Lec no 206 MDROs Dr Mohamad Hasan.pdf d d s. D. S s
MuhammadShayan99
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Aug 29, 2025
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About This Presentation
She. Ff d f. D f f f d. D d d d. D f d f e. F d. F. D. F d f d. F d. F e f. D f g ww. E w. S x. C. C z c. Xx. X. Cc c d. R. T r. R t.
Slide Content
ميحرلا نمحرلا الله مسب
MDROS ON A HOT TIN
Mohamed Hassan
Lecturer of pulmonary medicine
ZUH
November,2024
Mohamed Hassan
Lecturer of pulmonary medicine
ZUH
November,2024
AGENDA
Introduction
Mechanisms of bacterial resistance
Bacterial resistance detection
Classification bacterial resistance
Egyptian guidelines for MDRO
Top 10 golden rules for antibiotics use
Alternative to antibiotics
Take home message.
Introduction
Mechanisms of bacterial resistance
Bacterial resistance detection
Classification bacterial resistance
Egyptian guidelines for MDRO
Top 10 golden rules for antibiotics use
Alternative to antibiotics
Take home message.
Introduction
AMR (antibiotic multidrug resistance) is a serious public health problem, causing at least 1.27
million deaths worldwide annually and reportedly linked to more than 5 million deaths in
2019. In addition, it was reported that infections caused by 2.8 million resistant
microorganisms are seen in the U.S.A. every year.
In the Antibiotic Resistance Threat Report published in 2019, it was stated that more than
35,000 deaths were associated with AMR. In addition, in the U.S.A., it was stated that the
deaths reached 48,000, with the addition of deaths due to Clostridium difficile diarrhea
associated with antibiotic use.
Globally, it is estimated that AMR-related deaths exceeded 1.2 million in 2019, and if
adequate measures are not taken, AMR might cause approximately 10 million deaths per
year by 2050
AMR (antibiotic multidrug resistance) is a serious public health problem, causing at least 1.27
million deaths worldwide annually and reportedly linked to more than 5 million deaths in
2019. In addition, it was reported that infections caused by 2.8 million resistant
microorganisms are seen in the U.S.A. every year.
In the Antibiotic Resistance Threat Report published in 2019, it was stated that more than
35,000 deaths were associated with AMR. In addition, in the U.S.A., it was stated that the
deaths reached 48,000, with the addition of deaths due to Clostridium difficile diarrhea
associated with antibiotic use.
Globally, it is estimated that AMR-related deaths exceeded 1.2 million in 2019, and if
adequate measures are not taken, AMR might cause approximately 10 million deaths per
year by 2050
•The World Bank estimates that AMR could result in
US$ 1 trillion additional healthcare costs by 2050, and
US$ 1 trillion to US$ 3.4 trillion gross domestic product
(GDP) losses per year by 2030
.
•There is increasing evidence that the pandemic accelerated the
emergence and spread of AMR at least in hospital settings
particularly Acientobacter spp. Langford et al. reported that
more than 60% of patients with COVID-19 who had a
bacterial infection harbored a highly resistant organism
US$ 1 trillion additional healthcare costs by 2050, and
US$ 1 trillion to US$ 3.4 trillion gross domestic product
(GDP) losses per year by 2030
.
•There is increasing evidence that the pandemic accelerated the
emergence and spread of AMR at least in hospital settings
particularly Acientobacter spp. Langford et al. reported that
more than 60% of patients with COVID-19 who had a
bacterial infection harbored a highly resistant organism
History of antibiotic
discovery and resistance
discovery and resistance
Median reported rates in 76 countries of 42% for third-
generation cephalosporin-resistant E. coli
and 35% for methicillin-resistant Staphylococcus
aureus are a major concern.
For urinary tract infections caused by E. coli, 1 in 5
cases exhibited reduced susceptibility to standard
antibiotics like ampicillin, co-trimoxazole, and
fluoroquinolones in 2020.
generation cephalosporin-resistant E. coli
and 35% for methicillin-resistant Staphylococcus
aureus are a major concern.
For urinary tract infections caused by E. coli, 1 in 5
cases exhibited reduced susceptibility to standard
antibiotics like ampicillin, co-trimoxazole, and
fluoroquinolones in 2020.
The Antimicrobial Consumption Data in
Egypt
Penicillins make up the majority of Egypt's antimicrobial
consumption;
products containing a combination of penicillins and beta-
lactamase inhibitors make up 29.3% of the antibacterials
used,
while macrolides make up 23.93%.
Egypt
Penicillins make up the majority of Egypt's antimicrobial
consumption;
products containing a combination of penicillins and beta-
lactamase inhibitors make up 29.3% of the antibacterials
used,
while macrolides make up 23.93%.
What are the mechanisms of bacterial
resistance?
resistance?
Mechanism of resistance
Peptidoglycan
Outer membrane
Cell membrane
Gram positive
Antibiotic diffuse directly
through cell membrane``
Gram negative
ABx
ABx
Antibiotic diffuse through porins
because of thick outer membrane
Peptidoglycan
Outer membrane
Cell membrane
Gram positive
Antibiotic diffuse directly
through cell membrane``
Gram negative
ABx
ABx
Antibiotic diffuse through porins
because of thick outer membrane
Mechanism of resistance
Intrinsically resistance
independent to
previous Abx exposure
Acquired resistance
achieved through transfer
of genetic material that
confers resistance
Intrinsically resistance
independent to
previous Abx exposure
Acquired resistance
achieved through transfer
of genetic material that
confers resistance
Mechanism of resistance
Peptidoglycan
Outer membrane
Cell membrane
Gram positive Gram negative
Vancomycin is large molecule
cannot diffuse though the porin
Gram –ve is intrinsically resistant to
vancomycin
Vancomycin can diffuse through
cell wall of gram +ve
Vanc
o
Vanc
o vanco
Peptidoglycan
Outer membrane
Cell membrane
Gram positive Gram negative
Vancomycin is large molecule
cannot diffuse though the porin
Gram –ve is intrinsically resistant to
vancomycin
Vancomycin can diffuse through
cell wall of gram +ve
Vanc
o
Vanc
o vanco
ABx
Mechanism of resistance
Porin channel
Target site
1. Loss of porin
ABx
2.Change binding site
3.Efflux pump
4.Enzymatic modification
e.g. B-lactamases
Mechanism of resistance
Porin channel
Target site
1. Loss of porin
ABx
2.Change binding site
3.Efflux pump
4.Enzymatic modification
e.g. B-lactamases
•The observed sensitivity may depend on the number of
bacteria initially inoculated into the assay
•For colony count 10^5 the MIC may be < 4 however, when the
colony count increased to 10^7 the MIC > 128
Piperacillin-tazobactam and cefepime may be
subjected to inoculum effect
Inoculum effect
bacteria initially inoculated into the assay
•For colony count 10^5 the MIC may be < 4 however, when the
colony count increased to 10^7 the MIC > 128
Piperacillin-tazobactam and cefepime may be
subjected to inoculum effect
Inoculum effect
Heteroresistance
Presence of subpopulations of bacterial cells with higher levels of antibiotic resistance than
those of the rest of the population in the same culture.
