Drugs and Antibiotic treatment in critically ill surgical patients: What are

the considerations

Fathima ParukMBChB, FCOG, Crit Care(SA), PhD

Associate Professor, Head of Department: Critical Care Steve Biko Academic Hospital and Kalafong Hospital

University of PretoriaSouth Africa

S

Antibiotics

Drugs: Fluids

P

Antibiotics

Survival Benefit

Recognition of infection

Treat underlying Cause AggressivelySURGICAL SOURCE CONTROL

Right choice (empiric)Directed therapy of MDR,XDR and PDR pathogens Right doseRight duration

Efficacy, Safety,Cost

BacterialFungalSecond hits/response to therapy

INFECTION CONTROL

Host responseSource (infection)HR,RRTemperatureWCC

Investigations CXRCT scan

Pathogen: Blood cultureMicrobiology (MCCS)48-72 hours cultureBiofire(PCR)

Infection recognition

Biomarker paradigm

Now/Future

Pro AdenomedullinPresepsin Combination panelsRapid pathogen detectionPCR technologyNext generation sequencingMass spectrometryMolecular diagnosisProtein microarraysCoagulation

Current Biomarkers

PCTCRP

(INFLAMMATORY RESPONSE)

-

+ CRP

fungalinfection

Biomarker response to an infection

Meisner,2000Vijayan et al, J Int Care,2017

Severity of diseaseImmune responseComorbidities Site of surgery

SepsisPathogenCharacteristics

PCT < 0.05ng/mL(undetectable):HealthyPCT <0.5ng/mL: bacterial infection unliely

PCT < 0.05ng/mL(undetectable):HealthyPCT <0.5ng/mL: bacterial infection unliely

CRP and PCT post surgery CRP peaks D3-4 post op

PCT peaks 24 hours postopThen falls progressively

PCT post surgery

PCT Response- Detect ongoing sepsis- Detect new sepsis- Detect post op complications

Post surgery Concern if:

- PCT >10ng/mL- From 48 hours onwards PCT stagnant or increasing

Kinetics /Clearance

PCT ResponseAbdominal > Sternotomy >Thoracic

0.65 [0.08-5.46 ng/mL]

PCT

PCT: Candidaemia

9.75 [1-259 ng/mL] p < 0.001

n=50 blood culturesMICU Non-neutropenic

Charles at al.: BMC Infectious Disease 20098

21

PCT: Repeat infections

LOWER PCT peak valuewith subsequent infection

6.4ng/ml [9]

PCT

PCT

58 ng/ml[99]

n=179Similar SOFAICU

Abdominal sepsis evidence: CRP and PCT

PCT Utility: Special populations

Kinetics applicable

• Immunosuppression• Neutropenia• HIV infection• Autoimmune • Solid organ transplants

Specific scenarios (false positives)

• Early infection• Loculated infections

– Empyema– Mediastinitis

• Endocarditis

PCT elevation:Malaria, Small cell lung Ca, Medullary thyroid Ca, carcinoid syndrome, Immunomodulating agents

Empiric choice

• Suspected micro organisms– Site– HAI or CAI

• Microbiological profile unit• Resistance patterns• Antibiotic exposure (past 3/12 )• Clinical condition

De-escalation vital

Kumar A et al, Chest 2009; 136:1237-48MacArthur RD et al Clin Infect Dis 2003; 38:284-288.Harbarth S et al Am J Med 2003; 115:529-535.Ibrahim EH et al Chest 2000; 118:146-155.Kollef MH et al. Chest 1999; 115:462-474.

• Gram negative– ESBL– CRE– Pseudomonas

• Gram positive– MRSA– VRE

• Anaerobe• Fungal

Nosocomial or hospital pathogens…Bad Bugs, No Drugs: No ESCAPE

• Enterococcus (VRE)• Staph aureus (MRSA)• Clostridium difficile/Candida auris

• Acinetobacter• Pseudomonas • Enterobacteriaceae

[Klebsiella,Enterobacter,Ecoli, Proteus,Serratia, Morganella, Salmonella,Citrobacter]

Responsible for: Bulk of infections, resistance and poor outcomes

G+ nosocomial pathogens

G - nosocomial pathogens

Boucher H, et al, Clin Infect Dis 2009;48:1-12Bassetti M et al, Hematology Am Soc Hematol Educ Program2013;2013:428-32

