antibiotics in xdr organism,the mechanism of resistance ,cause of resistance ,effect of resistance, levels of resistance, classification, xdr organisms, gram positive and gram negative ,detection and latest idsa guidelines for management. ambler classification and detection latest antibiotics and mechanism of action of new antibiotics.

1. Antibiotics in XDR organisms
Dr M.SHASHI KIRAN
MODERATOR
DR MONIKA SONI

2. Case scenario
 57 yr male pt k/c/o chronic liver disese with
pleural effusion ,pleural tapping was done ,
culture found to have xdr klebsiella
pnemoniae for which X PERT CARBA R
showed bla NDM, bla OXA 48
 T/t: he was initially on empiric therapy,
later shifted to cefatazidime +avibactam
,aztreonam combination.
 43 yr female pt sridevi diagnosed to have
inavasive rhino occulo cerebral mucormycosis
,developed UTI during her prolong stay in the
icu,organism isolated from was xdr klebsiella
peumoniae sensitive to colistin only .CARBA-
R showed bla CTX-M
 She was started on colistin initially later
shifted to cefipime +tazobactam
combination

3. Discussion
• Types of drug resistance in bacteria
• Mechanism of antibiotic resistance
• Methods to detect antibiotic resistance and sensitivity
• most common gram positive and gram negative xdr bacteria
• Various resistance mechanism in these bacteria
• Treatment of xdr organisms

4. • -WHO defines Antibiotic Resistance as microorganisms that are not
inhibited by usually achievable systemic concentration of an
antimicrobial agent with normal dosage schedule and/or fall in MIC
range
MDR: non-susceptible to ≥1 agent in >3 antimicrobial categories.
XDR: non-susceptible to at least one agent in all but one or two
antimicrobial categories(susceptible to at least two class of antibiotics)
PDR: non-susceptible to all antimicrobial agents
Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim
standard definitions for acquired resistance. A-P Magiorakos 1, A Srinivasan, R B Carey et al

5. Consideration:
bacterial isolate considered resistant to an antimicrobial class when it is ‘non-susceptible to
at least one agent in a category
Antimicrobial agent was excluded from an organism group list if:
(i) organism was intrinsically resistant to the agent
(ii) agent achieved therapeutic concentrations only in urine (e.g. nitrofurantoin)
(iii) organism exhibits widespread acquired resistance to the agent (e.g. penicillin for S.
aureus)

6. WHY WORRY ABOUT RESISTANCE

8. How to bacteria acquire resistance?
chromosomal method- Mutation
Is a random, undirected, heritable
variation caused by an alteration in the
nucleotide sequence at some point of
DNA in the cell.
One step mutation-
Ex: resistance to streptomycin
Step wise mutation-where mutation is
acquired through series of small steps
Ex: resistance to penicillin
Extra chromosomal methods
Are transferrable type of resistance
1. Transformation is the first
example of genetic exchange
found in bacteria by GRIFFITH in
1928.
2. Transduction
3. Conjugation –plasmid mediated-
main mechanism of resistance
4. Transposon
5. Integrons

9. Mutation v/s transferable resistance which is
more dangerous
Low degree of resistance
One drug resistance at a time
Resistance does not spread
can overcome by high drug
overdose
Drug combination can prevent
Mutants may be defective
High degree of resistance
Multiple drug resistance
Resistance spread to same or
different species
High dose ineffective
Combination cannot prevent
Mutants not defective

10. The transferred genetic material makes the organism to develop of resistance mechanism against
antiboitics

11. How to check for resistance ?
Disc diffusion method
o The tested bacterium is seeded on to the
medium and its sensitivity to the drug is
determined by inhibition of its growth.
o The antibiotic are placed in filtered paper
discs of 6mm in diameter charged with
appropriate concentration of the drug
o The drug is allowed to diffuse through the
solid medium so that a gradient is
established highest near the disc and
decreasing with distance
o Modification E-test, AMT Ring test
 Dilution test
Serial dilutions of the drug are prepared
and inoculated with tested bacterium.
After overnight incubation
MIC is read by noting the lowest
concentration of the drug that inhibits the
growth of the bacteria
MBC is lowest concentration of the drug
that kills the bacterium.
It is estimated by subculturing the broth
tubes on to suitable solid media
This is used when therapeutic dosage is to
be regulated accurately.