The resistance phenotype is often unstable, it can rapidly return to susceptibility.
Its clinical relationship may be considerable, since more resistant subpopulations may be
selected during antibiotic therapy.
Presence of subpopulations of bacterial cells with higher levels of antibiotic resistance than
those of the rest of the population in the same culture.
The resistance phenotype is often unstable, it can rapidly return to susceptibility.
Its clinical relationship may be considerable, since more resistant subpopulations may be
selected during antibiotic therapy.
The use of nonstandard methods to define heteroresistance, which are costly and involve
considerable labor and resources, precludes evaluating the clinical magnitude and severity of
this phenomenon .
Since heteroresistance may have serious implications in antibiotic therapy, the development
of standardized criteria and protocols for detecting and measuring heteroresistance is essential.
considerable labor and resources, precludes evaluating the clinical magnitude and severity of
this phenomenon .
Since heteroresistance may have serious implications in antibiotic therapy, the development
of standardized criteria and protocols for detecting and measuring heteroresistance is essential.
Antibiotic and microbiome
Antibiotic use can have unintended consequences on
commensal intestinal microbiota dysbiosis.
Whereas susceptible bacteria are destroyed, the resultant
ecologic vacuum promotes the overgrowth of pathogenic
bacteria that may already be antibiotic-resistant
Antibiotic use can have unintended consequences on
commensal intestinal microbiota dysbiosis.
Whereas susceptible bacteria are destroyed, the resultant
ecologic vacuum promotes the overgrowth of pathogenic
bacteria that may already be antibiotic-resistant
Comparison of detection methods
of pneumonia pathogens
of pneumonia pathogens
Risk factors of antibiotic resistance
Prediction the
risk of P.
aeruginosa
infection in
elderly CAP
patients
risk of P.
aeruginosa
infection in
elderly CAP
patients
Risk factors for carbapenem-resistant
Klebsiella ... Giannella Score
Klebsiella ... Giannella Score
EAT & TAT
Empiric antibiotic therapy is prescribed to treat known or suspected infections based on the
patient's symptoms and likely causative pathogens before definitive diagnostic test
results, including antibiotic susceptibility testing, are available.
Targeted antibiotic therapy is initiated based on microbial identification and
susceptibility test results to identify the specific pathogen and ensure that the most effective
(ideally, also the most cost-effective), least toxic, and narrowest spectrum antibiotic is used as
therapy.
Empiric antibiotic therapy is prescribed to treat known or suspected infections based on the
patient's symptoms and likely causative pathogens before definitive diagnostic test
results, including antibiotic susceptibility testing, are available.
Targeted antibiotic therapy is initiated based on microbial identification and
susceptibility test results to identify the specific pathogen and ensure that the most effective
(ideally, also the most cost-effective), least toxic, and narrowest spectrum antibiotic is used as
therapy.
Bacterial resistance detection
Culture-based PCR-based
How can we detect the bacterial
resistance?
Culture-based PCR-based
How can we detect the bacterial
resistance?
Methods of detection of
antiobiotic resistance
antiobiotic resistance
Conventional Cultures
Coupled with antimicrobial susceptibility testing, this traditional aetiologic diagnostic
approach requires approximately 48 h to 72 h from sample acquisition to result delivery
Culture methods may fail to detect important pathogens due to the administration of
empirical antibiotics or strict growth requirements.
It may be difficult to distinguish whether the detected organisms are colonisers or actual
pathogens
Coupled with antimicrobial susceptibility testing, this traditional aetiologic diagnostic
approach requires approximately 48 h to 72 h from sample acquisition to result delivery
Culture methods may fail to detect important pathogens due to the administration of
empirical antibiotics or strict growth requirements.
It may be difficult to distinguish whether the detected organisms are colonisers or actual
pathogens
MIC & MBC
In order to obtain a therapeutic effect, the concentration at the site of infection
should exceed the MIC against the target bacteria for :
at least 40% of the dosing interval, and ideally longer (if killing is time-dependent)
or by > ten folds (if killing is concentration-dependent)
In order to obtain a therapeutic effect, the concentration at the site of infection
should exceed the MIC against the target bacteria for :
at least 40% of the dosing interval, and ideally longer (if killing is time-dependent)
or by > ten folds (if killing is concentration-dependent)
Bacterial resistance detection
Culture-based
Disc diffusion
E test
Antibiotic A
Antibiotic B
Antibiotic C
Resistant
Intermediate
Sensitive
Antibiotic A sensitive MIC=1 mg/L
Culture-based
Disc diffusion
E test
Antibiotic A
Antibiotic B
Antibiotic C
Resistant
Intermediate
Sensitive
Antibiotic A sensitive MIC=1 mg/L
Bacterial resistance detection
Culture-based
Vancomycin
disc
diffusion
Vancomycin Vancomycin
Sensitive Sensitive MIC=1 mg/L
Patient A Patient B
Vancomycin
E test
Vancomycin Vancomycin
Sensitive Sensitive
Patient A Patient B
MIC=1.5 mg/L
Vancomycin can be used
Vancomycin can be
used
Vancomycin is better to
be avoided if
MIC≥1.5
Culture-based
Vancomycin
disc
diffusion
Vancomycin Vancomycin
Sensitive Sensitive MIC=1 mg/L
Patient A Patient B
Vancomycin
E test
Vancomycin Vancomycin
Sensitive Sensitive
Patient A Patient B
MIC=1.5 mg/L
Vancomycin can be used
Vancomycin can be
used
Vancomycin is better to
be avoided if
MIC≥1.5
Matrix-assisted laser desorption/ionization time-
of-flight mass spectrometry.
