Antimicrobial Resistance and Clinical

Use in Respiratory Infections

Dr. Md. Wamique Izhar
Resident, Respiratory Medicine,
IPGME&R and SSKMH
What is Antimicrobial Resistance (AMR)?
Antimicrobial resistance is a natural process, driven by
selection pressure.
Can be caused either by genetic mutations or by
incorporation of resistance genes via mobile genetic
elements.
Resistance can be against a specific class, or can be
multidrug in nature.
How does AMR occur?
Mechanisms of AMR
Ambler classification
 Antibiotic Resistance Genes
Gene Effect
mecA Encodes protein PBP2A that has low affinity for
penicllin-like antibiotics and has transpeptidase
activity.
mcr-1 Encodes a phosphoethanolamine transferase that
catalyzes the addition of a phosphoethanolamine
moiety to lipid A in the bacterial outer membrane
(OM)
vanA Replacement of D-Ala by D-Lac/D-Ser
blaSHV Encode Beta-lactamases with varying antibiotic and
microbe specificity
blaNDM
blaCTX
blaTEM
blaOXA
 Important respiratory antimicrobials and
mechanisms of resistance
Antibiotic Mechanisms
Ceftriaxone CTX-M type of ESBLs
Cefoperazone TEM-2 type of ESBLs
Macrolides 23S rRNA methylation (A2058 residue in domain V)
Linezolid 23S rRNA muations (G2061, C2452, A2503 residues)
Carbapenems Carbapenemases, Efflux pumps, Downregulation of porins
Colistin Modulation of Lipid A, reduced negative surface charge
Polymyxin B Modulation of Lipid A, reduced negative surface charge
Piperacillin TEM-1 type of ESBLs, inhibitor resistant BLs
Teicoplanin vanRS-van HAX expression l(replacement of D-ala by D-Lac/D-
Ser)
 Why is AMR so concerning?
Globally 4.95 million deaths were associated with
antimicrobial resistance in 2019 (Murray et al.,
GLASS 2022)
Estimated loss in Global GDP by 2050 could be as
high as 3.8% (World Bank, GLASS 2022) –
comparison?
The rates of resistance are higher in LMICs as
compared to HICs in spite of per-capita less antibiotic
consumption in the former. (GLASS 2022) –
multifactorial? genetic diversity?
 Why is AMR so concerning? – Organisms
and Drugs
The antimicrobial consumption data worldwide is not
available for most countries – lack of understanding
trends makes it difficult to survey and identify
wrong/irrational usage. (GLASS 2022)
Over the last 5 years, the resistance patterns have
emerged and increased among Pseudomonas spp.,
Acinetobacter spp.and Enterobactericeae – major ICU
pathogens. (Blasi F., 2019 ERS Congress)
Increased use of broad-spectrum antibiotics –
increased DR, hospitalisation, cost. (Eur J Repir, 2019)
 Why is AMR so concerning? – Patient
Factors
Increased population aging, increased rates of acquired
immunosuppression – increased risk of infections, and
increased antibiotic usage.
Increased prevalence of renal impairment and diabetes
mellitus – increased and resilient infections – increased
antibiotic usage.
Sepsis as a major cause of admission, morbidity and
mortality – altered PK and PD, variable clearance,
variable Vd – antibiotic type and dosage adjustment.
 Why is AMR so concerning? – global
studies
Zumla et al., 2014 – 78% GNB sensitive to ONLY
colistin; 62% Acinetobacter, 59% Pseudomonas, 52%
Enterobacters resistant to colistin.
Guclu et al. 2021 – Carbapenem resistance (92.8% in
A.baumanii, 39.8% in P.aeruginosa, 47.3% in
K.pneumoniae); Colistin resistance (12.8% in
A.baumanii, 7.5% in P.aeruginosa, 18.5% in
K.pneumoniae).
Mirti et al., 2018 – Pseudomonas spp., Klebsiella spp.,
S.aureus – sensitive only to Gentamicin, Amikacin and
Cefuroxime; MDR rates 46.3%.
 Indian Scenario - general
India reported 1.04 million deaths associated with
AMR in 2019, higher than those associated with
neoplasms, tuberculosis, chronic kidney disease and
T2DM. (GLASS 2022)
Major organisms – E.coli (1.52L), K.pneumoniae
(1.23L), S.aureus (1.11L), A.baumanii (1.03L)
Major factors – easy OTC availability, lack of
awareness amongst HCPs, patient perception, lack of
institutional SOPs, weak surveillance
 Indian Scenario - studies
AIIMS, 2011 – detection of resistance amongst GNBs
– 50% to Carbapenems, 66% to Aminoglycosides and
88% to 3rd generation Cephalosporins.
