How to Give Better Lectures: Some Tips for Doctors
MDR_XDR_Management_2023.pptx
1.
2. AMR ( Impact, India vs Rest of the world)
Common myths around antibiotics
Principles of antibiotic use
Risk factors for MDRs/XDRs
Management of common MDRs-XDRs
3. Issue is as HOT as Global Warming
With no New Drugs in the Pipeline:
A very dark period in Modern Medicine
Delay what is inevitable as long as possible
7. Human and economic cost of AMR
7
• The results show a
considerable human and
economic cost. Initial
research, looking only at part
of the impact of AMR, shows
that a continued rise in
resistance by 2050 would
lead to
– 10 million people dying
every year
– reduction of 2% to 3.5% in
Gross Domestic Product
(GDP) costing the world
up to 100 trillion USD.
AMR in 2050
10 million
The Review on AMR Chaired by Jim O’Neill 2014
Cancer now
8.2 million
Cholera now
100,000-120,000
Diabetes now
1.5 million
Measles now
130,000
Diarrheal disease now
1.4 million
Road traffic
accidents now
1.2 million
Tetanus now
60,000
Deaths attributable to AMR every year compared to
other causes of death
8. 8
The Review on AMR Chaired by Jim O’Neill 2014
Asia
4.73 million
Europe
390,000
North America
317,000
Latin America
392,000
Africa
4.15 million
Oceania
22,000
5
Mortality per 100,000 population
6 7 8 9 10 >
Deaths attributable to AMR every year by 2050
Number of deaths
15. Antibiotic
Anarchy
Hospital environment not conducive
• Antibiotic protocols not
available or at rudimentary
stage or Not followed
• Minimal antibiotic surveillance
data & microbiology
infrastructure
Antibiotic usage not based on evidence
• Only a few qualified ID specialists
• Empiric antibiotic use in many cases
not based on microbiology data or
evidence
• Multiple antibiotic prescriptions
are common
Crowded market and Lax regulations
• Many generic copies of antibiotics
(>125 Pip/Tazo , > 50 meropenems) &
irrational combinations
• Indiscriminate promotion by
pharma companies
• Over the counter availability of
broad spectrum antibiotics
• ESBL rates in community 40%,
Nosocomial ESBL : 60-80%
• Carbapenem resistant
Pseudomonas and Acinetobacter:
20%-60%
• MRSA – 30-50%
Antibiotic Resistance Very High
Antibiotic is Automatic !!!!
(Like Antacids and Multi-vitamins)
16.
17. Not all post operative fevers are due to infection
Not all infections are due to bacteria
18. First 48 hours – physiological
◦ Do not escalate
◦ Do not over react
Four Ws“
◦ Wind (pneumonia, aspiration, and embolism)
◦ Water (urinary tract)
◦ Wound (surgical site)
◦ What did we do? (iatrogenic - drug fever, blood
products, intravenous lines)
19. IV usage
◦ Frequently unnecessary
◦ Local problems and systemic infections
◦ Prolonged in-patient stay
◦ Cost, monitoring levels
20. IV usage
◦ Rapidly achieved peak antibiotic levels after iv
Severe sepsis
Bacterial meningitis
If absorption compromised or patient can not take oral, parenteral is the
only way
With same serum concentrations
◦ IV antibiotics will work in 7 days
◦ Oral antibiotics take a week
21.
22. Multiple antibiotics for simplest of infections
Shotgun approach – if 1 is good, 2 or 3 can only be better
A single antibiotic can be effective against a single organism
A single wide-spectrum antibiotic may be used in many mixed
infections
23. No rationale in starting 2 antibiotics that show sensitivity
Adding metrogyl to Pip-Tazo/ carbapenems is futile
Ampi-Genta-Metro as prophylaxis is a passé
Antifungals have well defined indications
24.
25. Our patients are weaker
Our surroundings are dirtier
Antibiotic policies are for healthier whites
We need to use “higher” antibiotics in all cases
◦ Citius, Altius, Fortius
Limiting surgical prophylaxis to just 24 hours is not for us
Discharge medication is incomplete without a 5-7 day
course of antibiotics
26.
27. • The basic
principles of
microbiology
remain the same
• Yes, our bugs are
different and
more resistant
• Use Local Data
• Ask
microbiologist for
your ward
antibiogram
Hospital surveillance data Validity of these data
S.
