ICU MANAGEMENT

GRAM +VE SEPTICAEMIA

TABLE OF CONTENT

 Sepsis: Key facts

 Sepsis: New definition and criteria
 Prevalence of sepsis in India
 Clinical criteria for sepsis
 Symptoms and diagnosis of sepsis
 Treatment of sepsis [Surviving sepsis campaign (SSC) bundles]
 Methicillin-resistance Staphylococcus aureus (MRSA)
 Antibiotic treatment
 Conclusion
 SEPSIS: KEY FACTS

Worldwide, >30 million people gets affected to sepsis every year,

leading to 6 million deaths, mostly affecting low and middle
income countries

Globally, approximately 3 million newborns and 1.2

million children suffer from sepsis every year

Three out of every ten deaths due to neonatal sepsis is

caused due to resistant pathogens

One million newborn deaths are associated with maternal

infection, such as maternal sepsis, each year

Sepsis. World Health Organization. Available at: http://www.who.int/news-room/fact-sheets/detail/sepsis. Accessed on: 09 SEP 2018.
 SEPSIS: NEW DEFINITION AND CRITERIA

Definition of sepsis and septic shock has changed over a period of time.
The definition of sepsis was updated in 2017.

Term Definition Criteria

Sepsis Sepsis is life-threatening organ dysfunction caused by Suspected or documented infection and
a dysregulated host response to infection an acute increase of ≥2 SOFA points

Septic shock Septic shock is a subset of sepsis in which underlying Sepsis and vasopressor therapy needed
circulatory and cellular/metabolic abnormalities are to elevate MAP ≥65 mm Hg and lactate
profound enough to substantially increase mortality >2 mmol/L (18 mg/dL) despite
adequate fluid resuscitation

MAP: Mean arterial pressure; SOFA: Sequential organ failure assessment

Singer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016;315(8):801-10
 PREVALENCE OF SEPSIS IN INDIA
• A prospective 5-year study conducted between June 2006 and May 2011
• A total of 282 (6.2%) out of 4711 admissions were due to severe sepsis
• Commonly isolated microbes were Acinetobacter baumannii (21.2%), Pseudomonas Aeruginosa (17%) and equal
prevalence of Klebsiella and Escherichia coli (15.4%)

SIRS without organ 53.3

Percentage (%)
dysfunction
3458 (73.4%) SIRS with organ
No SIRS
dysfunction
790 (16.7%) 463 (9.8%)
14.9 14.3 12.9 1.3 1.3 0.6 0.6 0.4

ICU admissions
N=4711

Site of infection
CNS: Central nervous system; ICU: Intensive care unit; SIRS: Systemic inflammatory response syndrome
Chatterjee S et al. Epidemiology of adult-population sepsis in India: a single center 5 year experience. Indian journal of critical care medicine:Indian Society of Critical Care Medicine. 2017;21573.
 CLINICAL CRITERIA FOR SEPSIS
(SOFA SCORE)
Sequential organ failure assessment: A score of 2 or more than indicates the presence of sepsis

SOFA score 1 2 3 4
Respiration <100
<400 <300 <200
PaO2/FiO2 (mm Hg)
Coagulation
<150 <100 <50 <20
Platelets ×103 /mm3
Liver
1.2-1.9 2.0-5.9 6.0-11.9 >12.0
Bilirubin (mg/dL)
Cardiovascular Dopamine ≤5 or Dopamine >5 or Dopamine >15 or
MAP <70
Hypotension dobutamine (any) norepinephrine ≤0.1 norepinephrine >0.1
Central Nervous System
13-14 10-12 6-9 <6
Glasgow Coma Score
Renal Creatinine (mg/dL) or urine
1.2-1.9 2.0-3.4 3.5-4.9 or <500 >5.0 or <200
output (mL)
SOFA: Sequential organ failure assessment
Singer M,. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016 Feb 23;315(8):801-10.
 CLINICAL CRITERIA FOR SEPSIS
(qSOFA SCORE)
Quick sequential organ failure assessment (SOFA) score. Accordingly, an increase of 2
or more in the qSOFA score should create a suspicion of sepsis and organ dysfunction.