12. Pre requisite for sensitivity testing
It is important that sensitivity test be done only with known or
presumed pathogen.

14.  The MIC is defined as the minimal concentration of antibiotic that prevents a clear suspension of 10* 5
colony-forming units (CFUs) of bacteria/mL from becoming turbid after overnight incubation
 Turbidity usually denotes at least a 10-fold increase in bacterial density.
 If the minimal concentration of the antibiotic that prevented turbidity lowered the bacterial density from
10*5 to at least 10*2 CFU/mL, that is, a 99.9% (3-log10) reduction in bacterial inoculum considered as
the MBC.
 For each organism–antibiotic pair, there is a particular cut off MIC
that defines susceptibility. This particular MIC is called the breakpoint
 When the MBC is four times or less than the MIC, the drug is considered to be bactericidal.
Penicillins,cephalosporins,carbepenams,monobactams,vancomycin,flouroquinolones,aminoglycosides,m
etronidazole,daptomycin
 If the MBC/MIC ratio is greater than four, it is considered bacteriostatic. Macrolides Tetracyclines
Linezolid

15. Most common XDR organisms
• Gram positive
1. Sthaphylococcus aureus
2. Enterococcus faecalis
• Gram negative
1. Enterobacterales
2. Pseudomonas aeruginosa
3. Acinetobacter baumannii

17. Staphylococcus aureus
Penicillin
resistance due to
plasmid encoded
penicillinase Methicillin resistance
is due to production of
PB2A.
heterologous source
HA MRSA
Resist to
clindamycin
CA MRSA
T/t:clindamycin
VRSA resistance acquired from vancomycin-
resistant enterococci (VRE). vanA genes .
VanA genes encode the synthesis of D-Ala-D-
Lac in which vancomycin has much lower
affinity compared to the terminal wild type D-
Ala-D-Ala

18. other Antibiotic Resistance
trimethoprim-
sulphamethoxazole
Clindamycin
mutation in the genes
encoding target enzymes
that are essential for DNA
replication (mutation in
subunit gyrB of DNA gyrase
and subunit grIA of
Topoisomerase IV) and due
to changes in drug entry and
overexpression of an efflux
pump NorA
Resistance to trimethoprim is due to the
acquisition of the dfrA gene that encodes
DHFR enzymes that are not susceptible to
inhibition
The resistance to sulfamethoxazole is due to
chromosomal encoded DHPS mutation which
prevents the drug from binding to the
enzyme.
Resistance to this drug
rises from genes
designated erm. Leads to
methylation of adenosine
residuein23srRNA
preventing chain
elongation in preotein
synthesis
 Flouroquinolones
Linezolid single-
nucleotide
mutation in
thebinding site for
linezolid.
Linezolid
resistance was developed due to a mutation in at least three
distinct proteins. Leading to increased voltage difference across
the cytoplasmic membrane and reduced drug binding to its
target binding site
Daptomycin

19. https://doi.org/10.3390/antibiotics10040398

20. Enterococcus faecium
Gram-positive cocci
E. faecium is part of the normal
flora in human and animal guts,
but in immune-compromised
hosts
 E. faecium can act as an
opportunistic pathogen which
can cause severe morbidity and
mortality

21. Ampicillin/Penicillin Cephalosporins
resistance
 pbp5 chromosomal gene which
encodes a low binding affinity class B
PBP for ampicillin/penicillin and the
cephalosporins.
mutated PBP
the overexpression of β-lactamase
enzymes.
Vancomycin-resistance
 acquire genes through mobile genetic
elements (plasmids and transposons) encode
for
 Vancomycin-resistance gene clusters (such as,
van A, B, D, and M) are responsible for the
replacement of D-Ala-D-Ala with D-alanyl-D-
lactate termini.
 results in low binding affinity of vancomycin.
Van A gene cluster is the most common type.
Aminoglycoside resistance
 involve aminoglycoside-modifying
enzymes (AMEs)
 including aminoglycoside
nucleotidyltransferases (ANTs)
 aminoglycoside acetyltransferases
(AACs)
 aminoglycoside
phosphotransferases (APHs).