No
Most common
pathogens
%
prevalence
Most sensitive antibiotics
(% Sensitivity)
1 Pseudomonas 30% Colistin (98%) Imi (85%) Cef/Sul (79%)
*Pip/Taz (62%) *Amikacin (57%)
2 Klebsiella 25 % Imipenem (93%) Ertapenem (92%)
*Cef/Sul(76%) *Amikacin = Pip/Taz (65%)
3 Acinetobacter 14 % Colistin (98%) Cef/Sul (85%) Imipenem
(82%) *Pip/Taz(45%)
4 E.Coli 12 % Imipenem (95%) Ertapenem (94%) Cef/Sul
(79%) *Amikacin (70%) *Pip/Taz (67%)
5 Staph Aureus 9% Vancomycin (97%) *Ertapenem = Cef/Sul =
Pip/Tazo (70%)
28. Will not “prevent” complications
Wont make up for lack of basic surgical principles
◦ Sterilization techniques
◦ Basic antisepsis
Has the source been controlled?
29. If one doesn’t work, we will get a new drug/ class soon
My concern is my patient, AMR is not my problem
31. Who needs antibiotics?
◦ Prophylaxis
◦ Emergent situation/ overt sepsis
Has the source been controlled?
Dose and dose adjustments
Beta-lactams, glycopeptides, or macrolides - killing depends
on period of time the levels are above MIC, so give prolonged
infusions
FQs and AGs are concentration dependent antibiotics: Give
single shot high dose
32. Cmax = maximum plasma concentration
0
Cmax:MIC
Concentration
Time (hours)
MIC
Target value: Cmax:>8–10 MIC
Levison ME. Infect Dis Clin N Am 18 (2004) 451–465
34. For patients with septic shock, antibiotics should be
administered as soon as possible (within 1hr)
Antimicrobial therapy is considered for wound prophylaxis
for all patients undergoing intervention. Within 1 h before the
operation
35. Administer 30-60 minutes prior to skin incision
Maintain therapeutic levels of antibiotic in both serum and tissue
throughout the operation
If operation lasts longer than 4 hrs give a 2nd dose
Blood loss greater than 2000 ml give 2nd dose
Use Narrow spectrum Agent
Discontinue Prophylactic Antibiotics within 24hrs post-op
36. Source/ expected source of bacteremia
◦ Clinical acumen
Likely site/source
Likely pathogens
◦ Empirical therapy- universal and local data
Spectrum
Will it work?
◦ Penetration
Drug or Drugs
38. Route
◦ “Serious = parenteral?”
◦ Improved oral agents
Higher and persistent serum and tissue levels
Once culture is available
◦ Interpretation of the report
◦ Is the isolated actually the pathogen
◦ Was the specimen properly collected ?
◦ Is it a contaminant/ coloniser?
◦ Sensitivity reports are at best a guide
39. 1. Culture positive and
sensitivity report
available
2. Patient clinical
condition stable /
better than Day 1
3. GUTS !!!!!
1. Change from Broad
to narrow spectrum
antibiotic
2. Reduce the number
of antibiotics
3. Reduce the duration
of antibiotics
40. Antimicrobial therapy of established infection should be
limited to 4–7 days, unless it is difficult to achieve adequate
source control.
24hr prophylaxis is sufficient for most surgical procedures
Clinical indicators best guide
Prolonged treatment futile and harmful
41. International Expert Opinion on AB Stewardship Strategy
Local Microbiology Data
Patient Risk
Stratification for
drug resistant pathogens
De-escalation
Lab Diagnosis
Empirical
Targeted
42.
43. 43
Basetti M etal. EXPERT REVIEW OF ANTI-
INFECTIVE THERAPY, 2017
VOL. 15, NO. 1, 55–65
44. Carmeli Y. Predictive factors for multidrug-resistant organisms. In: Role of Ertapenem in the Era of Antimicrobial Resistance
[newsletter]. Available at: http://www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf. Accessed 7
April 2008;
45. Health Care Contact
Procedures
Antibiotic Rx History
Patients
Characteristics
No
No
No in last 90 days
Young – No co-
morbid conditions.
Yes
Minimum
Yes in last 90 days
Elderly
Few Co-morbid
conditions.
Prolonged
Major invasive
Procedures
Repeat multiple
antibiotics.
Immunocompromised,
or with many co-
morbid conditions.
Causative Pathogen
could be
Susceptible to
Common narrow
spectrum
antibiotics
ESBLs / MRSA ESBLs /
Pseudomonas
/Acinetobacter
MRSA
Possible Antibiotic
recommendations
- No Need for
Broad spectrum
antibiotics
- Use Non-
Pseudomonal
broad spectrum
antibiotics
- Use Anti-
pseudomonal
Broad spectrum
antibiotics
3 patient types based on Risk stratification
Ref: Based on stratification criteria suggested by Dr Yehuda Carmelli
Type 1 Type 2 Type 3
49. Slide 49
ESBLs and Amp C.