qSOFA criteria Score

Respiratory rate ≥22/min 1
Change in mental status 1
Systolic blood pressure ≤100 mmHg 1

qSOFA: Quick sequential organ failure assessment; SOFA: Sequential organ failure assessment
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS. The third international consensus definitions
for sepsis and septic shock (Sepsis-3). Jama. 2016 Feb 23;315(8):801-10
 WHAT ARE THE SYMPTOMS OF SEPSIS?
There is no single sign or
symptoms of sepsis. Shivering fever
or very cold
It is rather, a combination of Extreme pain or
symptoms.
Short of breath general
Since sepsis is the result of an discomfort
infection, symptoms can
include I feel like I might
Pale or
infection signs (diarrhea, die
vomiting, sore throat, etc.) as
discolored skin
well as ANY of the symptoms
mentioned in the infographic

Sleepy, difficult to
wake up, confused

Sepsis Fact Sheet. Sepsis Alliance. Available at: https://www.sepsis.org/downloads/2016_sepsis_facts_media.pdf. Accessed on: 09 SEP 2018
 DIAGNOSIS OF SEPSIS

Appropriate blood cultures must be initiated before antimicrobial therapy

For identification of causative organisms, at least two sets of blood cultures (both aerobic
and anaerobic bottles) should be obtained before antimicrobial therapy

If obtained from different sites, cultures can be drawn at the same

Cultures of other sites, such as urine, cerebrospinal fluid, wounds, respiratory secretions,
or other body fluids must be obtained before antimicrobial therapy

The 1,3 β-d-glucan assay, mannan and anti-mannan antibody assays should be used when
invasive candidiasis is in the differential diagnosis of infection.

Imaging studies should be performed immediately to confirm potential source

Sepsis: recognition, diagnosis and early management. NICE. Available at: https://www.nice.org.uk/guidance/NG51/chapter/Recommendations#risk-factors-for-sepsis . Accessed on: 09 SEP 2018
 SURVIVING SEPSIS CAMPAIGN (SSC)
BUNDLES
Increase awareness and improve care
Created in 2002 for patients with severe sepsis and
septic shock.
European Society of Intensive Care
Collaboration Medicine, and the Society of
Critical Care Medicine
Goal Reduce mortality from
sepsis by 25% by 2009
Phases Consisted of four phases
Evans L, Bender W. Bundled Therapies in Sepsis. InSepsis 2017 (pp. 225-236). Humana Press, Cham.
2002 and 2003: First campaign.
Consisted of introduction of campaign
to define the scope of the problem
posed by sepsis and increase aware
ness
2004: Second campaign. Consisted of
creation of evidence-based guidelines
for the management of severe sepsis
and septic shock
2008: Third campaign. Dissemination
of guidelines in everyday clinical care,.
Six element resuscitation bundle was
introduced to be given within first 6 h
of patient’s presentation
2012: Fourth campaign. Introduction
of 3 hour bundle and 6 hour bundle
 SSC HOUR-1 BUNDLE

Initial resuscitation for sepsis and septic shock must be started within 1 hour

Measure lactate level

Obtain blood cultures before

administering antibiotics

Administer broad-spectrum
antibiotics

Administer intravenous
fluid

Apply vasopressors
SSC: Surviving sepsis campaign
Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive care medicine. 2018 Jun 1;44(6):925-8.
 SSC HOUR-1 BUNDLE

Measure lactate level

• If initial lactate is elevated (>2 mmol/L), it should be remeasured within 2–4 h

Obtain blood cultures before administering antibiotics

• To optimize the identification of pathogens and improve outcomes

• At least two sets (aerobic and anaerobic) should be taken

Administer broad-spectrum antibiotics

• Broad-spectrum therapy with one or more intravenous antimicrobials should be started immediately
• After pathogen identification, antimicrobial therapy should be narrowed or must be stopped
SSC: Surviving sepsis campaign
Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive care medicine. 2018 Jun 1;44(6):925-8.
 SSC HOUR-1 BUNDLE

Administer intravenous fluid

• Fluid resuscitation started immediately after diagnosis of sepsis and/or hypotension with elevated lactate
(≥4 mmol/L), and completed within 3 h of recognition.
• A minimum of 30 mL/kg of i.v. crystalloid fluid must be administered

Apply vasopressors
• If hypotensive during or after fluid resuscitation to maintain a mean arterial pressure ≥65 mm Hg.

i.v.: Intravenous; SSC: Surviving sepsis campaign

Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive care medicine. 2018 Jun 1;44(6):925-8.
 BUNDLED THERAPY

Impact of sepsis bundle was A lower mortality of about

studied in 167 patient with 44% was reported in
sepsis in tertiary hospital patient who received
bundle therapy comparison
with who did not (25.6 vs.
Overall
45.7%; p = 0.01)
mortality noted
was 31.1%

