Antimicrobial therapy in Sepsis

Principles & Practice

Dr.Rajesh.K.R
Assistant Professor(ID)
GMC Thrissur
 Sepsis

• Leading killer – 19 million/year

• Time dependent condition.

• Early empirical treatment &effective source

control improve survival
• Rising antimicrobial resistance.

• Dry antibiotic pipeline.

Sepsis & Septic shock model
Role on antimicrobials…
Frapper fort et frapper vite”

Hit Early

Hit
Hit Hard
Appropriately
Multipronged strategy
Patient
Time
Target
Drug
Dose
Duration
De escalation
Source control
 1
Right patient
 Right patient
• No golden standard tests
• Rule out sepsis mimickers.
• History
• Examination
• Labs
• Radiological
• Rapid lab test
 2
Right time

“Time is tissue;life ”
Hit early
 Hit early

• Each hour delay measurable increase in

mortality.
• A/E on secondary end points.
Time is life…….
 3
Right target
 Identify the suspected source
• History
• Examination
• Lab findings
• Imaging
• Interventions
• Closed space infections
– Drainage
– Debridement
 Sources of sepsis
• Gastrointestinal. Community
• Genitourinary. Acquired
• Pelvic
• Biliary
• Urosepsis
• Pulmonary. Hospital
Acquired
• Skin & Soft tissue
• Blood stream
 Send appropriate
microbiological samples
 Early microbiological samples

• Sterilization occurs rapidly.

• Improved outcomes.

• Never delay treatment - 45 minutes

• All potential sites of infection.

• Avoid pan cultures.

 How much and when ?

• Minimum 10 ml in each bottle

• Volume Yield
 4
Right drug.
Pillars of effective antimicrobial therapy

Appropriate Adequate Optimal

Early administration
In vitro susceptible Penetration PK/PD driven
Intravenous dose strategy
 Appropriate drug

• Empirical

• Broad spectrum

• with 1 or more Abs.

• Cover all potentially likely pathogens

– Bacterial/potential Fungal/Viral.
Appropriate
s
“First choice should be the best choice”
 How to choose ?
• Clinical syndrome/ Site of infection.
• Previous Abs used.
• Recent known infection/colonisation.
• Local epidemiology.
• Co morbidities
• Immuno suppressants
• Indwelling devices.
• Toxicity
 ‘’Know the microbe ’’
Gram Gram
negative positive
Skin MSSA
E.Coli
GIT Staphylococcus
Klebsiella GIT
Genitourinary Enterococcus
Enterobacter Genitourinary

Acinetobacter Streptococcus
Pseudomonas Pneumococcus
 Microbes and source
Colon
Biliary Urosepsis
Pelvic
Aerobic GNB
E.Coli
Aerobic GNB Enterococci
Klebsiella

Enterococci Pseudomonas
Anaerobes
(VSE) (hospital)
Pulmonary

• Staphylococcus

• Klebsiella

• Pseudomonas

• Pneumococcus
SSTIs

• Group A Streptococci

• Staph

• Polymicrobial

• CA-MRSA-PVL toxin

• Clostridium
Know “our” enemy
Have a local antibiogram
Use guidelines judiciously….
Stratify the risk of infection with
drug resistant bugs.
 Bugs have changed!!!
NDM

• MRSA
AmpC

• VRSA

• VRE

• ESBL

• Carbapenemases OXA 48 KPC

Not every one requires “Kingcongopenems” or
“Gorillamycins

• Wrong choice increases

mortality.
• Selection of drug
resistant bugs.
• Unwanted colonisation
or infection with MDR
bugs.
 Sepsis etiology
Gram Gram Fungal
negative positive Candida
Aspergillus

E.Coli
Staphhylococcus
Klebsiella
Enterococcus
Enetrobacter

Acinetobacter Streptococcus
Pseudomonas Pneumococcus
Choice of the right antibiotic ?
 Spectrum
Quinolones
Antipseudomonals
Gram negative • Ceftazidime
Gram positive • Cefoperazone
Anaerobes • Cefepime
• Aminoglycosides
• Quinolones
Anaerobes
• Aztreonam
Metronidazole
BL/BLIs • BL/BLIs
Carbapenems • Carbapenems
Quinolones(3rd) • Colistin
 Anti Staph

MSSA MRSA Both

Vancomycin
Cloxacillin Cotrimoxazole
Linezolid

Teicoplanin Clindamycin
Cefazolin
Daptomycin Doxycycline
Know the holes in the spectrum
Cefotaxime
Pseudomonas Rickettsial
Ceftriaxone

MRSA
Carbapenems Burkholderia
Enterococcus

Colistin Proteus MRSA

Holes in the spectrum…..