KEEPSMSC

SPICE

SA INCREASING2012

USA- SENTRYUSA-SMARTEurope-EARSSSA surveillance

ESBLs

2015 ESAC rRportRottier WC et al, J antimic Theray,2012

Jean SEPTIC SHOCK et al,2016Sader HS et al,2014

• Carbapenems most reliable, BUT… • Between 2010-2015: 3 fold increase

carbapenem use- driving CPEs• Non carbapenem option

Mortality OR 2.235

Piperacillin Tazobactam ?Tigecycline?New β lactam-β lactamase inhibitor(BLBLI) combinations

Klebsiella,Enterobacter,Ecoli, Proteus, Serratia, Morganella,

Salmonella,Citrobacter-KEEPSMSC

CPEs

SA INCREASING2012

CPEs: Monotherapy vs combination

Tumbarello M et al. Clin Infect Dis;2012

KPC –KPN=125Day 30 Mortality

Colistin +HD CarbapenemD30 mortality 34%(n=79)

Triple therapy(n=16)D30 mortality 12.5%

MonotherapyD30 mortality 54%(n=79)

(P=0.02)

CPEs options• Carbapenem high dose + Colistin• Carbapenem + tigecycline• Ertapenem + Imipenem/Meropenem

– Ertapenem acts as a decoy (suicide inhibitor)

– Combines with KPC– 2nd carbapenem can bind to PBPs then

hydrolyse the KPC-KP

• Colistin + 2nd agent(non carbapenem)

T

TigecyclineColistinCarbapenemGentamicin

MICsCeccarelli, 2014

MICs: When to substitute

SUBSTITUTE WITH ANOTHER AGENTMIC (mg/L)

Colistin >2MeropenemImipenem

>16

Tigecycline >4Sulbactam >4

CPEs- Colistin resistance (MIC>2mg/L)

• MMIC ≤8-16 mg/LMero/Imipenem

Carbapenem high dose+ Tigecycline+ Riampicin(10mg/kg BD)

MIC >16 mg/LMero/Imipenem Tigecycline

+ Gentamicin+ Rifampicin+Fosfomycin (6g q6),never alone

Tigecycline substitution (MIC>4mg/L): Replace with Rifampicin

Screening for CRE

• Contact with a CRE patient• Transfers

• Between units within hopsital• Inter-hospital

• Hospital stay with 6 months• Long stayers in ICU (2 weeks)

Dosing: Pharmacokinetics

• Underdosing– Augmented renal

clearance (ARC)– Volume of distribution – Hypoproteinemia– Septic shock: poor tissue

penetration……Higher Doses

• Overdosing– Renal– Hepatic

Fuster-Lluch O et al, Anaes Int Care2008;36:674-80.

Dosing: PD PropertiesCmax

MIC

Cmin0 Time(Hours)8

Time dependent

Time>MIC >90% Time > MIC

Time DependentPip-TazobactamCephalosporinsCarbepenamsLinezolid

Continuous infusions?

Roberts JA et al. AJRCCM;2016Abdul AzizCrit Care Med;,2015

Vardakas et al. Lancet Infec Dis;2018

BLISS (n-140)2 sites65% higher cure rate with CI(P<0.05)T>MIC: 97%vs 68% (CI vsI B)No survival difference

MA: Roberts et alSuggested mortality reduction with CI

MA: Vardakas et al22 studiesLower all cause mortalitywith CI vs Intermit bolusRR0.7(CI;0.56-0.87)

Suggested Doses: Gram negative infections

Pipericillin – Tazobactam 4.5g LD/18g over 24 hours

Meropenem 2g over 3 hours q8

Imipenem 1g over 3 hours q6

Doripenem 1g over 4 hours q8

Ertapenem 1g BD

Cefipime 2g LD and 6g over 24 hours

Ceftazadime 2g LD and 6g over 24 hours

Tigecycline 200mg LD and 100mg BD

Gentamycin/Tobramycin 5-7 mg/kg/day (trough < 1 μg/ml)

Amikacin 20 mg/kg/day (trough < 5 μg/ml)Ciprofloxacin 400mg TDS

Colistin 12MU LD then 4.5 MU BDRenal dysfunction

– Loading dose same,– Infusions?