Therapies which are an Absolute No No…
• 2nd and 3rd Gen. Cephalosporins
• Aminoglycosides
• Flouroquinolones
• TMP/SMX
• Aztreonam
• Combination of any of the above drugs
Can only be used after culture report
or in Mild infections
50. Slide 50
Controversies
• What is DOC ? Carbapenems or BL/BLIs
• Where to use BL-BLIs ?
• Which BL-BLIs to use ?
• Which carbapenem to use and where for ESBLs ?
51. Slide 51
BL/BLI combinations: Are there too many ?
Approved / Available Globally
• Ampicillin + sulbactam
• Amoxicillin + Clavulanate
• Piperacillin + Tazobactam
• Cefoperazone + Sulbactam
• Ticarcillin + Clavulanate
Approved / Available in India
• Ceftriaxone + Sulbactam
• Ceftriaxone + Tazobactam
• Ceftriaxone + Clavulanate
• Ceftazidime + Sulbactam
• Ceftazidime + Tazobactam
• Cefepime + Tazobactam
52. Slide 52
Role of BL + BLIs
• uncomplicated UTIs ,
• low risk cIAIs and
• less severe Resp tract / Skin structure infections
(where bacterial load is less)
NOT for Sepsis / VAP
54. AAC 2013
Low MIC <=2
The breakpoint for
Pip-Taz is <16
For pathogens with MIC > 2
but < 16, use the highest
possible dose 4.5gm TID/QID
in prolonged infusion
Consider adding AG
55. Slide 55
Health Care Contact
Procedures
Antibiotic Rx History
Patients
Characteristics
No
No
No
Young – No co-
morbid conditions.
Yes
Minimum
Yes ( Last Month )
Elderly
Few Co-morbid
conditions.
Prolonged
Major invasive
Procedures
Repeat multiple
antibiotics.
Immunocompromise
d, with lots of co-
morbid conditions.
Causative Pathogen
could be
Susceptible ESBLs ESBLs +
Nonfermenters
Recommendations
should be based on
Losal resistance
data
- Non pseudomonal
- Non ESBL inducer
- Eg: Ampicillin-
sulbactam
- Ertapenem,
- FQs , AGCs
( only after
culture results)
- Avoid 4 GC and
BL+BLI in
severe
infections
Group 2
Carbapenem
( Imipenem/Mero
penem)
- 4GC / BL+BLI
combinations in
mild to modertae
infections.
Rx
Risk Stratification for MDRs
H
Age
T
56. Slide 56
Place in Therapy for Ertapenem in ESBLs
• Recently, a multinational retrospective cohort study showed that ertapenem
appears as effective as other carbapenems for empirical and targeted
therapy of bacteremia due to ESBL-producing Enterobacteriaceae.
• However, a sensitivity analysis showed a nonsignificant trend favoring other
carbapenems in patients with severe sepsis/septic shock.
• We recommend reserving the use of ertapenem for infections with
susceptible ESBL-producing strains that are not associated with
severe sepsis/septic shock.
• It can be a useful alternative for outpatient or de-escalation therapy of such
infections
Sheu CC etal. EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2018, VOL. 16, NO. 3, 205–218
57. Slide 57
Carbapenems: What and Where to use
Ertapenem (1gm OD)
cIAI ( Sec Peritonitis)
cUTI
cSSTI (DFI)
Pneumonia
• 1st line empirical for complicated community-acquired
infection where risk of ESBLs high
• Low risk of Pseudomonas/ Acinetobacter infection
• De-escalation
Imipenem
Meropenem
Doripenem
VAP
Sepsis
Tertiary Peritonitis / ANP
• Initial empirical for serious hospital-acquired infection
• High risk of Pseudomonas/ Acinetobacter infection
58. Treatment recommendations for infections with
ESBL producers
No treatment: colonisation
Imipenem or meropenem: BSI, HAP-VAP, Tertiary peritonitis, UTI with
urosepsis requiring ICU admission
Ertapenem: comp.UTI ( not severe, may be as OPAT or in Ward),
intra-abd ( Sec peritonitis) , limb threatening diabetic foot.
Pip-Tazo suitable for uncomplicated UTIs , low risk cIAIs and less severe
Resp tract / Skin structure infections where bacterial load is less & MIC <2
Quinolones/AGs : allergy to beta lactams, susceptible isolates
Nitrofurantoin: uncomplicated lower UTI for 5 days
Fosfomycin: complicated and uncomplicated UTI (oral 3gm stat)
Tigecycline, colistin or polymyxin B: resistance to all, beta-lactam allergy.