Greater ICU admissions as Bundle therapy is

compared to the ones who associated with lower
received bundle therapy mortality, less need for ICU
(28.3 versus 15.8%; p = 0.06) admission and shorter stay
on these units

ICU: Intensive care unit; P: p-value

Teles F, et al. Impact of a sepsis bundle in wards of a tertiary hospital. Journal of intensive care. 2017;5:45.
 NURSE-LED SEPSIS PROTOCOL

International sepsis guidelines must be followed in order to identify and improve the
gaps in care of sepsis patient. For example, data related to sepsis care must be
tracked

Enlist administrative and physician stakeholder support to develop and pilot a nurse
led sepsis protocol initiative

Educational campaign at every level must be provided that considers the varying
level of nursing training and experience

Nurse champions must be enlisted to spearhead the nurse-led protocol

Conduct ongoing data review and provide results to nursing staff and key
stakeholders

Refinement of processes based on ongoing audit data and feedback

Kleinpell R. Promoting early identification of sepsis in hospitalized patients with nurse-led protocols. 2017: 10
 OPERATIONALIZATION OF CLINICAL
CRITERIA WITH SEPSIS
Patient with suspected infection

No Monitor clinical condition;

No
qSOFA ≥2 Sepsis still suspected reevaluate for possible sepsis if
clinically indicated
Yes
Assess for evidence of organ dysfunction

Monitor clinical condition,

No
SOFA ≥2 reevaluate for possible sepsis if
clinically indicated
Yes
Sepsis

Despite adequate fluid resuscitation,

1. Vasopressors required to maintain No
MAP≥65mmHg
2. Serum lactate level >2 mmol/l?
Yes
Septic shock MAP: Mean arterial pressure; qSOFA: quick sequential organ failure assessment; SOFA: Sequential organ failure assessment
Singer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). Jama. 2016;315:801-10.
 TREATING SEPSIS: LATEST EVIDENCE

 Enteral feeding  Insulin therapy

 Antibiotics: early
Vasopressors: 1 to 6
administration
hours after onset
 Fluids: several liters Norepinephrine
initially Epinephrine
 Colloids, Vasopressin
crystalloids  Dopamine
Starches, high  Phenylephrine
chloride
 Goal-oriented  Deep sedation
therapy
EGDT ? Molecular targeted
Early goal-directed therapy
therapy
 Lung protection
 Urinary catheter ventilation
Gotts JE and Matthay MA. Sepsis: pathophysiology and clinical management. Bmj. 2016;353:i1585..
 METHICILLIN-RESISTANCE
STAPHYLOCOCCUS AUREUS
Methicillin-resistant Staphylococcus aureus: a gram positive bacteria that is resistant to
almost all antibiotics.1

Staphylococcus and MRSA can cause a variety of problems ranging from skin infections and
sepsis to pneumonia to bloodstream infections in severe cases.1

High rates of MRSA in clinical isolates from various studies in India have been documented,
with rates as high as 54.8% (ranging between 32% and 80%) recorded.2

A study conducted in northeast India to study epidemiology of MRSA, revealed 60.9% of

MRSA isolates from a total of 133 samples in March 2016 to February 2017.3

1. Methicillin-resistant Staphylococcus aureus (MRSA) . CDC. Available at: https://www.cdc.gov/mrsa/ . Accessed on: 09 SEP 2018. 2. Laxminarayan R and Chaudhury RR. Antibiotic resistance in India: drivers and
opportunities for action. PLoS medicine. 2016;13:e1001974. 3. Avinash Kumar and Anshul Kumar. Prevalence of Methicillin Resistant Staphylococcus Aureus (MRSA) In A Secondary Care Hospital In North Eastern Part of
India. Archives of Infectious Diseases & Therapy. 2018;1:1-2
 PREVALENCE OF MRSA IN INDIA
Prevalence of Methicillin-resistance Staphylococcus aureus Prevalence of MRSA colonization was studied in 200
(MRSA) was studied in 15 Indian territory care centers. healthcare workers and 200 patient. Resistance to co-
The overall prevalence in January 2008 to December 2009 trimoxazole (93.3%), ciprofloxacin (80%) and
was reported to be 41%.1 erythromycin (66.66%) was observed.2

60 8 7.5

49 7
50 47

Colonization of MRSA (%)

Prevalence of MRSA (%)