– Dose reduction (also if on SLED)– CRRT generally no dose adjustment- give maximal doses

When to stop antibiotics• Switch to oral (<37.9 0C and stable)• Paradigm shift: shorter duration• Generally: 5 -7 days (can stop in 3 days if source

control and improved)• Exceptions:

- Pseudomonas(10-12 days)- Endocarditis (4-6 weeks)- Bone sepsis (4-6 weeks)- Fungal (2 weeksafter negative culture)- Prosthetic infections (2-4 weeks)- Resistant pathogens

• Clinical response +biomarkers Chastre J et al. JAMA 2003; 290:2588-2598Singh et al. Am J Respir Crit Care Med 2000; 162:505-511

PCT guidance to stop antibiotics?

Clinically improving and- PCT threshold (<0.5ng/mL) OR- 80% ↓ in PCT (kinetics)

• Robust evidence• General approach

Bouadma L et al, Lancet; 2010Matthaiou DK et al, ICM, June 2012

Schuetz P et al , Coch Collab,2012Soni NJ et al, J Hosp Med, Sept 2013

Limit antibiotic duration in an infection which is deemed to be adequately treated

SAPS Trial

De Jong et al, Lancet Infect Dis, 2016

• Netherlands ICUs• Antibiotic stewardship• 15 Centers• n=1546 Clinically improving AND

- PCT threshold (≤0.5μg/L) OR

- 80% ↓ in PCT (kinetics)

De Jong et al, Lancet Infect Dis, 2016

SAPS Trial

Fluid responsiveness• Hemodynamically unstable

– Is the volume expansion likely to augment cardiac output and thereby tissue perfusion (PLR)

– Fluid responsiveness to administer or stop fluids

• Critically ill– Cumulative balance – D2-D3: negative balance

(500ml- 1L)– PLR…

Fluids Fluid is harmful and Fluid is harmful

Only 50% of patients will respond (SV by 10%) to fluid administration

• A

Fluid type : Endothelial glycocalyx

Fluids protecting the glycocalyx?

Balanced crystalloids (vs NS)FFP (trauma)Albumin and platelets?

NI Shapiro, How fluid resuscitaion can alter the glycocalyx,ISICEM,2019

Intravascular compartment

Intravascular compartment Colloid : Crystalloid 1 : 1.2For comparable volume expansion

Watch this space!

Practical Points - Hypovolemic resuscitation-individualise

• /Sepsis

Balanced crystalloidUntil more evidence(consider Albumin if remains unresponsive, need small volumes)

Trauma (not TBI)Balanced crystalloid

Emergency GIT SurgeryDepends on losses and comorbidities

GIT losses with Hypochloremic

M Alkalosis

Normal saline

TBI

Normal saline

Martin C et al, BMC Anesth, 2018

Fluid dose- sepsis resuscitation?R.E.B.E.L .EM

• This dose is challenged by multiple international organisations

• Not applicable to under resourced counties• Cannot extrapolate first world data to all settings

SSCG: 30mL/kg crystalloids within first 3 hoursRECOMMENDED for sepsis induced hypoperfusion

Petition: Time to retire the surviving sepsis guidelines?

HarmFEAST and SSSP-2

209 patientsZambiaMajority HIV and or TBSepsis +SBP<90mmHgNo hypoxemia

2L fluid within 1 hour + 2L next 4 hoursJVP,RR, SpO2, Dopamine,Hb at 7g%

Fixed fluid regimens!!!JVP!!!

Usual care<2L fluid within 6 hour, <20% TF ,<2% Dopamine

More fluids 3.5 vs 2 L (P<0.01)Higher mortality 48 vs 33%(P=0.03)

• 10 ml/kg BC – Especially pulmonary

sepsis• Consider 20 ml/kg

– Overt losses– Ongoing loss– Abdominal sepsis

• Vasopressors

Dose: Initial resuscitation

Adjudge response and re-Dose accordingly

How best to monitor reponse: PLR, SVV

GoalImprove perfusion deficits

Jozwiak et al, Annals Transl Med,2018Finfer et al, Nephrology,2018