MALDI-TOF-MS provides microorganism identification, subtyping and antibiotic
susceptibility testing.
It is able to identify a large number of targets simultaneously and has been used to
reduce the time needed for microbial identification and strain typing
MALDI-TOF-MS is a protein/peptide-based diagnostic method that relies on the
molecular mass of all cellular proteins to determine the characteristic profile of the
pathogen
of-flight mass spectrometry.
MALDI-TOF-MS provides microorganism identification, subtyping and antibiotic
susceptibility testing.
It is able to identify a large number of targets simultaneously and has been used to
reduce the time needed for microbial identification and strain typing
MALDI-TOF-MS is a protein/peptide-based diagnostic method that relies on the
molecular mass of all cellular proteins to determine the characteristic profile of the
pathogen
MALDI-TOF-MS
It requires only six minutes to identify each isolate
It can only use isolates from cultures; despite the initial cost to acquire the
equipment, it has been reported to be cost-effective
Although it allows for quick identification of the species involved (with rare exceptions
of poor discrimination or misidentifications between species with inherent
similarities), this is not always the case for the antibiotic susceptibility results.
It requires only six minutes to identify each isolate
It can only use isolates from cultures; despite the initial cost to acquire the
equipment, it has been reported to be cost-effective
Although it allows for quick identification of the species involved (with rare exceptions
of poor discrimination or misidentifications between species with inherent
similarities), this is not always the case for the antibiotic susceptibility results.
Syndromic Rapid
Multi-Pathogen PCR
Panels
Multi-Pathogen PCR
Panels
Bacterial resistance detection
PCR-based
Type of pathogen Resistant gene
Guide antimicrobial therapy
PCR-based
Type of pathogen Resistant gene
Guide antimicrobial therapy
Applied directly to raw clinical samples, surpass the
stage of pathogen culturing and, therefore, expedite even
further, the time required for microbiological diagnosis
early administration of appropriate treatment or the
early switch from broad-spectrum empirical to
targeted antimicrobial
however, that the sensitivity of the current rapid test
bears the risk of leading to overuse of antibiotics.
stage of pathogen culturing and, therefore, expedite even
further, the time required for microbiological diagnosis
early administration of appropriate treatment or the
early switch from broad-spectrum empirical to
targeted antimicrobial
however, that the sensitivity of the current rapid test
bears the risk of leading to overuse of antibiotics.
BioFire
®
FilmArray
®
Pneumonia Panel (BPP) (FDA)-cleared syndromic rm-PCR that
simultaneously identifies 33 targets:
15 typical and 3 atypical bacterial pathogens, 8 respiratory viruses and
7 genetic markers of antimicrobial resistance in BAL/mini-BAL, tracheal aspirates and
expectorated sputum specimens
This assay requires two-minutes hands-on time and about one hour turn-around time,
therefore operating as a point-of-care test for rapid detection of NP pathogens
®
FilmArray
®
Pneumonia Panel (BPP) (FDA)-cleared syndromic rm-PCR that
simultaneously identifies 33 targets:
15 typical and 3 atypical bacterial pathogens, 8 respiratory viruses and
7 genetic markers of antimicrobial resistance in BAL/mini-BAL, tracheal aspirates and
expectorated sputum specimens
This assay requires two-minutes hands-on time and about one hour turn-around time,
therefore operating as a point-of-care test for rapid detection of NP pathogens
BioFire® FilmArray® Pneumonia Panel
plus
manufactured by the same company France , identifies the same targets along with
MERS-CoV virus
both panels provide semi-quantitative results for the 15 typical bacterial targets which
helps in the differentiation between colonisers and actual pathogens
BPP has an overall sensitivity of 96.2% and 96.3% and a specificity of 98.3% and
97.2% in BAL and sputum samples, respectively
It should be noted that the falsely positive samples for BPP, could be attributed to
negative cultures due to the administration of antibiotics therefore
plus
manufactured by the same company France , identifies the same targets along with
MERS-CoV virus
both panels provide semi-quantitative results for the 15 typical bacterial targets which
helps in the differentiation between colonisers and actual pathogens
BPP has an overall sensitivity of 96.2% and 96.3% and a specificity of 98.3% and
97.2% in BAL and sputum samples, respectively
It should be noted that the falsely positive samples for BPP, could be attributed to
negative cultures due to the administration of antibiotics therefore
Curetis Unyvero multiplex PCR
Panels, Germany
The Unyvero P55 Pneumonia panel, capable of
identifying 20 causative agents of lower respiratory
tract infections and 19 antibiotic resistance
determinants, was compared to routine
microbiological culture and antimicrobial resistance
diagnostics,
compared to BPP, Unyvero P55 assay was found to have
a lower sensitivity (63.8–88.8% vs. 98.5%) and take
longer for the sample-to-result time (5 h vs. 1 h)
Panels, Germany
The Unyvero P55 Pneumonia panel, capable of
identifying 20 causative agents of lower respiratory
tract infections and 19 antibiotic resistance
determinants, was compared to routine
microbiological culture and antimicrobial resistance
diagnostics,
compared to BPP, Unyvero P55 assay was found to have
a lower sensitivity (63.8–88.8% vs. 98.5%) and take
longer for the sample-to-result time (5 h vs. 1 h)
Similarly, the RespiFinder
®
SMART 22
(PathoFinder
®
, Maastricht, Limburg, The
Netherlands) and VERIGENE
®
Respiratory
Pathogens Flex Test (Luminex
®
, Austin, Texas, USA)
detect only viral and atypical pathogens
®
SMART 22
(PathoFinder
®
, Maastricht, Limburg, The
Netherlands) and VERIGENE
®
Respiratory
Pathogens Flex Test (Luminex
®
, Austin, Texas, USA)
detect only viral and atypical pathogens
GeneXpert®, USA
It helps identify mechanisms of resistance and is capable of delivering most test results
in one hour, including sample preparation time, faster than alternative technologies
such as enzyme immunoassays
Using advanced microfluidics, the process of nucleic acid extraction, amplification and
detection is performed within each single-use cartridge, minimising the risk of cross
contamination
It helps identify mechanisms of resistance and is capable of delivering most test results
in one hour, including sample preparation time, faster than alternative technologies
such as enzyme immunoassays
Using advanced microfluidics, the process of nucleic acid extraction, amplification and
detection is performed within each single-use cartridge, minimising the risk of cross
contamination
The GeneXpert CarbaR is capable of detecting carbapenem resistance genes (K.