22. • resistance to
fluoroquinolones
Transferred
resistance
determitant
“ermB”gene
Leads to
methylation of
adenosine
residuein23srRNA
preventing chain
elongation in
preotein synthesis
confers resistance
to clindamycin also
resistance to Macrolide-lancosamide-
streptogramin
 point mutations in
gyrA and parC
genes that encode
subunits A of DNA
gyrase and
topoisomerase IV
 NorA-like efflux
pump results in
high resistance
levels to FQs.
Resistance to
tetracyclines
 Tranferred by plasmid
pAMα1
 Promotes efflux of the
drug.
 Protects ribosomes
from inhibition by
tetracycline

23. Gram negative bacteria
Gram-negative bacteria can cause serious diseases in humans
Especially in immuno-compromised individuals
Ventilator-associated pneumonia
Catheter-related bloodstream infections
ICU-acquired sepsis such as urinary tract infections
An extended hospitalisation
Repeated contact with health care system(ex:multiple hospital
admissions)

24. known to
cause
endotoxic
shock
protective
and unique
determines
the cell
shape
responsible for like
structure, transport, and
biosynthetic functions,
site for DNA anchoring

25. What makes gm-ve bacteria more xdr than
gm +ve bacteria
• The outer membrane of Gram-negative bacteria is the main reason
for resistance to a wide range of antibiotics including β-lactams,
quinilons, colistins and other antibiotics.
• Any alteration in the outer membrane by Gram-negative bacteria like
changing the hydrophobic properties or mutations in porins and
other factors, can create resistance. Gram-positive bacteria lack this
important layer, which makes Gram-negative bacteria more resistant
to antibiotics than Gram-positive ones.

26. Enterobacterales
• Escherichia coli, Klebsiell spp.,
and Enterobacter spp.
• is the major cause of urinary
tract infections (UTIs),
• blood-stream infections,
hospital,
• and healthcare-associated
pneumonia.

27. • Resistance to
penicillins,ampicill
in,amoxicillin
Penicillinase
class A β-lactamases, like
TEM-1, TEM-2, and SHV-
1 are responsible for the
resistance to ampicillin,
amoxicillin
There are two types of CRE:
carbapenemase-producing CRE (CP-
CRE) due to AmpC β-lactamase
production
Non carbapenemase-producing CRE
(non-CP-CRE) loss of outer membrane
protein
Carbapenam
resistance
Resistance to 3rd
Generation
Cephalosporin
mutation of genes
encoding TEM-1, TEM-2, or
SHV-1 gives rise to new β-
lactamases that can
hydrolyze them.
CTX-M (CTX-Munich),
AmpC β-lactamases

29. Based on functional similarities,
substrate and inhibitory profile

30.  Class A: which regroups
penicillinases (which
hydrolyze generally only
penicillins and sometimes
early-generation
cephalosporins),
 extended-spectrum beta-
lactamases (ESBL) which
hydrolyze late-generation
cephalosporins
 class A carbapenemases
which hydrolyze
penicillins,
cephalosporins and
carbapenems
 Detected by Combination
disk test (Ceftazidime and
cetftazidime + clavulanic
acid), Three dimensional
test (best method).
 Class C:AmpC beta-
lactamases (AmpC) are
enzymes which convey
resistance to penicillins,
second and third
generation cephalosporins
and cephamycins.
 Are resistant to
combinations of these
antibiotics and substances
which are actually
intended to inhibit the
effect of beta-lactamases.
 They do not convey
resistance to fourth
generation cephalospor-
ins.
 Detected by AmpC disk
test using cefoxitin disk.
 Class D:
Oxacillinase
regroups enzyme
able to hydrolyze
cloxacillin or
oxacillin. It’s a wide
group of beta-
lactamase
(esbl)and some of
them can
hydrolyse
carbapenem .
 Susceptible to
clavulinic acid
 Class B or metallo-
beta-lactamase (MBL)
they possess active site
metallic ions whereas
group A, C and D are
serine-active enzymes.
 This group exhibits a
broad-spectrum
hydrolysis including all
beta-lactams except
aztreonam and these
enzymes are not
inhibited by
clavulanate/tazobactam
 Detected by EDTA disk
synergy test, modified
Hodge test.
Serine active beta lactamases

