Anti microbial resostance

1. Antimicrobial Resistance
Dr. Vipul V Shah MD, FICP
Consultant : Infectious Diseases
Ahmedabad

3. What is antimicrobial resistance?
• The inability to kill or inhibit the organism with clinically achievable
drug concentrations

4. Point to be discussed
• Scale of problem
• Resistance mechanism
• Detection of resistance
• Prevention of resistance

8. JAPI 2010 ;58 :147-149
XDR Gram negatives

9. AMR burden in India
• In 2019 - 297,000 deaths attributable to AMR and 1,042,500 deaths associated
with AMR
• India has the 145th highest age-standardized mortality rate per 100,000
population associated with AMR across 204 countries
https://amrcountryprogress.org/dow
nload/AMR-self-assessment-survey-
responses-2020-2021

10. Placing AMR in context with other causes of
death in 2019, India
https://amrcountryprogress.org/download/AMR-
self-assessment-survey-responses-2020-2021

11. Globally, the Majority of ICU infections Are Due to Gram-
Negative Bacteria
70% of infected patients had positive cultures
63% were gram negative;
Vincent et al. JAMA. 2009;302:2323-9.
Data from the Extended Prevalence of Infection in Intensive Care (EPIC II) Study, a global,
1-day point prevalence study of 13,796 patients from 1,265 ICUs in 75 countries in 2007.
Pseudomonas
spp.
Escherichia
coli
Klebsiella
spp.
Other
Enterobacter
spp.
Acinetobacter
spp.

12. J Assoc Chest Physicians 2017;5:10-7.

13. Its real challenge………
Antibiotic resistance is a worldwide phenomenon and a global public
health crisis
The overuse and misuse of antibiotics in the human sector as well as
animal, food, agricultural arenas have contributed it
The challenge is greater in developing countries, where the burden of
infectious diseases is high
ID consultants faced novel peculiar challenges in the treatment of severe
infections especially in critically ill patients, due to MDR-GNB
Prim Care Clin Office Pract 45 (2018) 467–484
BMJ 2012;344:e1567 doi: 10.1136/bmj.e1567
Front. Med. 6:74. doi: 10.3389/fmed.2019.00074

14. The intensive care units (ICUs) are often called “the
hubs” of infections
• Extremely vulnerable group
• Reduced/dysregulated immune responses
• Multiple procedures
• Transfer between hospitals, prolonged stay
• Previous antibiotic administration
• Invasive devices
• Endotracheal intubation
• Central venous cannulations
• Mechanical ventilation (MV)
• Urinary catheterizations
Curr Opin Infect Dis 2009;22:364‐9
CID 2011:53 (15 July)

15. Why resistance is concern?
• Resistant organism Leads to
treatment failure
• Increased mortality
• Spread in community
• Increased health care cost
• Threatens return to pre-
antibiotic era

16. Factors affecting AMR
• Drug related factor
• OTC
• Irrational FDC
• Irrational use of Abx
• Patient related factor
• Lack of sanitation
• Self medication
• Poverty
• Misconception
• Following the same prescription
• Environment related factor
• Poor sanitation
• Prescriber related factor
• Treating serology – eg widal test
• Using antibiotics in Viral URTI,
bronchitis
• Improper diagnosis

17. Point to be discussed
• Scale of problem
• Resistance mechanism
• Detection of resistance
• Prevention of resistance

18. Antimicrobial resistance
• Intrinsic (Innate) resistance
• All gram positives: Aztreonam
• Gram negative bacilli: Glycopeptides
(Vanco), Lipopeptides (Dapto)
• Proteus, Serratia marcescens : Colistin
• Acquired resistance
• Mutation
• Acquisition of foreign DNA (horizontal
gene transfer)

19. AMR: General mechanisms of resistance
• Altered permeability
• Inactivation / destruction of antibiotic
• Altered binding site
• Novel (new) binding sites
• Efflux (pumps) mechanisms
• Bypass of metabolic pathways

20. Mechanisms of Resistance
Interdisciplinary Perspectives on Infectious Diseases Volume 2014, Article ID 541340, 7 pages

