection type

Three procedures for applying NAT assays in ID

(3) Universal broad-range assays

involving conserved target

sequences, eg. eubacterial 16S/ 23S

rDNA, & pan fungal 8S or 18S rDNA

• These rDNAs are usually in

multiple copies.

• More sensitive detection

• Initial assays: designed for detection of single

pathogen of interest

– Not useful

• Current assays are based on two main strategies:

• Identification of a selected group of pathogens using

specific targets (i.e., SeptiFast, VYOO, Magicplex)

• Detection of a broad range of pathogens using

universal/conserved targets (i.e., SepsiTest, PCR/ESI-

MS).

Commercially Available Molecular Assays for

Diagnosis of BSIs from Whole Blood

1. LightCycler®SeptiFast (Roche)

• Multiplex real-time PCR assay

that detects 25 pathogens

including five Candida species

and Aspergillus fumigatus.

• mecA gene may be detected

with a separate test

• Initial volume of blood: 3 mL

• Pathogen detection: specific

fluorescent probes.

• The time-to-result: 4.5–6

hours.

• Widely evaluated

• Recent meta-analysis on

6,012 patients from 35

selected studies.

– Sensitivity 75.0% (95%

confidence interval, 65.0–

83.0%)

– Specificity 92.0% (95%

confidence interval, 90.0–95.0

2. SepsiTest (Molzym, Germany)

• Based on broad-range PCR

amplification followed by

sequencing.

• Two 1 mL aliquots of blood

are processed in duplicate

• Human DNA is selectively

degraded

• Largest study (𝑁 = 342) – sensitivity 87%

– specificity 85.8%

• Slow turnaround time of 8–12

hours

VYOO (SIRS-Lab)

• Multiplexed PCR analysis

• Detects 34 pathogens

• 6 species of Candida & A.

fumigatus

• Several resistance genes

• mecA, vanA & vanB, blaSHV

& blaCTX-M

• Result: 8 hours

• 5 mL of blood

• Total DNA: applied to an affinity

chromatographic column that

specifically binds the microbial

DNA

• Human DNA is depleted during

the extraction step

• Sensitivity 38.0% - 60.0%.

Magicplex Sepsis Real-Time Test (Seegene)

• Three PCR reactions: to achieve ID at species level

Conventional PCR amplification

• Primers for 91 microorganisms

• 85 bacteria, 5 Candida &

A. fumigatus

• 3 resistance genes (mecA, vanA

and vanB)

Real-time PCR for identification of group

or genera level of pathogens present.

Second real-time PCR is performed

to achieve the identification at

species level • Human DNA is removed prior to the lysis of microorganisms.

• Result: 6 hours.

• Only one study published.

– Sensitivity: 65.0%

– Specificity: and 92.0%

T2 magnetic resonance

(MR; T2 Biosysystems)

• Automated nanoparticle-based PCR assay; can detect ~1 CFU /mL

Candida sp. in blood in ~ 3 hours.

• Initial pilot study using spiked blood samples: 98% PPV

• 100% negative predictive value between T2 MR results & BC for

Candida sp.

• First FDA-approved assay for direct detection

• Five most common Candida sp.

Biofire Film- Array system (bioMerieux)

• Uses nested multiplex PCR – Identify 19 bacterial pathogens

(staphylococci, streptococci, Enterococcus,

Listeria, Acinetobacter, N.meningitidis, P.

aeruginosa & members of

Enterobacteriaceae

– 5 yeast

– 3 resistance markers (mecA, vanA/B, & KPC)

– Directly from positive blood cultures.

• Sensitivities for pathogen ID >90%;

resistance markers is 100% .

• The turnaround time: 1 hour.

PCR–electrospray ionization mass spectrometry

• Combines PCR & mass

spectrometry in an automated,

high-throughput platform

• Not FDA approved

• Can identify nearly all human

pathogens & selected ABR

markers (cultured

material/directly from blood

samples)

• Actionable information: 8 hours

• Only one study – High concordance between

conventional ID from blood culture &

this method

• Costly

• Robust

PCR/ESI-MS technology

• The base compositions of multiple amplicons from

different regions of the genome are compared to an

extensive database: Pathogen ID is achieved

• Not as informative as sequencing

• Broad bacteria and Candida detection assay (BAC

assay; Ibis): identifies > 600 bacteria & Candida species.

– BAC assay also detects resistance genes (mecA), (vanA and

vanB), and blaKPC.

• Especially relevant when the different microorganisms are present in different abundances

• Using several non-overlapping primer pairs may allow amplification of the less abundant

species

New Version of PCR/ESI-MS

• Principal changes: larger volume of blood (5mL)

• 1-6 specimens can be analyzed at a time.

• Mass spectrometer: Bench-top instrument

• Better sensitivity for detection in direct clinical

specimens.