42 43 6
40
5
Outpatient
30 28 27 4
Inpatient 3
ICU 3
20
2
10
1

0 0
2008 2009 HCW Patients

HCW: Health care worker; MRSA: Methicillin-resistant Staphylococcus aureus

1. Ray P, et al. Methicillin resistant Staphylococcus aureus (MRSA) in India: prevalence & susceptibility pattern. The Indian journal of medical research. 2013;137:363. 2. Singh S, et al. Antimicrobial resistance profile of
Methicillin-resistant Staphylococcus aureus colonizing the anterior nares of health-care workers and outpatients attending the remotely located tertiary care hospital of North India. Journal of laboratory physicians. 2017;9:317.
 TREATMENT OF MRSA

• Suggested target value for AUC0-24h to MIC ratio is ≥400μg·h/mL, which is most
Vancomycin important parameter correlating with efficacy

• 80-90% Protein Bound , Achieves Rapid Concentration

Teicoplanin • Prolonged Half Life & reduced renal clearance

• Semisynthetic lipoglycopeptide that inhibits cell wall synthesis and disrupts cell
Telavancin membrane permeability
• 10-fold more potency than vancomycin due to the presence of lipophilic side chain

• A lipopeptide antibiotic drug that disrupts function of cell membrane .

Daptomycin • It acts via calcium-dependent binding, resulting in bactericidal activity in a concentration-
dependent fashion

AUC: Area under curve; MIC: Minimum inhibitory concentration

Choo EJ and Chambers HF. Treatment of methicillin-resistant Staphylococcus aureus bacteremia. Infection & chemotherapy. 2016;48:267-73.
 TREATMENT OF MRSA

• A fifth-generation cephalosporin with bactericidal activity against MRSA and

Ceftaroline VISA as well as Gram-negative pathogens
• Ceftaroline fosamil, a prodrug of Ceftaroline was approved in US in 2010

• Linezolid, a bacteriostatic oxazolidinone inhibits nhibits initiation of protein

Oxazolidinones synthesis at the 50S ribosome
• achieves high levels in the epithelial lining fluid of the lungs

• First drug in the class glycylcyclines, inhibits bacterial protein synthesis

Tigecycline • Broad coverage for drug resistance gram-positive bacteria

MRSA: Methicillin resistant Staphylococcus aureaus; US: United states

Choo EJ and Chambers HF. Treatment of methicillin-resistant Staphylococcus aureus bacteremia. Infection & chemotherapy. 2016;48:267-73.
 COMBINATION THERAPY
Infection Example of antibiotic regimens
β-lactama + azithromycin; β-lactama + respiratory fluoroquinoloneb;
Community-acquired pneumonia1
β-lactam plus an aminoglycoside and an anti-pneumococcal
Antipseudomonal β-lactamc + aminoglycosided or antipseudomonal
Health care–associated pneumonia1 fluoroquinolonee
+ Glycopeptides as Gram positive agent
Glycopeptides or daptomycin (vancomycin or linezolid- Gram positive agent)
Catheter-related bloodstream infection2
+ antipseudomonal β-lactamf +/- aminoglycosidesg
Fungemia risk factors2 Fluconazole or echinocandinh
3rd generation cephalosporini; piperacillin in combination with a beta-lactamase
Urosepsis3
+/- aminoglycosidej or fluoroquinolonek
Urological interventions or MDR risk factors3 Antipseudomonal β-lactaml,m

a: ceftriaxone, cefotaxime, ampicillin/sulbactam; b: levofloxacin, moxifloxacin; c: piperacillin/tazobactam, cefepime, meropenem, imipenem, doripenem; d:
gentamicin, tobramycin, amikacin; e: levofloxacin, ciprofloxacin; f: piperacillin/tazobactam, cefepime; g: gentamicin, tobramycin, amikacin; h: caspofungin,
micafungin, anidulafungin; i: ceftriaxone, cefotaxime; j: gentamicin, tobramycin, amikacin; k: levofloxacin, ciprofloxacin;
l: piperacillin/tazobactam, cefepime; m: meropenem, imipenem, doripenem
1. Mandell LA, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical infectious diseases. 2007;44:S27-72. 2. American Thoracic
Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. American journal of respiratory and critical care medicine.
2005;171:388.3. Mermel LA, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clinical infectious diseases. 2009 ;49:1-45.
4. Wagenlehner FM, et al. Diagnosis and management for urosepsis. International Journal of Urology. 2013 ;20:963-70.
 PK/PD PRINCIPLE ON SELECTION OF
DRUG
In patients with renal and hepatic failure, antimicrobials with increased volume of distribution must be
administered due to the rapid expansion of extracellular volume as a consequence of aggressive fluid
resuscitation