Ertapenem Pseudomonas

Tigecycline Pseudomonas

Aminoglycosides Salmonella
• BL-BLIs

• Meropenem

With

Clindamycin/Linezolid

/Vancomycin /Rifampicin if

there is concern of

toxin /MRSA CA PVL.

VAP
 CRBSI/CLBSI

• MSSA

• MRSA

• CONS

• GNB

• Candida
 Scrub typhus
• 39 year old male
• Estate worker
• Fever 8 days.
• Sepsis
• MODS
• On ceftriaxone/C.S /
meropenem
 “Do not mistake virulence for resistance”

• Comorbidities are important in community

acquired infections.
• Community acquired infections may be
virulent but are usually not resistant.
• Nosocomial infections may not be virulent but
often resistant.
• Broader spectrum does not means always
potent
Virulence Resistance
Empirical choice in sepsis of unclear origin

• In sepsis /bacteremia
– Carbapenems

– BL/BLI

• In septic shock
– Carbapenems.

• Ceftriaxone + Doxycycline

• MRSA cover
– SSTI/Pulmonary

– Reistance rate high

MERINO Trial
When to consider empirical antifungals ?

• In sepsis / septic shock with

1.Immunosuppression.
2.Prolonged CVC.
Echinocandins
3.TPN.
4.Candida colonization.
5.Recent abdominal surgeries.
6.Severe pancreatitis.
5
s

Microbe
Time dependent Concentration
dependent
Inj Pip-Tazo 4.5 g iv Q6H over 4 hrs

Inj Cefo-Sulbact 3g iv Q12h over 4 hrs

Aminoglycosides as Once Daily.

BLISS Trial
Beta lactams as continous Infusion.
Higher
dosing.
Loading
doses.
 Treatment effects
• Augmented renal clearance.
– Glomerular hyperfiltration-CrCl >130 ml/mt.
– Enhanced clearance of renally eliminated Abs
– Vancomycin /Betalactams/Carbapenems – Failure
– TDM ideal.
– Highest approved dose/ frequent administration.

• Body fluid restoration & Improved tissue perfusion.

• Restoration of liver function
 Antibiotic pearls

• BL/BLI / Carbapenems – anaerobic coverage

• Clindamycin not a good choice in bacteremia.

• Daptpmycin inactivated by lung surfactant.

• Tigecycline not ideal in bacteremia.

Adjust dose according to renal and hepatic
impairment.

Mode of elimination doesnot predispose to toxicity always.

 6
Targeted therapy
 Targeted therapy
• Targeted to a specific pathogen.
• After microbiological identification.
• Monotherapy or Combination.
• No broad spectrum

Antibiotics not needed for all bacteria

cultured
 Definitive therapy Policy

• Distinguish Colonisers
Vs True infection .
– Location of bug.
– Clinical condition.
– Characteristics of
pathogen.
– Long term follow up.
 Colonizer Vs Pathogen

• No test can
differentiate
Between
Colonizer and
Pathogen .
 The antibiograms are not
commandments………

• Limitations .
• Learn to interpret results.
• Know antibiotic gaps.
• Repeat tests if needed.
Interpret investigations wisely
 Discuss with the microbiologist

• Antibiogram.

• Unusual resistance
patterns.

• Collection.

• Communicate .

• Rapid diagnostic testing

Case 1
 ESBL
• BL BLIs • E.Coli
• Most consistent
– Carbapenems • Klebsiella
• Fluoroquinolones
• Aminoglycosides
• Tigecycline
• Pseudomonas
• Cephamycins
• Colistin /Polymyxin??
Case 2
In MSSA

• Cloxacillin.
– 2g iv Q6h

• Cefazolin
– 2g iv q8h

• Vancomycin is
inferior.
Case 2

• If D test positive don’t

use clindamycin .
 Case 4

Vancomycin Teicoplanin
Linezolid Daptomycin
 Enterococcus rules
• Intrinsically resistant to
– Cephalosporins
– Clindamycin
– Cotrimoxazole
– Aminoglycosides

• Susceptible to
– Penicillin
– Amox/Ampi/Amox-Clav
– BL/BLI
VRE

Linezolid
Quiopristin
Dalfopristin
Daptomycin
Tigecycline
 Acinetobacter
Susceptible

• Ceftazidime

• Cefipime

• BL/BLIs

• Carbapenem

• Ampi Sulbactum
 Pseudomonas
• Monotherapy – if resistance rate < 10-15%
• Combination therapy.
– BL + AG
Pseudomonas
 7
De escalation
 Wining horses can be changed

• Clinical status

• Based on culture .