• Further evaluations are currently underway.

Peptide Nucleic Acid Fluorescent In Situ

Hybridization Molecular Stains

• PNA FISH stains (AdvanDx)

• Commercially available for direct identification of

selected pathogens from + BC

• Targets species-specific rRNA, (abundant in

growing bacteria and yeast

• Kits are currently available to differentiate between

S. aureus & CoNS; E.faecalis & Enterococcus

species; E. coli, K.pneumoniae & P. aeruginosa; &

Candida species.

• Turnaround time: ~ 90 minutes.

• ST & SP: 96%- 100%.

• In 2013, a faster and less labor-intensive

QuickFISH (AdvanDx) assay was introduced

with a turnaround time of 20 minutes.

• Excellent sensitivity and specificity results,

similar to those seen with the original PNA- FISH

assays

Yeast Traffic Light PNA-FISH assay

• PNA-FISH assay with clear antimicrobial therapy implications

• 3-probe system that stains C. albicans & C. parapsilosis green, C. tropicalis yellow, C. glabrata & C. krusei red

• Color scheme designed to provide input on whether fluconazole therapy is likely to be effective.

• When associated with concomitant antimicrobial stewardship: reduced use of echinocandins and saved $1729 per patient

Assays for S. aureus and resistance determinants

• S. aureus: 20% of nosocomial BSI

• Empiric therapy with vancomycin

• β-lactams are superior to vanco for T/t of MSSA

• 2 FDA-approved real-time PCR assays that detect

S aureus & MRSA from positive blood cultures:

• GeneOhm StaphSR (BD, Sparks, MD)

• Xpert MRSA/SA (Cepheid, Sunnyvale, CA) assays.

• Both have clinical accuracy >97% for detection of

S. aureus and differentiation of MR

The Xpert MRSA/SA (Cepheid)

• Rapid, automated PCR for SA & MR

in +BC.

• Novel multiplex real-time assay for 2

genes:

• staphylococcal protein A (spa)

gene (specific for S. aureus)

• mecA gene

• 98.3%–100% sensitivity

• 98.6%–99.4% specific

• < 1 hour

The Verigene assay

(Nanosphere)

• Automates NA extraction from

positive BC broth

• Has GP microarray panel for

mecA ,vanA/vanB & GN

panel for MDR

• Labs can select which panel

to test based on the Gram

stain morphology.

• Polymicrobial BSI poses a

challenge.

Challenges of NAT

• Use of whole blood is challenging. • Excess of human DNA • Hemoglobin

• Use of small volume of blood (1 to 5mL) – Conventional culture methods use 20–30 ml – Bacterial load in BSIs can be as low as 1–10 CFU/mL; limitation for detection

of pathogen DNA.

• Range of detection • Antimicrobial susceptibility • Technical complexity • Effort • Overall costs • Differentiation of viable from nonviable

microorganisms – microbial DNA aemia – ? Higher sensitivity/ only DNA (degraded pathogens)

Economic Evaluation

• Decreased time of reporting

• Cost savings are derived from targeted de-

escalation of empiric broad-spectrum

antimicrobial therapy

• Reduced time to appropriate targeted therapy

• Patient’s length of hospital stay

• No economic evaluation studies that comply with

guidelines for full economic evaluation done till date for

rapid testing techniques

Clinical and economic impacts of rapid pathogen

identification in positive blood cultures

Impact of GeneXpert MRSA/SA (Cepheid) on clinical outcomes

• Reduced mean time to initiation of

appropriate therapy (49.8 hours to 5.2 hours)

• Significantly shorter LOS (6.2 days)

• cost saving of $21 387 per patient

• Trend toward lower mortality rates (18% vs 26%).

Clinical and economic impact of MALDI-TOF for

direct identification of organisms in

positive blood cultures

• Using near real time antimicrobial stewardship based on MALDI-TOF results, time to adjustment of antimicrobial therapy was shortened by 46 hours in BSI.

• Significant decrease in ICU LOS by 1.2 days hospital LOS by 1.8 days

• Cost saving: $19 547 per patient

Feasibility of Implementation

• Considerable capital investment

• Cost-per-test of the NATs: higher

• Implementation may be affected – specific hospital environments

– Laboratory settings

– staff competencies

– specimen volume

– budget considerations

• Ability to provide active notification of test results to clinicians or pharmacists: Crucial

• Implementing any new test in a hospital setting often encounters resistance

– efforts to control budgets related to reagents

– human resources

– other factors

• Selection of an appropriate laboratory technique that best suits an institution often depends on making a business case, demonstrating potential quality outcomes or cost- effectiveness metrics

Which Practices are best to

improve patients outcome?