31. Acinetobacter baumannii.
• is associated with hospital-
acquired infections worldwide and
rapidly develops resistance to
antimicrobials.
• which can incorporate exogenous
DNA into its genome
• multidrug efflux pumps
• A. baumannii is intrinsically
resistant to several groups of
antimicrobials, including
glycopeptides, lincosamides,
macrolides, and streptogamins.

32. ; https://doi.org/10.3390/antibiotics8020037

33. Pseudomonas aeruginosa
• is a Gram-negative aerobic
bacterium
• responsible for ICU-acquired
infections in critically ill patients.
• opportunistic pathogen in
immuno-compromised patients
• can survive on dry surfaces of
hospital environments such as
respiratory equipment and
dialysis tubing.
• Intrinsically resistant to many
antibiotics like
rifampin,tetracycline,
chloamphinicole, trimethoprim
and sulphmethaoxazole

35. TREATMENT OF XDR BACTERIA
Newer antibiotics
Use of combination of
antibiotics
Novel Antibiotics
Malacidins
Bacteriophage therapy
Antimicrobial Peptides (AMPs)
Dodecyl Deoxy Glycosides
DCAP
Odilorhabdins
Probiotic Approach to Prevent
Antibiotic Resistance
Photodynamic Light Therapy
Silver Nanoparticles in Therapy
Resistance of Gram-Positive Bacteria to Current Antibacterial
Agents and Overcoming Approaches
Buthaina Jubeh, Zeinab Breijyeh, and Rafik Karaman*
Resistance of Gram-Negative Bacteria to Current
Antibacterial Agents and Approaches to Resolve It
Zeinab Breijyeh, Buthaina Jubeh, and Rafik Karaman*

36. Newer antibiotics
5th generation cephalosporins that inhibit cell wall synthesis by
binding to PBP proteins with higher affinity than other β-lactam
drugs.
• Ceftaroline is active against many Gram-positive organisms like MRSA,
VRSA, Streptococcus pyogenes, and others.
• ceftobiprole is active against Gram-positive and Gram-negative
microorganisms

37. Oxazolidinones: tedizolid phosphate is the first generation of oxazolidinones, acts
by inhibiting protein synthesis by binding to the 23S rRNA on the 50S ribosomal
subunit with greater potency and bioavailability than linezolid.
 Quinolones: act by inhibiting DNA synthesis by binding to DNA gyrase and
topoisomerase IV.
 Besifloxacin is active against Gram-positive bacteria, especially S. aureus,
Staphylococcus epidermidis, S. pneumoniae, and Haemophilus influenzae, and
Gram-negative bacteria
 delafloxacin is active against S. aureus, S. pneumoniae, and fluoroquinolone-
resistant strains except for enterococci.
ozenoxacin is active against MRSA, MSSA, MRSE, and S. pyogenes and was
approved by the FDA to treat impetigo caused by S. aureus and S. pyogenes [62].

38. Glycopeptides: are vancomycin derivatives and analogs .
 Dalbavancin inhibits cell wall synthesis and has an additional
lipophilic side chain that enhances its activity and potency against
wide-spectrum of Gram-positive organisms such as MRSA, S.
pyogenes, Streptococcus anginosus, and E. faecalis susceptible to
vancomycin.
Telavancin inhibits cell wall synthesis and is active against aerobic and
anaerobic Gram-positive bacteria.
 Oritavancin acts by inhibiting cell membranes and also inhibits RNA
synthesis. It is active against MSSA, MRSA, VRE, and VISA VRSA

39. • Omadacycline is a tetracycline analog that inhibits protein synthesis by binding
on the 30S ribosomal subunit. It is active against a wide spectrum of bacteria
such as resistant Gram-positive pathogens (MRSA, VRE, S. pneumoniae, S.
pyogenes, and Streptococcus agalactiae), Gram-negative aerobes, anaerobes,
and atypical bacteria.

