SEPTICAEMIA Dr. Urvesh V. Shah Associate Professor Editor in Chief, Dept. of Microbiology, GCSMC Journal Of GCS Medical College Medical Sciences

Sepsis is a condition characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) that is triggered by an infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues inflammatorysystemic inflammatory response syndrome infectionimmune systemmicrobes bloodurinelungsskin

Bacteremia  is the presence of viable bacteria in the bloodstreambacteria

Septicemia  is a related medical term referring to the presence of pathogenic organisms in the bloodstream, leading to sepsis  is the term used when the organisms causing the sepsis are identified in the blood. Sepsis + Bacteremia

Blood culture Diagnose: ? Bacteremia Presence of Bacteria in Blood

Bacterial colonization Bacteremia Local Multiplication & invasion Inflammation Local pyogenic infection with SIRS Multiplication & invasion in blood SIRS Septicaemia Multiple organ invasion & SIRS Transient bacteremia & no invasion systemic infection i.e. Typhoid, Brucellosis

Bacteremia systemic infection i.e. Typhoid, Brucellosis

Bacterial colonization Bacteremia Local Multiplication & invasion Inflammation Local pyogenic infection with SIRS <20% Up to 50%

Bacterial colonization Bacteremia Local Multiplication & invasion Inflammation Local pyogenic infection with SIRS Multiplication & invasion in blood SIRS Septicaemia Multiple organ invasion & SIRS Transient bacteremia & no invasion systemic infection i.e. Typhoid, Brucellosis

Bacterial colonization Bacteremia Multiplication & invasion in blood SIRS Septicaemia Multiple organ invasion & SIRS Transient bacteremia & no invasion - Highly invasive bacteria -Neutropaenia or immuno- compromised - Instrumentation -Foreign body / prosthesis

Bacterial colonization Bacteremia Local Multiplication & invasion Inflammation Local pyogenic infection with SIRS Multiplication & invasion in blood SIRS Septicaemia Multiple organ invasion & SIRS Transient bacteremia & no invasion systemic infection i.e. Typhoid, Brucellosis

Incidence of bacteremia in adults  who are febrile with elevated WBC or neutrophil band counts,  elderly patients who are febrile, and  patients who are febrile and neutropenic.  These populations have less than 20% incidence of bacteremia. The incidence of bacteremia is about 50% in patients with sepsis and evidence of end-organ dysfunction.

Isolation rate depend upon bacterial concentration in blood.  Sensitivity of blood culture system bacilli ( If organisms were present at densities of < 4 colony forming units (cfu)/ml, blood volumes of 0.5 ml or less had a significantly diminished chance of detecting bacteraemia. This finding did not differ between organisms. Brown and colleagues, 31 however, using similar in vitro techniques, found that placental blood seeded with more than 10 cfu/ml E coli or group B streptococcus required only 0.25 ml blood to be consistently detected.) 31

Concentration of Organisms in Bacteremia In Children:  Gram Negative Bacteremia 5 to 1000 organisms / mL  75% of children have > 100 organisms / mL of blood In Adults:  Streptococcus Endocarditis 1 to 30 organisms /mL  Gram Negative Bacteremia < 1 to 10 organisms /mL ©Cop y right BD Europe

To increase isolation rate: Volume of blood to be cultured should increase. Cockerill F R et al. Clin Infect Dis. 2004;38:

 Isolation of bacteria also depend upon inhibitors of bacterial growth in blood i.e. antibiotics, antibodies etc.  Their activity can be reduced by diluting them So,  More than one bottle can be utilized for higher volume of blood Not more than 10 ml of blood permitted in one bottle

How many sets of blood culture

How many sets of cultures? Rev Infect Dis.Rev Infect Dis Sep-Oct;8(5): Blood cultures: issues and controversies. Washington JA 2ndWashington JA 2nd, Ilstrup DM.Ilstrup DM the volume of blood cultured appears to be most important. It is recommended that at least 10 ml, and preferably ml, of blood be obtained. More than three separate blood cultures per septic episode is rarely necessary

 In pre septic conditions <20% incidence of Bacteremia (Blood culture positive)  In end stage sepsis up to 50% incidence of bacteremia (Blood culture positive)

How can I make best utilization of culture practice in sepsis?