Recent Meta-analysis

Interventions

• Rapid molecular technique, with additional direct communication

• Rapid molecular technique, with no additional direct communication

• Rapid phenotypic technique, with additional direct communication

• Rapid phenotypic technique, with no additional direct communication

• Rapid Gram stain

Outcomes

• Time to targeted therapy is the primary outcome of interest

Results

• Rapid Gram stain reporting decreases

– time to targeted antimicrobial therapy

– decrease morbidity/mortality

– length of a hospital stay

– associated hospital costs

Rapid Molecular Techniques without Additional

Direct Communication

• Treatment is inconsistent but often substantially faster than after standard testing

Rapid Molecular Techniques with

Additional Direct Communication

• PNA-FISH method/ GeneXpert real-time PCR

platform - MRSA.

• Timeliness of treatment in hospital settings is improved

• Significant and homogeneous reduction in mortality

Rapid Phenotypic Techniques with Additional Direct Communication

• Additional direct communication interventions

were initiated by:

• ID fellow making recommendations directly to the physician in charge

• By laboratory staff immediately phoning ID & AST results directly to physicians

• By a clinical microbiologist phoning clinically relevant information and treatment advice

• Generally substantial improvement over standard testing practices.

• Rapid phenotypic techniques with direct communication likely improves the timeliness of targeted therapy.

Impact on mortality

• ? whether the implementation of a rapid technique and communication practice(s) reduces mortality.

• Strong correspondence between the timeliness of targeted therapy & mortality can be observed

• The relationship fails to reach significance.

IDSA

Should ASPs Advocate for Rapid Diagnostic Testing on Blood Specimens to Optimize Antibiotic Therapy and

Improve Clinical Outcomes?

• Comment: Availability of rapid diagnostic tests is expected to increase; thus, ASPs must develop processes and interventions to assist clinicians in interpreting and responding appropriately to results.

• Evidence Summary – The use of rapid molecular assays and mass

spectrometry is associated with improvements in time to initiation of appropriate antibiotic therapy, rates of recurrent infection, mortality, length of stay, and hospital costs

Should ASPs Work With the Microbiology Laboratory to

Perform Selective or Cascade Reporting of Antibiotic Susceptibility Test Results?

• Comment: some form of selective or cascaded reporting is reasonable.

• After implementation, ASPs should review prescribing to ensure there are no unintended consequences.

Potential harm of rapid identification techniques

• Lack of timely and accurate detection of a BSI

agent, despite rapid testing of positive blood culture bottles.

• Inaccurate identification of the microorganism might lead to inappropriate and ineffective changes in antimicrobial therapy.

• Polymicrobial – If rapid methods are unable to detect them,

outcome would be similar to that of the false-negative result

• BSI-causing microbes identified by the rapid technique may not behave according to the institutional antibiogram.

IDSA ASP Guidelines April 13, 2016

• Should ASPs Work With the Microbiology Laboratory to Develop Stratified Antibiograms, Compared With Non-stratified Antibiograms?

• Stratification can expose important differences in susceptibility, which can help ASPs develop optimized treatment recommendations

• A single institutional, or hospital-wide antibiogram may mask important susceptibility differences across units within the institution

Potential harm…

• False-positive (contaminated cultures)

• False-negative (insufficient growth in the blood culture)

• Rapid reporting of results may give physicians a false sense of accuracy, causing them to overlook the basic limitations inherent in the blood culture process itself.

Routine methods are still the definitive reference standard, and any discrepancies be- tween a rapid method and the definitive culture result should be closely monitored

Future research needs

• Limited number of good-quality studies evaluating the impact of rapid testing on reducing the time to targeted therapy for hospitalized patients.

• Both immediate and longer-term outcome data necessary

• Impact in varied hospital settings, such as small or nonacademic institutions

• A better understanding of how batching and other such routines for testing samples

BIOMARKERS OF SEPSIS

C-reactive protein

• If CRP fails to reduce after Treatment:

• Signifies inappropriate treatment

• Increased Morbidity & Mortality

• Prognostic importance

Prohormone of calcitonin

• Normal Serum PCT levels: <0.1 ng/mL

• During sepsis, PCT is constitutively released from tissues

• Levels of PCT increase in 4–12 h after inflammation

• Circulating levels declines with treatment: Better kinetic profile than CRP and cytokines.

IDSA

In Adults in ICUS With Suspected Infection, Should ASPs Advocate PCT Testing as an Intervention to Decrease

Antibiotic Use?

• Recommendation: Suggest the use of serial PCT measurements as an ASP intervention to decrease antibiotic use

Lipopolysaccharide-binding protein

• Acute-phase protein stimulated by IL-6 & IL-1

• Baseline levels low (1–15 g/ml)

• Greatly increase during infection

• Limitations: it cannot differentiate between recent and old infection

• Recently: Soluble form of CD14 used as a biomarker of sepsis because its levels are equivalent to PCT.