40. Novel antibiotics-a new class of antibiotic which
seek and destroy resistance genes in bacteria
Teixobactin
A novel antibiotic named teixobactin produced by Eleftheria terrae, a
species of β-proteobacteria, was discovered in 2015
inhibits the synthesis of cell wall peptidoglycan by binding to highly
conserved precursors like lipid II and lipid III and found to be very active and
potent against Gram-positive bacteria including drug-resistant strains.
In vivo studies in murine models indicated that teixobactin has the potential
to be a good treatment for human MRSA infections
walkmycin B (di-anthracenone) specifically targets WalK, a histidine kinase
essential for S. aureus growth, by inhibiting WalK autophosphorylation.
 bacitracin (affect VraRS by uncoupling energy required for ATP synthesis)
on S. aureus is shown.

41. Malacidins- calcium-dependent antibiotics
In 2018,by Hover et al
Malacidins inhibit bacterial wall biosynthesis by interacting with lipid
II. Although calcium is essential for malacidins antibiosis.
 Malacidins were potently active against Gram-positive pathogens
even those are resistant to vancomycin.

42. Antimicrobial Peptides
essential part of the innate immune response in humans and other higher
organisms.
AMPs exert their microbicidal activity by increasing permeation and causing cell
lysis after targeting the cytoplasmic membrane. Most AMPs affect the
transmembrane potential and result in cell death
AMPs neutralize or disaggregate lipopolysaccharide, the main endotoxin
responsible for Gram-negative infections. Therefore, AMPs collectively protect
against sepsis.
Antimicrobial peptides are found to have antimicrobial, anti-attachment and anti-
biofilm properties, which makes them one of the agents that can treat chronic
infections effectivel.
Resistance to AMPs is relatively rare due to their attraction to the negatively
charged lipid bilayer structure of bacterial membranes +

43.  Venoms of insects and arachnids are a rich source of AMPs; many of
them have been tested for their antimicrobial activity on bacteria and
fungi . The South American social wasp Polybia paulista has a venom
with a large variety of AMPs, polybia-CP is one of them

44. Dodecyl Deoxy Glycosides -Antimicrobials that Target
Membrane Lipid Polymorphism
• Dodecyl deoxy glycosides interact with phosphatidylethanolamine
(PE) of the membrane and induce membrane disruption through
phos.

45. Odilorhabdins. are naturally produced peptides, produced by the
enzymes of the non-ribosomal peptide synthetase gene cluster of
Xenorhabdus nematophila,
ODLs represent a new class of antibiotics that is active against both
Gram-positive and Gram-negative bacteria.
ODLs are unique ribosome targeting bactericidal agents
these peptides inhibit protein synthesis by binding to the small subunit
of bacterial ribosome at a site that is not exploited by existing
antibiotics, increasing the affinity of non-cognate aminoacyl tRNAs to
the ribosome, and inducing miscoding in the translation system.

46. Antibiotic Adjuvants-they enhance the activity of the
drug or block the resistance of the bacteria toward that drug
they enhance the activity of the drug or block the resistance of the
bacteria toward that drug.
have no antibiotic activity, or very little antibiotic activity/
β-Lactamase inhibitors are the most clinically used antibiotic
adjuvants.
clavulanic acid, sulbactam, and tazobactam capable of efficient
irreversible inhibition of β-lactamase of class A

47. • LN-1-255 is a 6-alkylidene-2′-substituted penicillanic acid sulfone
synthesized by Buynak and coworkers among other compounds in a
search for new OXA β-lactamase inhibitors .
• LN-1-255 had in vitro activity against OXA, a clinically important β-
lactamase (CHDL class) found in A. baumannii that inactivates
carbapenems. LN-1-255′s efficacy of inhibition was 10-1000 folds
higher than tazobactam and avibactam.
• LN-1-255 has the potential to be a new treatment for resistant A.
baumannii strains combined with carbapenems or cephalosporins.