Singh S, et al., 2018 – increased resistance seen among
A.baumanii, K.pneumoniae and P.aeruginosa to
Piperacillin, 3rd and 4th generation Cephalosporins,
aminoglycosides, and carbapenems.
Regha IR, et al., 2017 – increased resistance seen
among K.pneumoniae, P.aeruginosa and NFGNB to
3rd generation Cephalosporins and aminoglycosides.
WHO AWaRe classification
 WHO AWaRe classification
Reserve Category
Aztreonam Colistin Iclaprim Oritavancin
Carumonam Dalbavancin Imipenem/ Plazomicin
cilastatin/
relebactam
Cefiderocol Dalfopristin/ Lefamulin Polymyxin B
quinupristin
Ceftaroline- Daptomycin Linezolid Tedizolid
fosamil
Ceftazidime/ Eravacycline Meropenem/ Telavancin
avibactam vaborbactam
Ceftobiprole- Faropenem Minocycline Tigecycline
medocaril
Ceftolozane/ Fosfomycin Omadacycline
tazobactam
 Our Institutional Policy
Steps of Rational Antibiotic Use
Step 1: Make an appropriate clinical diagnosis.
Step 2: Limit empiric antibiotic use to critically ill
patients.
Step 3: Know your bugs! Predict microbes and the local
resistance patterns.
Step 4: Choose appropriate antibiotic as per the
antibiogram.
Step 5: Modify empiric antibiotics as per C/S pattern and
patient status; de-escalate
Step 6: Stop antibiotics if – symptoms resolved/cultures
negative for pathogens/course completed/biomarkers
normalize.
BioFire
 Treatment of CAP
In-patient, non-ICU: Beta-lactams + Macrolide
preferred; if Pseudomonas suspected, anti-
pseudomonal Beta-lactams + anti-pseudomonal
fluoroquinolones; if MRSA suspected, add
vancomycin/linezolid to preferred regimen.
In-patient, ICU: Beta-lactams + Fluoroquinolones +
Macrolide preferred; if risk factors for Pseudomonas,
anti-pseudomonals (beta-lactams) with or without
aminoglycosides to be considered; if MRSA risk
factors, vancomycin or teicoplanin to be considered
(linezolid if factors present); if anerobes suspected,
consider clindamycin or moxifloxacin.
 Treatment of HAP/VAP
Most commonly caused by MDR pathogens.
Our institutional data reveals:
K.pneumoniae- 39% isolates; sensitive to Colisitin and
Imi/Cila.
A.baumanii – 32% isolates; sensitive to Colistin,
Minocycline and Cefoperazone-sulbactum.
P.aeruginosa – 8% isolates; sensitive to Amikacin,
Imipenem and Tobramycin.
S.aureus – 5% isolates; sensitive to Vancomycin,
Teicoplanin and Linezolid.
 Treatment of HAP/VAP
Empiric treatment of HAP/VAP:
Early onset/minimum Abx exposure: Piperacillin-
Tazobactam +/- Amikacin.
Late onset/prior Abx exposure:
Imipenem-Cilastatin/Meropenem +
Amikacin/Colistin/Polymyxin B.
Culture proven HAP/VAP: as per the organism isolated
and the appropriate antibiotic(s) found sensitive in the
C/S testing.
 Takeaways
Antimicrobial resistance is REAL! The focus has shifted
from monotherapy to combination therapy and
identification of appropriate isolates across guidelines
(2007 IDSA/ATS – 2019 IDSA/ATS – 2023 ESI/ALAT),
but more regional participation and research is needed.
Healthcare professionals need to be educated about when
NOT to use antibiotics, and when they do, what are the
appropriate PK and PD they need to ensure.
Institutional data needs to be compiled, assessed, reviewed
and uploaded to GLASS in order to understand our bugs
and resistance patterns better – compare with global
trends.
 Takeaways
If there is an institutional protocol, it must be followed
to the T. Failure to comply would complicate the
resistance patterns and drug sensitivity, potentially
worsening the existing crisis.
Vaccination against common organisms to be made the
norm, especially in high-risk groups – reduces Abx
usage, reducing risk of resistance.
Improve infection control – ensure stricter policies
amongst everyone involved in handling the patient.
Public awareness – antibiotics are NOT the only cure!