pneumoniae carbapenemase (KPC), oxacillinase-type carbapenemase (OXA-48, OXA-181,
OXA-232),
and metallo-beta-lactamases (MBLs) which include imipenemase MBL-1 (IMP), New
Delhi MBL (NDM) and Verona integron-encoded MBL(VIM)) within 48 min
The diagnostic performance of the GeneXpert CarbaR was evaluated using 408 rectal swabs
and found to have 100% sensitivity, 96.7% specificity, a positive predictive value of
53.6% and a negative predictive value of 100%
pneumoniae carbapenemase (KPC), oxacillinase-type carbapenemase (OXA-48, OXA-181,
OXA-232),
and metallo-beta-lactamases (MBLs) which include imipenemase MBL-1 (IMP), New
Delhi MBL (NDM) and Verona integron-encoded MBL(VIM)) within 48 min
The diagnostic performance of the GeneXpert CarbaR was evaluated using 408 rectal swabs
and found to have 100% sensitivity, 96.7% specificity, a positive predictive value of
53.6% and a negative predictive value of 100%
Hence, its use is limited by the narrow panel of detected genes and should be guided
by the local epidemiology of antimicrobial resistance profiles;
The performance and clinical utility of the GeneXpert CarbaR could be augmented by
the inclusion of more genes (e.g., OXA-23) and alleles of certain gene families (e.g.,
OXA-181)
by the local epidemiology of antimicrobial resistance profiles;
The performance and clinical utility of the GeneXpert CarbaR could be augmented by
the inclusion of more genes (e.g., OXA-23) and alleles of certain gene families (e.g.,
OXA-181)
Advantages of multiplex PCR
panels.
Exceptionally faster time to results for pathogen and resistance profiles: major utility for
prompt treatment modification and effective patient management
Multiple targets detection at the same and Detection of viral and atypical pathogens
as well
Detection of pathogens even when antimicrobial treatment has been initiated
Potential for better antibiotic utilisation and positive impact on:
-nosocomial pneumonia management, shortening hospital stay and decreasing healthcare
costs,-antibiotic stewardship programs
Early identification of MDR pathogens should facilitate enhanced infection control
practices and reduce spread
panels.
Exceptionally faster time to results for pathogen and resistance profiles: major utility for
prompt treatment modification and effective patient management
Multiple targets detection at the same and Detection of viral and atypical pathogens
as well
Detection of pathogens even when antimicrobial treatment has been initiated
Potential for better antibiotic utilisation and positive impact on:
-nosocomial pneumonia management, shortening hospital stay and decreasing healthcare
costs,-antibiotic stewardship programs
Early identification of MDR pathogens should facilitate enhanced infection control
practices and reduce spread
disadvantages of multiplex PCR
panels
Over-detection of microbial and viral genome: problem in results interpretation:
pathogen or coloniser?
The presence of a resistance gene marker may not be linked to the detected
microorganism, but to other co-existent organisms either undetectable or below the
detection limit
Initial cost to buy the equipment
Not widely available among different institutions yet
panels
Over-detection of microbial and viral genome: problem in results interpretation:
pathogen or coloniser?
The presence of a resistance gene marker may not be linked to the detected
microorganism, but to other co-existent organisms either undetectable or below the
detection limit
Initial cost to buy the equipment
Not widely available among different institutions yet
culture-based techniques
still necessary in many
cases
still necessary in many
cases
ELECTRONIC NOSE
-VOCS
-VOCS
an artificial sensor system consisting of a range of chemical
sensors that resemble biological olfactory receptors to detect
VOCs
VOCs attach to the sensor polymer surface and induce swelling of
the polymer film, increasing the electrical resistance and
generating an electrical signal.
These signals can be classified into VOC signatures using
algorithms and a database of previously recorded VOC patterns.
sensors that resemble biological olfactory receptors to detect
VOCs
VOCs attach to the sensor polymer surface and induce swelling of
the polymer film, increasing the electrical resistance and
generating an electrical signal.
These signals can be classified into VOC signatures using
algorithms and a database of previously recorded VOC patterns.
Oxidative stress and inflammation, as well as invading microorganisms produce
specific compounds, which can induce alterations in the compositions of VOCs, leading
to distinct VOC profiles in exhaled breath.
Exhaled breath samples were collected from ventilated patients directly before BAL was
performed, which were measured by gas chromatography-time -of-flight-mass
spectrometry (GC-tof-MS). This resulted in a set of 12 chemically diverse VOCs which
have the potential to determine the presence of VAP with sensitivity of 75.8% and
specificity of 73.0%
Although GC-tof-MS, the current gold standard, is a highly sensitive method to
accurately measure trace gases in exhaled air, it is time-consuming and carries a risk of
contamination, limiting its use as a point-of-care testing technology for VOC
specific compounds, which can induce alterations in the compositions of VOCs, leading
to distinct VOC profiles in exhaled breath.