21. How Antibiotic Resistance Moves Directly
Germ to Germ

22. Problematic Gram-Negatives and Mechanisms of
Resistance
 Pseudomonas aeruginosa
◦ AmpC production, efflux pumps (MexAB-OprM, etc), outer membrane porin changes (i.e., loss of OprD), Metallo-
Beta-Lactamase production (e.g., blaVIM, blaIMP), gyrA/parC mutations, aminoglycoside-modifying enzymes (AME),
ESBL / KPC production
 Acinetobacter species
◦ AmpC, ESBL (TEM-1, SHV-type, CTX-M-type), and serine (blaOXA) and metallo (blaVIM, blaIMP) carbapenemase
production, outer membrane porin changes, AME, gyrA/parC mutations, efflux pumps
 Enterobacteriaceae (Klebsiella species, E. coli, Enterobacter species)
◦ ESBL, Klebsiella-producing-carbapenemase (KPC-2, -3, -4, etc.) production, New Delhi Metallo-Beta-Lactamase
(NDM-1, -2), AmpC, outer membrane porin changes, plasmid mediated quinolone resistance gene (qnrA)
Bonomo RA, et al. Clin Infect Dis 2006;43:S49-56, Nicasio AM, et al. Pharmacotherapy 2008;28:235-49

23. Mechanisms of Resistance in GNB to -lactams (Penicillin,
cephalosporin, carbapenem, monobactum)
Porin-mediated resistance
• Antibiotic does not reach target
ß-lactamases
• Majority of resistance to ß-lactam antibiotics mediated through ß-lactamases
• Many different types of ß-lactamases with different substrate (antibiotic)
specificities

24. -Lactamases
• Well over 340 different enzymes
• Broad spectrum -lactamases
• Extended spectrum -lactamases (ESBLs)
• AmpC -lactamases
• Chromosomal
• Plasmid-mediated
• Carbapenemases

25. Clin Infect Dis. 2014;58:1439-1448

26. ESBLs and its clinical significance
• ESBLs are plasmid-mediated enzymes capable of hydrolysing and
inactivating all cephalosporins, penicillins, and monobactams
• Derivatives (mutants) of original TEM-1 and SHV-1 -lactamases
• Susceptible in-vitro to clavulanate and cefoxitin
• Despite appearing susceptible to one or more penicillins, cephalosporins,
or aztreonam in vitro, the use of these agents to treat infections due to
ESBL-producers has been associated with poor clinical outcome
• ESBL genes are often carried on plasmids that also encode resistance to
multiple classes of antimicrobials (Aminoglycosides, FQs, TMP/SMX)
• Treatment experience is largely based on classical ESBL producers
(Carbapenems, ß-lactam/inhibitor combinations)

27. AmpC ß-lactamases
• Chromosomally encoded as well as plasmid mediated
• Normally are repressed, so produced at low levels
• Capable of hydrolyzing a number of ß-lactam agents some in basal
AmpC production and others in setting of increased AmpC production
• Increased production occur in presence of specific antibiotic and later
that antibiotics stops working most notably ceftriaxone, cefotaxime,
and ceftazidime

28. ESBLs vs AmpCs
ESBLs AmpCs
Inhibitors (pip/tazo,
amp/sulbactam, amox/clav)
S R
Cefoxitin, cefotetan S R
Ceftazidime, ceftriaxone R R
Cefepime S/R S

29. Mechanisms of Carbapenem Resistance in GNB
• Carbapenemase - hydrolyzing enzymes
• Porin loss “OprD”
• ESBL or AmpC + porin loss (NC-CRE)

30. Carbapenemases
• The most versatile family of -lactamases
• Either chromosomal encoded or plasmid mediated
• Plasmid mediated is associated with other resistant genes (aminoglycosides,
fluoroquinolones)
• Two major groups based on the hydrolytic mechanism at the active site
• Serine at the active site: class A( KPC) and D (OXA)
• Zinc at the active site: class B (MBL- VIM, IMP, NDM)
• All carbapenemases hydrolyze penicillins, extended spectrum cephalosporins, and
carbapenems

31. Clin Infect Dis. 2014;58:1439-1448

32. Emerging carbapenem resistance in Gram-
negatives
• Significantly limits treatment options for life-threatening infections
• Options left with
◦ Polymyxin, Tigecycline/Minocycline, Fosfomycin
◦ Ceftazidime/Avibactum ± Aztreonam