69. Slide 69
• Biggest study on monotherapy vs
combination for CRE
• 480 patients with BSI due to CRE,
10 countries
• 90% had Klebsiella infection
• Majority were KPC (75%), OXA
(15%) and MBLs (10%)
81. Slide 81
Summary: CRE Management
(Mainly KPC, No major evidence for MBLs)
High Risk Patient (INCREMENT score > 7)
• If Isolate susceptible to Avy Caz or Carbapenem MIC <16
- Backbone: Avy Caz or High dose prolonged infusion Carbapenem
+
COL or TG or AG or FOS
• If Isolate resistant to Avy Caz or Carbapenem MIC >16
- Backbone: COL
+
AG or FOS or TG
• If Isolate resistant to Carbapenem/Avy Caz and COL
Combination of any active drugs ( eg: FOS + TG or TG + AG)
Or
Two carbapenems : ERT + MER
Note: If Pneumonia: Add Inhaled antibiotic: colistin 2 MU every 8 h or
tobramycin 300mg every 12 h or amikacin 250 mg every 24 h.
87. Slide 87
When and Why Combination therapy still ?
• Structural Lung Disease (eg:
Bronchiectasis / CF)
• prior intravenous antibiotic use
within 90 days
• septic shock, acute respiratory
distress syndrome in patients
with HAP/VAP
• >10% resistance locally to a
single agent
Maralo AE etal. EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2017 VOL. 15, NO. 9, 861–871
88. Slide 88
MDR PA: Start with combination as empirical and
then move to monotherapy preferably
Bassetti M etal. EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2017 VOL. 15, NO. 1, 55–65
Maralo AE etal. EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2017 VOL. 15, NO. 9, 861–871
Choice of two empirical agents should be
determined by local ecology
• If C/S shows susceptible/Non MDR Pseudo
- Continue monotherapy with Ceft/Tazo or
Pip-Tazo or Cefepime or Carbapenem
- If C/S shows MDR Pseudomonas/CRPA
suscpetible to Cef/Taz or Colistin
Use Cef/Taz +/- Amikacin
or
Colistin High Dose +/- Amikacin/Fosfo
92. Slide 92
Colistin and/or Amp Sulbactam based triple combinations are
preferred today but Colistin sparing regimens are being looked at.
Infect Dis Ther (2021) 10:2177–2202
93. Slide 93
Role and Status of Cefiderocol for CRAB
•Initially showed lot of promise with good in-vitro susceptibility vs CRAB
•However, Ph III CREDIBLE CR trial showed 8% hetero-resistance in CRAB
In-vitro Data
•In Ph III CREDIBLE CR, higher mortality in Cefiderocol vs Colistin combination for CRAB
•In a recent observational study, Cefiderocol combination arm showed lower morality vs Colistin Combination in
CRAB. Higher mortality in Cefiderocol monotherapy arm vs Cefiderocol combination arm
Cefiderocol Mono
vs
Combi therapy
•The arrival of cefiderocol initially offered hope for a single-agent regimen for the management of CRAB infections.
•However, available data do not support its use as monotherapy.
• In clinical practice, cefiderocol may be an option as a component of combination therapy, but data regarding the use
of cefiderocol as a component of combination therapy are scarce and no preferred combination has been identified.
Current Status
93
94. Slide 94
Summary: IDSA 2022 Guidelines for the management of CRAB
-There is no “standard of care” regimen for CRAB
-Ampicillin-sulbactam is the preferred single agent for mild CRAB infections
-Combination therapy with at least two agents, with in-vitro activity whenever
possible, is suggested for the tmt of mod to sev CRAB infections
-
-Polymyxin B may be considered as monotherapy for mild CRAB infections and in
combination with at least one other agent for mod to sev CRAB
- Minocycline/ Tigecycline may be considered as monotherapy for mild CRAB infections
and in combination with at least one other agent for mod to sev CRAB.
- Eravacycline is not suggetsed
-High-dose ampicillin-sulbactam is a preferred therapy for CRAB infections
when susceptibility has been demonstrated.
-High-dose ampicillin-sulbactam remains a treatment consideration as a
component of combination therapy even when susceptibility has not been
demonstrated.
-High dose, extended infusion Meropenem can be considered as a component of
combination therapy for mod to sev CRAB. The combination of a polymyxin and
meropenem, without a third agent, is not suggested for the treatment of CRAB infections
-Cefiderocol should be limited to the treatment of CRAB infections refractory to other
antibiotics or in cases where intolerance to other agents precludes their use. When
cefiderocol is used to treat CRAB infections, use as a part of a combination regimen.
IDSA 2022
CRAB
3/21/2023
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