Inflammatory cytokines

• TNF-α, IL-1β, IL-8, and IL-6: released in infections

• In GN sepsis, TNF and IL-1β levels elevated.

• IL-6 can be measured more reliably in plasma; long half-life

• Elevated levels of IL-6 in septic patients are associated with an increased mortality

Chemokines

• Many inflammatory chemokines: considered as potential biomarkers of sepsis

• Chemokine IL-8 for diagnosis of sepsis

• Monocyte chemoattractant protein-1 (MCP) for prediction of sepsis mortality

Pro-adrenomedullin and pro-vasopressin

• Serum levels rise during the early phase of septic shock; decrease during later phases

• Pro-ADM: excellent prognostic biomarker for the severity and outcome of sepsis

Pentraxin

• Belong to the superfamily of proteins involved in acute immunological responses which act as pattern recognition receptors.

• Increased levels of PTX3 are associated with the severity of sepsis.

Macrophage migration inhibitory factor

• Distinguishes among survivors and non-survivors

• Fails to discriminate infectious from non-infectious causes of inflammation.

New biomarkers

• Triggering receptor expressed on myeloid cells-1 (TREM-1)

– bacterial or fungal infections induces expression of TREM-1.

• Sensitivity and specificity: more than CRP and PCT.

CD163

• Trans-membrane molecule

• Until now only revealed on the membrane of mononuclear phagocytes.

• Blood levels of serum sCD163 can be used as a biomarker of inflammatory diseases

microRNAs

• Type of endogenous noncoding small RNAs with approximately 22 nucleotides in length.

• Circulating miRNAs have been recently identified as promising biomarkers for sepsis.

• miR-150 might be in related to immune system dysfunctions in sepsis;

SUMMARY

• Septicemia remains a major cause of hospital

mortality. • Rapid pathogen ID in BSI can lead to improved

clinical outcomes, shorter hospital stays, lower health- care costs.

• Rapid pathogen ID, with/ without ABR genes enables targeted treatment

• Several rapid pathogen identification methods, such as PNA-FISH, MALDI-TOF, PCR, multiplex microarrays, are being applied to positive blood cultures.

• PNA-FISH: Well-validated method; new QuickFISH system has reduced turnaround time to 20 minutes, enabling species- identification results to be reported in the same time frame as Gram staining.

• Application of MALDI-TOF directly to positive blood cultures: in experimental phase; has the potential to identify a much broader range of organisms than PNA-FISH.

• PCR-based methods, including GeneXpert (1 hour), FilmArray (1 hour), and Verigene (2.5 hours), are somewhat slower than QuickFISH and MALDI-TOF but have little or no sample processing and include selected antibiotic resistance genes.

• It is now technically feasible to amplify microbial pathogen NA targets directly from blood samples

• Large body of literature, evaluating the accuracy of systems such as SeptiFast, SepsiTest, & most recently, T2 MR.

• Molecular approaches provide information that is clinically relevant and complementary but not equivalent to that provided by conventional blood culture methods.

• Before these methods can be adopted and gain wide- spread acceptance, clinicians must learn how to use the information in managing BSIs.

• None of the methods will replace sub-culturing positive blood culture isolates to agar plates for definitive identification and antimicrobial susceptibility testing.

• Adoption of such technologies involves additive clinical laboratory costs, expertise.

• Clinical and economic benefits only when such approaches are combined with a robust AMSP to help translate the results from the laboratory to the end users (ie, clinicians) and help them make informed patient care decisions.

• ACTIVE LIASONING, COMMUNICATION

QUALITY PROGRAM For hospital patients with bloodstream infections, lack of timely identification of the microorganism and targeted therapy results in preventable adverse patient outcomes (e.g., mortality) PREVENTABILITY/IMPROVEMENT Time to report organism identification commonly ranges from 2-48+ hrs

PRACTICES/ INTERVENTION Rapid Gram stain Rapid molecular technique Rapid molecular technique, with rapid/direct communication Other rapid phenotypic technique Other rapid phenotypic technique, with rapid/direct communication

IMMEDIATE OUTCOMES Time to target therapy Time to report organism identification

HEALTH CARE/ HEALTH OUTCOMES Mortality Broad-spectrum antibiotic use Associated hospital costs Hospital length of stay

ASSOCIATED HARMS Lack of timely detection of BSI agent Inaccurate identification of agent and target antimicrobial Atypical microorganism susceptibility not defined by rapid technique Reporting results for false positive blood cultures False negative results

LMBP QI analytic framework: BSI evidence review question. For hospital inpatients who are admitted for, or are found to have BSIs, what practices are effective at increasing the timeliness of providing targeted therapy to improve clinical outcomes?