33. Plasmid-mediated resistance to colistin
(Nov. 18th, 2015)
The Lancet Infectious Diseases
0
0.05
0.1
0.15
0.2
0.25
0.3
2011 2012 2013 2014
Food animal
Retail meat
Inpatient
15-20% in animals (Pigs/Chicken)
5-25% in food animal products
<1% in hospital patients

34. …and other colistin-resistance
mcr-1 resistance gene variants
BB Xavier et al., Eurosurveillance, July
2016
mcr-2 in animals (pigs)
-76% nucleotide identity with
mcr-1
-in Belgian in porcine coli-R E.
coli
-Located on a transferable
plasmid IncX4
-harboured on a mobile
element
Di Pilato et al., Antimicrob
Agents, Chemother, September
2016
mcr-1.2 in humans
-99% nucleotide identity with mcr-1
-KPC-3 producing K. pneumoniae (ST
512) ---Surveillance culture (rectal
swab) in a hospitalized patient
-IncX4 plasmid (very similar to mcr-1)
-found in E. coli and K. pneumoniae in
distant geographic areas

35. • Recently, emerging reports of plasmid-mediated colistin resistance,
mcr genes in E. coli is alarming
• Notably, mcr-1, mcr-2, mcr-3 and mcr-4 genes were first reported in
E. coli
• Plasmid mediated in E coli while chromosomal mediated in Klebsiella
• Colistin resistance in A. baumannii can be due to mutations in lipid A
biosynthesis genes and point mutations in PmrAB two-component
regulatory system (TCS)
Indian J Med Res 149, February 2019, pp 87-96

36. Community-Associated Extended-Spectrum β-Lactamase–
Producing Escherichia coli Infection in the United States
• A substantial portion of community-onset, ESBL-producing E. coli infections now
occur among patients without healthcare-associated risk factors in the United
States
• 91.3% of the isolates produced CTX-M–type ESBL
Clinical Infectious Diseases 2013;56(5):641–

37. Point to be discussed
• Scale of problem
• Resistance mechanism
• Detection of resistance
• Prevention of resistance

38. Antibiotics 2021, 10(2), 209; https://doi.org/10.3390/antibiotics10020209

39. Xpert Carba R

40. Film Array - Biofire

41. Point to be discussed
• Scale of problem
• Resistance mechanism
• Detection of resistance
• Prevention of resistance

42. Challenges in prevention
• MDR-GNB spread through five steps
• Presence of microbes on patient skin and/or in environment
• Transfer of these organisms to health care workers (HCWs) hands
• Microbe survival on HCWs’ hands
• Incorrect hand cleansing by HCWs
• Cross-transmission to other patients

43. Strategies that work in healthcare system
• Preventing device and procedure related infections, such as from
urinary catheters
• Stopping the spread of resistant germs within and between
healthcare facilities
• Containing emerging threats through early detection and aggressive
response
• Tracking and improving appropriate antibiotic use
• Infection and prevention control

44. Preventive strategies
• Core measures
• Administrative support
• Surveillance
• Hand hygiene
• Contact precautions
• Protocol for lab notification
• Dedicated equipment
• Device use
• Environmental
• Education (Diagnostic stewardship and Antimicrobial stewardship)
• Supplemental measures
• Active surveillance culture
Am J Infect Control. 2008;36(7):504–535. doi:10.1016/j.ajic.2008.06.001

45. Strategies to control AMR
• Judicious use of Abx
• Developing new Abx
• Farmers and food industry: Stop using Abx
• Prevent unnecessary use in animals
• No OTC Abx

46. Prevent infections
and spread of
Germs
Improve antibiotic
prescription
Be alert and take
action

47. In summary
• AMR is global crisis, India is struggling with Resistant GNBs
• For GNB, multiple mechanisms of resistance to previously useful
antibiotics is becoming the norm
• Beta lactamases production is an important mechanism of resistance
• Need for rapid diagnostics and efficient laboratories to anticipating
diagnosis rapidly
• Relatively few new drugs are being developed
• Containment should be pursued through implementation of adequate
infection prevention procedures and antimicrobial stewardship