Failure to achieve peak plasma target for initial dosing causes treatment failure with aminoglycosides

Efficacy of vancomycin is partially concentration-dependent. Trough concentration target of 15–20 mg/L

must be attained

Early vancomycin trough plasma concentrations (in relation to pathogen MIC) is associated with clinical
failure for serious MRSA infections

PK: Pharmacokinetics; PD: Pharmacodynamics

Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive care medicine. 2017;43:304-77.
 TEICOPLANIN
VS. VANCOMYCIN
SVETITSKY S ET AL

 Meta analysis
 24 RCTs and 2,332 patients
 Primary outcome
- all-cause mortality

Svetitsky S, Antimicrob Agents Chemother. 2009;53(10):4069-79.

 TEICOPLANIN
VS. VANCOMYCIN
SVETITSKY S ET AL

adequate allocation concealment unknown methods or inadequate concealment

Over all (Total studies)

Svetitsky S, Antimicrob Agents Chemother. 2009;53(10):4069-79.
 TEICOPLANIN
VS. VANCOMYCIN
SVETITSKY S ET AL

 No significant differences between teicoplanin and vancomycin in

 Clinical failure (RR, 0.92; 95% CI, 0.81 to 1.05)
 Microbiological failure (RR, 1.24; 95% CI, 0.93 to 1.65)
 Other efficacy outcomes
 Teicoplanin better in terms of less clinical failure
 When treatment was initiated for gram-positive organisms rather than empirically.
 Teicoplanin better than Vancomycin in
 Total adverse events (RR, 0.61; 95% CI, 0.50 to 0.74),
 Nephrotoxicity (RR, 0.44; 95% CI, 0.32 to 0.61), and
 Red man syndrome significantly less frequent with teicoplanin.

Svetitsky S, Antimicrob Agents Chemother. 2009;53(10):4069-79.

 TEICOPLANIN
VS. VANCOMYCIN
CAVALCANTI AB ET AL

 24 studies 2,610 patients, Teico vs Vanco

Cavalcanti AB, et al. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD007022.
 TEICOPLANIN
VS. VANCOMYCIN
CAVALCANTI AB ET AL

Cavalcanti AB, et al. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD007022.
 TEICOPLANIN
VS. VANCOMYCIN
CAVALCANTI AB ET AL

 No significant differences between Teicoplanin and Vancomycin in

 Clinical cure (RR 1.03, 95% CI 0.98 to 1.08) , Microbiological cure (RR 0.98, 95% CI 0.93 to
1.03), Mortality (RR 1.02, 95% CI 0.79 to1.30)
 Adverse events were less frequent with Teicoplanin
 Cutaneous rash (RR 0.57, 95% CI 0.35 to 0.92), Red man syndrome (RR 0.21, 95% CI 0.08 to
0.59), Total adverse events (RR 0.73, 95% CI 0.53 to 1.00)
 Teicoplanin reduced risk of nephrotoxicity (RR 0.66, 95% CI 0.48 to 0.90).
 A lower risk of nephrotoxicity with teicoplanin was observed in patients
 with aminoglycosides(RR 0.51, 95% CI 0.30 to 0.88)
 without aminoglycosides (RR 0.31, 95% 0.07 to 1.50),
 when vancomycin dosing guided by serum levels (RR 0.22, 95% CI 0.10 to 0.52)

Cavalcanti AB, et al. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD007022.
 VANCOMYCIN CREEP

 14 publications, Meta analysis

 2439 patients (1492 high MIC and 947 low MIC)

 High MIC vs Low MIC

 Increased risk of failure (RR 1.40, 95% CI=1.15–1.71).
 Overall mortality risk was greater (RR 1.42, 95% CI 1.08–1.87)

A susceptible but high MIC to vancomycin is associated with increased

mortality and treatment failure among patients with MRSA infections

J.T. Jacob, C.A. e94 DiazGranados / International Journal of Infectious Diseases 17 (2013) e93–e100
 CONCLUSION

Sepsis is considered one of the leading factor of healthcare burden

Early diagnosis and proper treatment of sepsis can prevent septic shock and
mortality

International guidelines must be followed for the treatment of sepsis

Bundled therapy must be started within 1 hour of hospitalization

Nurses and healthcare professionals must be made vigilant about the guidelines
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