Exhaled breath samples were collected from ventilated patients directly before BAL was
performed, which were measured by gas chromatography-time -of-flight-mass
spectrometry (GC-tof-MS). This resulted in a set of 12 chemically diverse VOCs which
have the potential to determine the presence of VAP with sensitivity of 75.8% and
specificity of 73.0%
Although GC-tof-MS, the current gold standard, is a highly sensitive method to
accurately measure trace gases in exhaled air, it is time-consuming and carries a risk of
contamination, limiting its use as a point-of-care testing technology for VOC
Class A
Serine-beta-lactamase
Class C
Cephalosporinases
Class D
Oxacillinase
Beta-lactamases (Ambler classification)
Penicillinases
TEM and SHV
ESBL
CTX-M
Cabapenemases
KPC
Class B
Metallo-beta-lactamase
Cabapenemases
VIM, IMP, NDM
Cephalosporinases
AmpC
Cabapenemases
OXA-48
Serine-beta-lactamase
Class C
Cephalosporinases
Class D
Oxacillinase
Beta-lactamases (Ambler classification)
Penicillinases
TEM and SHV
ESBL
CTX-M
Cabapenemases
KPC
Class B
Metallo-beta-lactamase
Cabapenemases
VIM, IMP, NDM
Cephalosporinases
AmpC
Cabapenemases
OXA-48
Carbapenemases/ β-Lactamases
Serine- β-Lactamases Metallo- β-Lactamases
Class A: KPC, IMI, SME, CTX-M
Class C: AmpC, ACT, CMY, DHA
Class D: OXA-48
Class B: NDM, VIM, IMP
Serine- β-Lactamases Metallo- β-Lactamases
Class A: KPC, IMI, SME, CTX-M
Class C: AmpC, ACT, CMY, DHA
Class D: OXA-48
Class B: NDM, VIM, IMP
Bacterial resistance detection
PCR-based
Klebsiella CTX-M
Type of pathogen Resistant gene
Avoid cephalosporin
and use carbapenem
PCR-based
Klebsiella CTX-M
Type of pathogen Resistant gene
Avoid cephalosporin
and use carbapenem
Multi-resistant Gram-negative
bacilli
In 2008, the “ESKAPE” acronym was coined to name those bacteria that may
“escape” the effects of antibiotics including Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii-
calcoaceticus complex, Pseudomonas aeruginosa, and Enterobacter spp.
The list of AMR bacteria is no longer up-to-date,
as Escherichia coli,
Mycobacterium tuberculosis and
Neisseria gonorrhoeae
are currently among the most prevalent bacterial pathogens affected by
AMR issues.
bacilli
In 2008, the “ESKAPE” acronym was coined to name those bacteria that may
“escape” the effects of antibiotics including Enterococcus faecium,
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii-
calcoaceticus complex, Pseudomonas aeruginosa, and Enterobacter spp.
The list of AMR bacteria is no longer up-to-date,
as Escherichia coli,
Mycobacterium tuberculosis and
Neisseria gonorrhoeae
are currently among the most prevalent bacterial pathogens affected by
AMR issues.
Gram –ve
pathogens
Enterbacterals
Enterobacteriacae
Pseudomonas
aeruginosa
Acinetobacter
baumanii
•Klebsiella
•Ecoli
•Enterobacter
•Citrobacter
•Proteus
•Serratia
pathogens
Enterbacterals
Enterobacteriacae
Pseudomonas
aeruginosa
Acinetobacter
baumanii
•Klebsiella
•Ecoli
•Enterobacter
•Citrobacter
•Proteus
•Serratia
Gram –ve pathogen
Enterbacterals
Enterobacteriacae
Pseudomonas
aeruginosa
Acinetobacter
baumanii
Sensitive to carbapenem
and resistant to 3
rd gen
cephalosporin
Resistant to carbapenem
3
rd generation cephalosporin
resistant enterobacteriacae
(3GCephRE)
Carbapenem-resistant
enterobacteriacae
(CRE)
Resistant to carbapenem
Carbapenem-resistant
Pseudomonas aeruginosa
(CRPA)
Carbapenem-resistant
Acinetobacter Baumanii
(CRAB)
Resistant to carbapenem
Enterbacterals
Enterobacteriacae
Pseudomonas
aeruginosa
Acinetobacter
baumanii
Sensitive to carbapenem
and resistant to 3
rd gen
cephalosporin
Resistant to carbapenem
3
rd generation cephalosporin
resistant enterobacteriacae
(3GCephRE)
Carbapenem-resistant
enterobacteriacae
(CRE)
Resistant to carbapenem
Carbapenem-resistant
Pseudomonas aeruginosa
(CRPA)
Carbapenem-resistant
Acinetobacter Baumanii
(CRAB)
Resistant to carbapenem
ESBLE & MBL & difficult-to-treat
Extended-spectrum beta-lactamases (ESBL)– transferable resistance to 3rd and 4th
generation cephalosporins, mostly found in E. coli, Klebsiella and Enterobacter species.
Metallo-beta-lactamases (MBL) – similar to ESBL, but can also include resistance to
carbapenems, mostly found in Pseudomonas aeruginosa. - Carbapenemase-producing
Enterobacterales (formerly known as Carbapenemase-producing Enterobacteriaceae),
Difficult-to-treat, based on non-susceptibility to “first-line” antibiotics,
generally beta-lactams or fluoroquinolones, that necessitates the use of
second-line, often more toxic, agents.
Extended-spectrum beta-lactamases (ESBL)– transferable resistance to 3rd and 4th
generation cephalosporins, mostly found in E. coli, Klebsiella and Enterobacter species.
Metallo-beta-lactamases (MBL) – similar to ESBL, but can also include resistance to
carbapenems, mostly found in Pseudomonas aeruginosa. - Carbapenemase-producing
Enterobacterales (formerly known as Carbapenemase-producing Enterobacteriaceae),
Difficult-to-treat, based on non-susceptibility to “first-line” antibiotics,
generally beta-lactams or fluoroquinolones, that necessitates the use of
second-line, often more toxic, agents.
Difference between colonization and true infection
Colonization
It is the presence of bacteria on a body surface (like on the skin, mouth,
intestines or airway) without causing disease for the person.
Isolates were classified as colonization when no adverse clinical signs
or symptoms were documented.