48. Use of antibiotic combinations

49. IDSA Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative
Infections: Version 1.0
Published by IDSA, 3/7/2022
A Focus on Extended-Spectrum β-lactamase Producing
Enterobacterales, Carbapenem-Resistant Enterobacterales, and Pseudomonas
aeruginosa with Difficult-to-Treat Resistance
Pranita D. Tamma*, Samuel L. Aitken, Robert A. Bonomo, Amy J. Mathers, David van
Duin, Cornelius J. Clancy
*Corresponding Author

50. Agent
Adult Dosage
(assuming normal renal and liver function) Target Organisms b,c
Amikacin Cystitis: 15 mg/kg/dose c IV once
All other infections: 20 mg/kg/dose d IV x 1 dose, subsequentdoses
and dosing interval based on pharmacokinetic evaluation
ESBL-E, AmpC-E, CRE, DTR-
P. Aeruginosa
Ampicillin-sulbactam 9 g IV q8h over 4 hours OR 27 g IV q24h as a continuousinfusion
For mild infections caused by CRAB isolates susceptible to ampicillin-
sulbactam, it is reasonable to administer 3g IV q4h
– particularly if intolerance or toxicities preclude the use ofhigher
dosages.
CRAB
Cefepime
Cystitis: 1 g IV q8h
All other infections: 2 g IV q8h, infused over 3 hours
AmpC-E (with cefepime
MICs ≤2 mcg/mL)
Cefiderocol
2 g IV q8h, infused over 3 hours
CRE, DTR-P. aeruginosa,
CRAB, S. maltophilia
Ceftazidime-
avibactam
2.5 g IV q8h, infused over 3 hours CRE, DTR-P. aeruginosa
Ceftazidime-
avibactam and
aztreonam
Ceftazidime-avibactam: 2.5 g IV q8h, infused over 3 hours
PLUS
Aztreonam: 2 g IV q8h, infused over 3 hours, at the sametime as
ceftazidime-avibactam
Metallo-β-lactamase-
producing CRE, S.
maltophilia

51. Agent
Adult Dosage
(assuming normal renal and liver function) Target Organisms b,c
Ceftolozane-
tazobactam
Cystitis: 1.5 g IV q8h, infused over 1 hour
All other infections: 3 g IV q8h; infused over 3 hours
DTR-P. aeruginosa
Ciprofloxacin
ESBL-E or AmpC infections: 400 mg IV q8h-q12h OR 500 –750 mg PO
q12h
DTR-P. aeruginosa, pneumonia: 400 mg IV q8h OR 750 mgPO q12h
ESBL-E, AmpC-E
Colistin Refer to international consensus guidelines on polymyxins e CRE cystitis, DTR-P.
aeruginosa cystitis, CRAB
cystitis
Eravacycline 1 mg/kg/dose IV q12h CRE, CRAB, S. maltophilia
Ertapenem 1 g IV q24h, infused over 30 minutes ESBL-E, AmpC-E

52. Agent
Adult Dosage
(assuming normal renal and liver function) Target Organisms b,c
Fosfomycin
Cystitis: 3 g PO x 1 dose ESBL-E. coli cystitis
Gentamicin
Cystitis: 5 mg/kg/dose c IV once
All other infections: 7 mg/kg/dose d IV x 1 dose, subsequentdoses
and dosing interval based on pharmacokinetic evaluation
ESBL-E, AmpC-E, CRE, DTR-
P. Aeruginosa
Imipenem-cilastatin Cystitis (standard infusion): 500 mg IV q6h, infused over 30
minutes
All other infections (extended-infusion): 500 mg IV q6h;infused
over 3 hours
ESBL-E, AmpC-E, CRE, CRAB
Imipenem-cilastatin-
relebactam
1.25 g IV q6h, infused over 30 minutes CRE, DTR-P. aeruginosa
Levofloxacin
750 mg IV/PO q24h ESBL-E, AmpC-E, S.
Maltophilia
Meropenem Cystitis (standard infusion): 1 g IV q8h
All other ESBL-E or AmpC-E infections: 1-2 g IV q8h, can
consider a 3-hour infusion
All other CRE and CRAB infections: 2 g IV q8h, infused over 3
hours
ESBL-E, AmpC-E, CRE, CRAB