Organ injury Inflammatory response Toxic load Microbial load Shock threshold Acknowledgement to Anand Kumar Septic shock: the golden hour

Organ injury Inflammatory response Toxic load Microbial load Shock threshold Acknowledgement to Anand Kumar Antimicrobials Septic shock: the golden hour

sepsis – 1- start strong empirical antibiotics 1. ?? Gram positive – Glycopeptides / Linezolid 2. ?? Gram negative – Imipenem / Meropenem / colistin 3. ?? Anaerobic – Clindamycin / Metronidazole 4. ?? Polymicrobial – one from each of above group. 5. May add quinolones, aminoglycosides

2 - Pre requisite to start antibiotic – take culture – before starting antibiotics

Selection of antibiotic-resistant pathogens Resistant Strains Rare x x Resistant Strains Dominant Antibiotic exposure x x x x x x x x x x x Blood culture - negative

Patient immunity  Equally important for clearance of infection.

3 - Pre requisite to start antibiotic – take culture

3 A blood cultures - The important factors  volume of blood drawn  dilution: the ratio of blood to culture medium in the blood culture bottle  number of cultures taken  blood culture technique, including skin preparation and choice of culture site

 timing of culture  Prior to starting antibiotic  Just before next dose of antibiotic  Rising fever  choice of blood culture system (Automated, having neutralizing agents for inhibitors) temperature bacteria

 Best  Sample  properly collected,  at proper time

A bacterial infection anywhere in the body may lead sepsis, 3B- culture from infected site  The bloodstream  The bones (common in children)  The bowel (usually seen with peritonitis)peritonitis  The kidneys (upper urinary tract infection or pyelonephritis)urinary tract infection  The lining of the brain (meningitis)  The liver or gallbladder  The lungs (bacterial pneumonia)bacterial pneumonia  The skin (cellulitis)cellulitis  For patients in the hospital, common sites of infection include intravenous lines, surgical wounds, surgical drains, and sites of skin breakdown known as bedsores (decubitus ulcers). intravenous

4 - IS THE ISOLATED ORGANISM FROM SITE OF INFECTION SIGNIFICANT ? e.g. Ventilator associated infection

Culture report suggests mere presence of bacteria at sampling site  Severity of infection varies  Colonization of ET tube  Colonization of trachea / bronchi with increase secretion  Pneumonia  Septicaemia Blood culture – highly specific Clinical & radiological

Correlate with  Fever  Purulent secretion  Neutrophilia  Other bio markers – CRP, Procalcitonin etc.

Distinguishing between true bacteremia and a false-positive blood culture result  is important, but complicated by a variety of factors in the ICU. False-positive culture results are costly because they often prompt more diagnostic testing and more antibiotic prescriptions, and increase hospital length of stay  ? Specificity (contamination) – depend upon type of organism ( i.e. CONS in more than 2 samples only should be considered significant )

5 - De escalation - ?  During initial presentation – a broad spectrum antibiotic started.  After C / S report, therapy switched over to more specific, relative narrow spectrum, less toxic, cheap antibiotic.  shortening the course of therapy to <5 days in cases with negative culture results and ≥48h without fever

De escalation  The only way to minimize development of antibiotic resistance without compromising intensive treatment of critically ill patient.

De - escalation  MSSA – amoxy clav, Cloxacillin  Enterobacteriaecae – Ertapenem, BL+BLI combinations  Pseudomonas – Piperacillin + Tazo, Cefepime, Ceftazidime  Acinetobacter – sulbactum, Tigecycline  ( may be needed to go for escalation ) Candida – Azoles, Ampho. B

Unresolved situations!!  Patient of suspected sepsis - should start antibiotics or not (?? SIRS ?? Sepsis)  Culture report awaited, What to do ?  Culture report negative, what to do? Answer:  Bio markers  Procalcitonin  CRP

1. Support in clinical diagnosis Bacterial vs. non bacterial 2. Support in prognosis If severe bacterial infection is worsening 3. Support in antibiotic stewardship (monitoring) Decision to start/stop antibiotics Decision to modify antibiotics PCT test results must be associated with clinical findings. Procalcitonin