Colonization
It is the presence of bacteria on a body surface (like on the skin, mouth,
intestines or airway) without causing disease for the person.
Isolates were classified as colonization when no adverse clinical signs
or symptoms were documented.
Infection
It is the invasion of a host organism's bodily tissues by disease-causing
organisms. Infection also results from the interplay between pathogens
and the defenses of the hosts they infect.
Infections were defined by the presence of a major bacterial load
associated with clinical manifestations within the infection window
period (±3 days from specimen collection).
It is the invasion of a host organism's bodily tissues by disease-causing
organisms. Infection also results from the interplay between pathogens
and the defenses of the hosts they infect.
Infections were defined by the presence of a major bacterial load
associated with clinical manifestations within the infection window
period (±3 days from specimen collection).
PUZZLE
- Method by which sample obtained
- Gram stain results
- Culture results
- Body temperature
- Radiographic findings
- Change in oxygenation or ventilation status
- Underlying medical conditions
- Results of white blood cell count &
differential
- General clinical condition
- Method by which sample obtained
- Gram stain results
- Culture results
- Body temperature
- Radiographic findings
- Change in oxygenation or ventilation status
- Underlying medical conditions
- Results of white blood cell count &
differential
- General clinical condition
Fever
is not a sign of
antibiotic deficiency.
is not a sign of
antibiotic deficiency.
Diagnostic criteria for infections
Primary Blood Stream Infection : 2 percutaneous blood samples + eventual blood from
catheters
Fever/chills/hypotension + No further sign of localized infection
If Common Commensal organisms (i.e., diphtheroids (Corynebacterium spp. not C.
diphtheria), Bacillus spp. (not B. anthracis), Propionibacterium spp., coagulase-negative
staphylococci (including S. epidermidis), viridans group streptococci, Aerococcus spp.
Micrococcus spp. And Rhodococcus spp.): necessary two or more blood specimens drawn
on separate occasions.
Primary Blood Stream Infection : 2 percutaneous blood samples + eventual blood from
catheters
Fever/chills/hypotension + No further sign of localized infection
If Common Commensal organisms (i.e., diphtheroids (Corynebacterium spp. not C.
diphtheria), Bacillus spp. (not B. anthracis), Propionibacterium spp., coagulase-negative
staphylococci (including S. epidermidis), viridans group streptococci, Aerococcus spp.
Micrococcus spp. And Rhodococcus spp.): necessary two or more blood specimens drawn
on separate occasions.
Conclusions
Treatment decisions for suspected VAP or VAT should be tailored to clinical picture,
nature of the specimen, diagnostic confidence, balanced against the cost and risk of
worsening AMR.
Treatment decisions for suspected VAP or VAT should be tailored to clinical picture,
nature of the specimen, diagnostic confidence, balanced against the cost and risk of
worsening AMR.
Recommended treatment options
for infections due to (CRAB)
Resistance to at least anyone carbapenem (meropenem or imipenem).
Combination therapy with at least two active agents, is recommended
for the treatment of CRAB infections, even if a single agent demonstrates
activity, at least until clinical improvement is observed,
In situations when prolonged durations of therapy may be needed (e.g.,
osteomyelitis), step-down therapy to a single active agent can be
considered.
for infections due to (CRAB)
Resistance to at least anyone carbapenem (meropenem or imipenem).
Combination therapy with at least two active agents, is recommended
for the treatment of CRAB infections, even if a single agent demonstrates
activity, at least until clinical improvement is observed,
In situations when prolonged durations of therapy may be needed (e.g.,
osteomyelitis), step-down therapy to a single active agent can be
considered.
Pneumonia: Recommended Treatment
Colistin + Meropenem +Ampicillin/sulbactam (even if non susceptible)
Colistin + (Imipenem/cilastatin or Meropenem)
Colistin + Tigecycline + Ampicillin/Sulbactam
Consider concomitant administration of inhaled Colistin when it is used
intravenously for VAP
IDSA does not suggest the use of nebulized antibiotics as adjunctive
therapy for CRAB pneumonia, due to the lack of benefit observed in
clinical trials.
Colistin + Meropenem +Ampicillin/sulbactam (even if non susceptible)
Colistin + (Imipenem/cilastatin or Meropenem)
Colistin + Tigecycline + Ampicillin/Sulbactam
Consider concomitant administration of inhaled Colistin when it is used
intravenously for VAP
IDSA does not suggest the use of nebulized antibiotics as adjunctive
therapy for CRAB pneumonia, due to the lack of benefit observed in
clinical trials.
Bloodstream Infections: Recommended
Treatment
Colistin + Meropenem + Ampicillin/sulbactam. (for critically ill patients if
the local rate of MDR/carbapenem resistance > 10-15%).
Colistin + (Imipenem/cilastatin or Meropenem).
Colistin + (Tigecycline OR Ampicillin/ Sulbactam)
Treatment
Colistin + Meropenem + Ampicillin/sulbactam. (for critically ill patients if
the local rate of MDR/carbapenem resistance > 10-15%).
Colistin + (Imipenem/cilastatin or Meropenem).
Colistin + (Tigecycline OR Ampicillin/ Sulbactam)
ESBL
ESBLs are enzymes that inactivate most Penicillins, Cephalosporins, and
Aztreonam.
EBSL-E generally remains susceptible to Carbapenems.
Organisms carrying ESBL genes often harbor additional genes or mutations in
genes that mediate resistance to a broad range of antibiotics.
ESBLs are enzymes that inactivate most Penicillins, Cephalosporins, and
Aztreonam.
EBSL-E generally remains susceptible to Carbapenems.
Organisms carrying ESBL genes often harbor additional genes or mutations in
genes that mediate resistance to a broad range of antibiotics.
The antibiotics avoided empirically
Piperacillin tazobactam is not suggested for the treatment of infections outside
of the urinary tract caused by ESBL-E
if cefepime or piperacillin tazobactam Were initiated as empiric therapy for
uncomplicated cystitis caused by an ESBL-E and clinical improvement occurs,
no change or extension of antibiotic therapy is necessary.