53. Agent
Adult Dosage
(assuming normal renal and liver function) Target Organisms b,c
Meropenem-
vaborbactam
4 g IV q8h, infused over 3 hours CRE
Minocycline 200 mg IV/PO q12h CRAB, S. maltophilia
Nitrofurantoin
Cystitis: Macrocrystal/monohydrate (Macrobid®) 100 mg PO
q12h
Cystitis: Oral suspension: 50 mg q6h
ESBL-E cystitis, AmpC-E
cystitis
Plazomicin Cystitis: 15 mg/kg d IV x 1 dose
All other infections: 15 mg/kg c IV x 1 dose, subsequent dosesand
dosing interval based on pharmacokinetic evaluation
ESBL-E, AmpC-E, CRE, DTR-
P. aeruginosa
Polymyxin B Refer to international consensus guidelines on polymyxins e DTR-P. aeruginosa, CRAB
Tigecycline 200 mg IV x 1 dose, then 100 mg IV q12h CRE, CRAB, S. maltophilia

54. Agent
Adult Dosage
(assuming normal renal and liver function) Target Organisms b,c
Tobramycin Cystitis: 5 mg/kg/dose d IV x 1 dose
All other infections: 7 mg/kg/dose d IV x 1 dose; subsequent
doses and dosing interval based on pharmacokinetic evaluation
ESBL-E, AmpC-E, CRE, DTR-
P. aeruginosa
Trimethoprim-
sulfamethoxazole
Cystitis: 160 mg (trimethoprim component) IV/PO q12h
Other infections: 8-12 mg/kg/day (trimethoprim component)
IV/PO divided q8-12h (consider maximum dose of 960 mg
trimethoprim component per day)
ESBL-E, AmpC-E, S.
maltophilia

55. • AmpC-E: ApmC β-lactamase-producing Enterobacterales;
• CRAB: Carbapenem-resistant Acinetobacter baumannii;
• CRE: Carbapenem-resistant Enterobacterales;
• DTR-P. aeruginosa: Pseudomonas aeruginosa with difficult-to-treat resistance;
• E. coli: Escherichia coli;
• ESBL-E: Extended-spectrum β-lactamase-producing Enterobacterales; IV: Intravenous;
• MIC: Minimum inhibitory concentration;
• PO: By mouth; q4h: Every 4 hours; q6h: Every 6 hours;
• q8h: Every 8 hours; q12h: Every 12 hours; q24h: Every 24 hours;
• S. maltophilia: Stenotrophomonas maltophilia
• For additional guidance on the treatment of ESBL-E, CRE, and DTR-P. aeruginosa, refer to:
https://www.idsociety.org/practice-guideline/amr-guidance/.

57. Polymyxin B-based two- or three-drug combinations were the commonest iACT-guided therapy prescribed
(33/39, 84.6%).
Nebulized colistin was initiated in all patients with pneumonia who were prescribed intravenous polymyxin B
(16/39, 41.0%).
The most common combination recommended against A. baumannii infections were polymyxin B plus a
carbapenem (7/13, 53.8%).
Against the P. aeruginosa isolates, polymyxin B plus carbapenem plus aminoglycosides were most commonly
recommended (5/20, 25.0%).
Antibiotic combination regimens recommended for K. pneumoniae infections were highly strain-specific; no
single regimen was universally effective against all K. pneumoniae strains.

58. "Novel Antibiotic Combinations of Diverse Subclasses for Effective Suppression of Extensively Drug-
Resistant Methicillin-Resistant Staphylococcus aureus (MRSA)", International Journal of
Microbiology, vol. 2020, Article ID 8831322,
Shumyila Nasir, Muhammad Sufyan Vohra, Danish Gul, Umm E Swaiba, Maira Aleem, Khalid Mehmood,
Saadia Andleeb,
 Our findings on pairwise combinations suggest that
fluoroquinolones (especially levofloxacin and
moxifloxacin) are very effective when combined with
cephalosporin and carbapenem antibiotics.
 We report that a novel combination of levofloxacin-
ceftazidime (LVX/CAZ) acts synergistically to produce
bactericidal effect on XDR MRSA isolate LR-2.
Previously, fluoroquinolone-cephalosporin
combination was shown to have synergistic effect
against P. aeruginosa

59. O1121 The MERINO Trial: piperacillin-tazobactam versus meropenem
for the definitive treatment of bloodstream infections caused by
third-generation cephalosporin nonsusceptible Escherichia coli or
Klebsiella spp.: an international multi-centre openlabel non-
inferiority randomised controlled trial
 Conclusions and relevance: Among patients with E coli or K pneumoniae bloodstream infection and
ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did
not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in
this setting.