Organ injury Inflammatory response Toxic load Microbial load Shock threshold Acknowledgement to Anand Kumar Septic shock: the golden hour

Organ injury Inflammatory response Toxic load Microbial load Acknowledgement to Anand Kumar Shock threshold Antimicrobials Septic shock: the golden hour It is very crucial to diagnose sepsis and start iv antibiotic in early hours

A case of SIRS 2 or more of following criteria  Temperature > 38 or <36 *C  Heart rate: > 90 /m  Respiratory rate: >20/m  WBC: > 12,000 or 10% band cells

Sepsis  SIRS + evidence of bacterial infection  Procalcitonin / CRP raised

Illustration from Brahms Increasing concentration in the blood as sepsis goes to severe sepsis and septic shock PCT concentration µg/ml Clinical Condition Healthy condition Local infection Systemic bacteria infection (Sepsis ) Severe Sepsis Shock < Kinetics of PCT in Evolving Sepsis

Accurate Diagnosis of SEPSIS for Rapid Initiation of Antibiotics On admission  Pt of SIRS *Guidelines from the German Sepsis Society Is it really sepsis? Question <0.5ng/ml Procalcitonin cut off* >2.0ng/ml Sepsis very unlikely Sepsis very likely Clinical Interpretation Other Diagnosis ? Start AB Therapy Consequence for physician

Schuetz P, Curr Opin Crit Care, 07 Patient Admitted to the ICU With Systemic Inflammatory Response Syndrome (SIRS) Microbiological Workup Identification of Organism No Identification Exclusion of Contamination Clinical Evaluation Consider Antibiotic Therapy Depending on Clinical Setting Withhold / Stop Antibiotics < Start / Continue Antibiotic Therapy Measurement of Procalcitonin Reevaluation of the Clinical Course and Procalcitonin after h, 48h, 72h No Infectious Cause of Fever Infection Stop Antibiotics Consider Surgery Drainage, Removal of Foreign Body or Obstruction Patient Deteriorating Patient Improving >2.0 Diagnosis of Sepsis ? Evaluation of Procalcitonin Cut off Range Very Unlikely LikelyUnlikely Very Likely

Use of a clinical PCT algorithm safely and markedly improves diagnosis and antibiotic stewardship in upper and lower LRTI Local sepsis: LRTI Guidelines: Support Diagnosis & Antibiotic Guidance Schuetz P et al, BMC HSR 07 & pro HOSP 2009

 PCT < 0.1 ng/mL in healthy subject’s blood  Increases specifically when body is bacterialy challenged  Rapidly increases 2-3 hours with a peak after 6-12 hrs  Rapidly decreases with effective therapy with half-life time (~ 24 hr) PCT Kinetics

Be careful Increased PCT may be due to  Other infections: invasive fungal, acute P.falciparum  Neonates ( up to 20 ng / ml in initial 48 hours)  Severe burns, major trauma, major surgical interventions, prolonged or severe cardiogenic shock PCT may not raise in  Some local infections e.g. Arhtritis, osteomilitis, endocarditis

Conclusion  Sepsis is an important cause of morbidity and mortality in the critical care unit. An average attributable mortality of 26%  Clinical parameters are often not reliable predictors of bacteremia.  Blood cultures remain a valuable diagnostic tool.  Every effort should be made to improve the yield of this diagnostic modality, and results obtained should be interpreted in light of clinical and other laboratory data and culture reports of other speciemens.

Conclusion  Once bacteremia is identified, repeated cultures with each temperature elevation, especially in patients who are clinically unchanged, are unnecessary.  Till culture reports available or culture report is negative, Antibiotic therapy should be started and modified with Procalcitonin / CRP ? level monitoring  The judicious use of cultures, while paying attention to factors that improve blood culture yield and decrease contamination rates, will improve the utility of blood cultures as diagnostic tools in critically ill patients.

Bid adieu to infection Thanks for Your Participation! Dr. Urvesh V. Shah Associate Professor Editor in Chief, Dept. of Microbiology, GCSMC Journal Of GCS Medical College Medical Sciences