Piperacillin tazobactam is not suggested for the treatment of infections outside
of the urinary tract caused by ESBL-E
if cefepime or piperacillin tazobactam Were initiated as empiric therapy for
uncomplicated cystitis caused by an ESBL-E and clinical improvement occurs,
no change or extension of antibiotic therapy is necessary.
The active antimicrobial agents
• Carbapenems
• Ciprofloxacin
• Levofloxacin
• Trimethoprim sulfamethoxazole
• Gentamicin
• Piperacillin/tazobactam (only for UTI)
• Carbapenems
• Ciprofloxacin
• Levofloxacin
• Trimethoprim sulfamethoxazole
• Gentamicin
• Piperacillin/tazobactam (only for UTI)
Carbapenemases/ β-Lactamases
Serine- β-Lactamases Metallo- β-Lactamases
Class A: KPC, IMI, SME, CTX-M
Class C: AmpC, ACT, CMY, DHA
Class D: OXA-48
Class B: NDM, VIM, IMP
Serine- β-Lactamases Metallo- β-Lactamases
Class A: KPC, IMI, SME, CTX-M
Class C: AmpC, ACT, CMY, DHA
Class D: OXA-48
Class B: NDM, VIM, IMP
Class A
Serine-beta-lactamase
Class C
Cephalosporinases
Class D
Oxacillinase
Beta-lactamases (Ambler classification)
Penicillinases
TEM and SHV
ESBL
CTX-M
Cabapenemases
KPC
Class B
Metallo-beta-lactamase
Cabapenemases
VIM, IMP, NDM
Cephalosporinases
AmpC
Cabapenemases
OXA-48
Serine-beta-lactamase
Class C
Cephalosporinases
Class D
Oxacillinase
Beta-lactamases (Ambler classification)
Penicillinases
TEM and SHV
ESBL
CTX-M
Cabapenemases
KPC
Class B
Metallo-beta-lactamase
Cabapenemases
VIM, IMP, NDM
Cephalosporinases
AmpC
Cabapenemases
OXA-48
CRE
Members of the Enterobacterales resistant to at least one Carbapenem antibiotic or
producing a carbapenemase enzyme.
Carbapenamases enzymes, belong to Ambler class A, B or D beta-lactamases.
CRE : These include
serine b-lactamases Klebsiella pneumoniae carbapenemase (KPC) (Ambler class A),
metallo-blactamase (MBL) including
New Delhi MBL (NDM) Verona integron-encoded MBL (VIM), imipenemase (IMP)
(Ambler class B)
and OXA-48-like carbapenemases (Ambler class D).
Members of the Enterobacterales resistant to at least one Carbapenem antibiotic or
producing a carbapenemase enzyme.
Carbapenamases enzymes, belong to Ambler class A, B or D beta-lactamases.
CRE : These include
serine b-lactamases Klebsiella pneumoniae carbapenemase (KPC) (Ambler class A),
metallo-blactamase (MBL) including
New Delhi MBL (NDM) Verona integron-encoded MBL (VIM), imipenemase (IMP)
(Ambler class B)
and OXA-48-like carbapenemases (Ambler class D).
KPCs hydrolyse penicillins, cephalosporins, monobactams and carbapenems.
KPC, NDM and OXA-48 enzymes are among the carbapenem resistance mechanisms of
greatest concern.
KPC, NDM and OXA-48 enzymes are among the carbapenem resistance mechanisms of
greatest concern.
The drugs of choice for
treatment of CRE:
Tigecycline,
Aminoglycosides
and Colistin
Infections caused by Enterobacterales isolates
without carbapenemase production that remain
susceptible to Meropenem and Imipenem (i.e.,
MICs ≤1 μg/mL)
but are not susceptible to Ertapenem (i.e., MICs ≥1
μg/mL)
→ the use of extended infusion Meropenem (or
Imipenem - cilastatin) is suggested.
treatment of CRE:
Tigecycline,
Aminoglycosides
and Colistin
Infections caused by Enterobacterales isolates
without carbapenemase production that remain
susceptible to Meropenem and Imipenem (i.e.,
MICs ≤1 μg/mL)
but are not susceptible to Ertapenem (i.e., MICs ≥1
μg/mL)
→ the use of extended infusion Meropenem (or
Imipenem - cilastatin) is suggested.
For patients with CRE infections who within the previous 12
months have received medical care in countries with a relatively
high prevalence of metallo-β-lactamase-producing organisms or
who have previously had a clinical or surveillance culture where a
metalo- β-lactamase (NDM, VIM, IMP) producing isolate was
identified,
preferred treatment options include the combination of:
Ceftazidime-avibactam plus Aztreonam.
months have received medical care in countries with a relatively
high prevalence of metallo-β-lactamase-producing organisms or
who have previously had a clinical or surveillance culture where a
metalo- β-lactamase (NDM, VIM, IMP) producing isolate was
identified,
preferred treatment options include the combination of:
Ceftazidime-avibactam plus Aztreonam.
The active antibiotics against CRE:
Serine- β-Lactamases
Ceftazidime-avibactam
Tigecycline (only for infections not
involving the bloodstream or urinary
tract)
Serine- β-Lactamases
Ceftazidime-avibactam
Tigecycline (only for infections not
involving the bloodstream or urinary
tract)
Meropenem MIC
Carbapenem-resistant Enterobacteriaceae
CRE
MIC ≤ 8 or unknown
High dose
Meropenem-based
combination
MIC > 8
Are New BLBLIs susceptible in vitro
Yes
No
Are they available
Combination without
adding meropenem
Yes No
Use new BLBLIs
without combination
Carbapenem-resistant Enterobacteriaceae
CRE
MIC ≤ 8 or unknown
High dose
Meropenem-based
combination
MIC > 8
Are New BLBLIs susceptible in vitro
Yes
No
Are they available
Combination without
adding meropenem
Yes No
Use new BLBLIs
without combination
Pseudomonas aeruginosa
• In 2018, the concept of “difficult-to-treat” resistance was proposed which
is defined as P. aeruginosa exhibiting non-susceptibility to all the following:
piperacillin-tazobactam,
ceftazidime, cefepime,
aztreonam, meropenem , imipenem-cilastatin,
ciprofloxacin, and levofloxacin.