60. Diazabicyclooctanes (DBOs)
• are efficient β-lactamase inhibitors that are very potent against class
A and class C β-lactamases.
• DBOs have a five-membered ring with an amide group that targets
the serine of the active site of the β-lactamase and forms a carbamoyl
adduct.
• Avibactam (NXL104)is a semi-synthetic compound approved by the
FDA in 2014 as a combination therapy with ceftazidime to treat
complicated intra-abdominal and complicated urinary tract infections.
Avibactam has excellent inhibitory activity against Ambler class A,
class C, and some class D β-lactamases,

61. Probiotic
• Concomitant use of probiotics with antibiotics reduces the incidence,
duration and/or severity of antibiotic-associated diarrhea, which
contributes to better adherence to the antibiotic prescription and
consequently reduces the evolution of resistance.
• Lactobacillus casei from Argentina has been reported to increase
phagocyte activity and secretory immunoglobulin A(IgA)

62. Bacteriophage Therapy
• Bacteriophages are self-amplifying, they kill bacteria by penetrating
bacterial cells and disrupting many or all bacterial processes.
• At the same time, they are unable to penetrate eukaryotic cells, a
fact that led to the safety of bacteriophages for human use.
• Bacteriophages are especially effective for the eradication of bacterial
biofilms
• they penetrate into biofilms by exploiting water channels within the
biofilm, disrupt the extracellular biofilm matrix by expression of
depolymerases.

63. Prevention of resistance
In HOSPITALS
 Establish infection control programmes, based on current best practice, with the responsibility for
effective management of antimicrobial resistance in hospitals and ensure that all hospitals have access
to such a programme.
 Establish effective hospital therapeutics committees with the responsibility for overseeing
antimicrobial use in hospitals.
 Develop and regularly update guidelines for antimicrobial treatment and prophylaxis, and hospital
antimicrobial formularies.
 Monitor antimicrobial usage, including the quantity and patterns of use, and feedback results to
prescribers.
 Ensure access to microbiology laboratory services that match the level of the hospital, e.g. secondary,
tertiary.
 Ensure performance and quality assurance of appropriate diagnostic tests, microbial identification,
antimicrobial susceptibility tests of key pathogens, and timely and relevant reporting of results.
 Ensure that laboratory data are recorded, preferably on a database, and are used to produce clinically-
and epidemiologically-useful surveillance reports of resistance patterns among common pathogens
and infections in a timely manner with feedback to prescribers and to the infection control programme.
 Control and monitor pharmaceutical company promotional activities within the hospital environment
and ensure that such activities have educational benefit.
http://www.who.int/emc

64. Approach in our hospital for xdr

65. Thank you

66. Antibiotics tested in our hospital

68. National and International Approaches and
Commitment
• Global action is needed to face the danger of antibiotic resistance. Several strategies should be applied globally to combat
bacterial resistance.
 These strategies include surveillance of antibiotics to detect resistance in humans and animals,
 cautious use of antibiotics,
 decontamination or isolation of patients with resistant pathogens,
 improved antibiotic stewardship in healthcare facilities and community,
 restricted antibiotic advertising,
 good healthcare infrastructure,
 development of health insurance policies, development of diagnostic tools for prudent antibiotic prescription,
 and consistent disease control strategies
 One successful example on how national strategies affect resistance emergence is when the United Kingdom has implemented
mandatory MRSA surveillance in 2001, the result was a significant reduction in MRSA bacteremia in hospitals in the UK .
 Another good example is the efforts of the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS) of
the United States. which is a national public health surveillance system that tracks changes in the antimicrobial susceptibility of
certain enteric bacteria found in ill people, retail meats, and food animals in the United States.