• Narrow spectrum.

• Stop if no infection.

• Multiple to single.
 When to deescalate?

• Resolution /absence of sepsis/hypotension.

• Afebrile in last 24-48 hrs.

• Source control done.

• Supportive evidence for PO transition.

• Able to receive enteral feeding.

Assess patient daily.
 Actions
• Daily review and document.
• Assess clinically /investigations
– Stop Rx.
– Narrow spectrum.
– Reduce no of Abs.
– Not to deescalate.
• Document reasons
 Improving
Cultures negative

Continue
Antibiotics

Narrow
Oral agent Minimum duration spectrum
“Since no pathogen is identified in
approximately 50% cases de escalation needs
a component of sound clinical judgment “
Consider combination in specific
situations only….
 Combination therapy

• Multiple antibiotics with different MOA.

• Cover known or suspected pathogen.

• Accelerate pathogen clearance.

• Inhibit toxin production( Clinda + BL)

• Immunomodulation( Macrolide + BL)

 When ??

Septic shock Higher survival

MDR Acinetobacter.
MDR Pseudomonas.
• Not for
Pneumococcal bacteremia
– Bacteremia.
– Sepsis with out shock.
– Neutropenic sepsis with out bacteremia.
 8
Decide on duration of therapy
 Longer duration…disadvantages.
• Adverse effects.
– C.difficile.
– Selection/super infection with MDR
• Resistance.
• Mortality.
• Prolonged stay.
• Increased cost.
 “Short is sweet”
• “Shorter treatment is the mantra”.
• Sepsis and septic shock.
• If no source control issues.
• < 7 days 7-10 days
– Uncomplicated cellulitis.
– Acute pyelonephritis.
– SBP.
• 3-5 days
– Intrabdominal infections.
sss
 Who need longer course ?

• Slow clinical response. Sanctuary sites

Abscesses
• Undrainable focus of infection. Device

• MRSA bacteremia.

• Candidemia.
Pulmonary infiltrates
Leucocytosis
• Neutropenia.
Drug fevers
• Highly resistant GNB.
 9
Source control
 Source control

• Vascular devices

• Implants

• Hardwares

• Abscess drainage.

• Debridement

• Amputation

• Surgery
 10
Implement an Antibiotic
Stewardship Programme.
Team work…………
The war against microbes…..
 Daily review
• Clinical
• Fever
• General well being.
• Complications
• WBC
• CRP??
• Procalcitonin ??
 Pk/Pd issues in sepsis

• Sufficient amount of antibiotics to be at the

target site.
• Tissue hypoperfusion.

• Third spacing

• Hypoproteinemia

• Organ dysfunction
 GI tract
• Distal GIT-Colon
• Anaerobes (75%)
• Coliforms(20%)
• Aerobic GNB
– except Pseudomonas
• Enterocccus (D) permissive
– E.faecalis
– E.faaecium
 If pseudomonas is less likely
• Vancomycin

• Ceftriaxone/Cefotaxime
• Cefipime
• Piperacillin tazobactum
• Ticarcilln clavulanic acid
• Meropenem/Imipenem
 If pseudomonas is likely
• Vancomycin

• Cefazidime /Cefipime
• Piperacillin tazobactum
• Meropenem/Imipenem
• Ticarcilln clavulanic acid
• Ciprofloxacin
• Genta/Amikacin
• Aztreonam
Risk factors for MRSA
S
 Target site concentration

Devices
Drugs

Hydrophilic Lipophilic

Abscess

Intravascular Intracellular

Vancomycin
Poor lung
concentration
 Know the antibiotic gaps
Antimicrobials Bugs

Penicillins / Aminopenicillins . Most GNB/ Anaerobes

Cephalosporins Enterococci/Listeria/
Rickettsiae/Mycoplasma /Chlamydia
Aminoglycosides Enterococci/Most streptococci/Anaerobes

Clindamycin Enterobacteria

Vancomycin/Teicoplanin/ Linezolid Gram negative organisms

Carbapenems MRSA/ Enterococci /Clostridium difficile

Polymyxins (Colistin) Gram positive/

Salmonella/Proteus/Burkholderia/
Anerobes
 Duration of antibiotic therapy
• Antibiotics are not an entirely benign therapy.
• In low risk patients adverse effects can
outweigh any benefits.
• Avoid unnecessary reasons for prolongation.
• Duration decided by
– Host factors - Immune status.
– Infecting pathogen.
Lesser resistance