Carbapenem resistant PA (CRPA): Resistance to at least anyone carbapenem
(meropenem or imipenem).
• In 2018, the concept of “difficult-to-treat” resistance was proposed which
is defined as P. aeruginosa exhibiting non-susceptibility to all the following:
piperacillin-tazobactam,
ceftazidime, cefepime,
aztreonam, meropenem , imipenem-cilastatin,
ciprofloxacin, and levofloxacin.
Carbapenem resistant PA (CRPA): Resistance to at least anyone carbapenem
(meropenem or imipenem).
Any clinical syndrome due Pseudomonas
aeruginosa
• When P. aeruginosa isolates test susceptible to both non carbapenem β-lactam
agents (i.e., piperacillin tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems,
the non carbapenem β-lactam agents are preferred over carbapenem therapy.
If the isolate remains susceptible to a traditional non-carbapenem β-lactam (e.g., cefepime)
on repeat testing, it is recommended to administer the non-carbapenem agent as high-dose
extended infusion therapy (e.g., cefepime 2 g IV every 8 hours, infused over at least 3
hours)
aeruginosa
• When P. aeruginosa isolates test susceptible to both non carbapenem β-lactam
agents (i.e., piperacillin tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems,
the non carbapenem β-lactam agents are preferred over carbapenem therapy.
If the isolate remains susceptible to a traditional non-carbapenem β-lactam (e.g., cefepime)
on repeat testing, it is recommended to administer the non-carbapenem agent as high-dose
extended infusion therapy (e.g., cefepime 2 g IV every 8 hours, infused over at least 3
hours)
Any clinical syndrome due to CRPA
susceptible to other antimicrobial agents
Use one of the following antibiotics:
• Piperacillin/tazobactam
• Ceftazidime
• Cefepime
• Ciprofloxacin
• Levofloxacin
• Amikacin (only if urinary tract infection)
susceptible to other antimicrobial agents
Use one of the following antibiotics:
• Piperacillin/tazobactam
• Ceftazidime
• Cefepime
• Ciprofloxacin
• Levofloxacin
• Amikacin (only if urinary tract infection)
For critically ill patients or those with poor source control with P. aeruginosa
isolates resistant to carbapenems but susceptible to traditional
βlactams,
use of a novel β-lactam agent that tests susceptible (e.g., ceftolozane-
tazobactam & ceftazidime-avibactam) is a reasonable treatment approach.
isolates resistant to carbapenems but susceptible to traditional
βlactams,
use of a novel β-lactam agent that tests susceptible (e.g., ceftolozane-
tazobactam & ceftazidime-avibactam) is a reasonable treatment approach.
• Combination of two agents from different classes with in vitro activity against P.
aeruginosa for empiric treatment of serious infections known or suspected to be caused by P.
aeruginosa in the following conditions:
1. When signs of severe sepsis or septic shock are present
2. Neutropenic patients with bacteremia
3. Burn patients (who have a high incidence of multidrug-resistant P. aeruginosa infections) with
serious infections.
4. In other settings where the incidence of resistance to the chosen antibiotic class is high (e.g.,
>10 to 15 %)
aeruginosa for empiric treatment of serious infections known or suspected to be caused by P.
aeruginosa in the following conditions:
1. When signs of severe sepsis or septic shock are present
2. Neutropenic patients with bacteremia
3. Burn patients (who have a high incidence of multidrug-resistant P. aeruginosa infections) with
serious infections.
4. In other settings where the incidence of resistance to the chosen antibiotic class is high (e.g.,
>10 to 15 %)
CRPA
For patients with severe
infections caused by CRPA
susceptible in vitro only to
Colistin or
aminoglycosides a
combination therapy is
suggested.
Colistin plus other agent to
which organism has
demonstrated susceptible
MIC.
For patients with severe
infections caused by CRPA
susceptible in vitro only to
Colistin or
aminoglycosides a
combination therapy is
suggested.
Colistin plus other agent to
which organism has
demonstrated susceptible
MIC.
Any clinical syndrome due to DTRPA
• Ceftolozane/tazobactam (preferred empirical choice in absence of concomitant risk of CRE)
• Ceftazidime/avibactam
• Colistin + (Imipenem/cilastatin OR Meropenem)
• Combination of Colistin, Tigecycline, Aminoglycosides.
• (Colistin or Aminoglycoside) + (Carbapenem and/or tigecycline)
• Ceftolozane/tazobactam (preferred empirical choice in absence of concomitant risk of CRE)
• Ceftazidime/avibactam
• Colistin + (Imipenem/cilastatin OR Meropenem)
• Combination of Colistin, Tigecycline, Aminoglycosides.
• (Colistin or Aminoglycoside) + (Carbapenem and/or tigecycline)
Spectrum of activity of novel
antibiotics
ESBL AmpC
KPC OXA MBL Carb-R
A.B.
MRSA
Ceftolozane/tazobact
am
+ +/− − − − − −
Ceftazidime/avibacta
m
++
+ + + - - -
Meropenem/vaborba
ctam
+ + + - - - -
Ceftobiprol medocaril - - - - - - +
Telavancin - - - - - - +
antibiotics
ESBL AmpC
KPC OXA MBL Carb-R
A.B.
MRSA
Ceftolozane/tazobact
am
+ +/− − − − − −
Ceftazidime/avibacta
m
++
+ + + - - -
Meropenem/vaborba
ctam
+ + + - - - -
Ceftobiprol medocaril - - - - - - +
Telavancin - - - - - - +
Vancomycin-
resistant
Enterococci
(VRE)
Clinical Syndrome Recommended Treatment
Pneumonia Linezolid
Bloodstream infections Linezolid OR (Daptomycin +/-
Carbapenem)
Complicated intraabdominal
infections
Linezolid OR Tigecycline
Complicated urinary tract
infections
Linezolid OR Daptomycin
resistant
Enterococci
(VRE)
Clinical Syndrome Recommended Treatment
Pneumonia Linezolid
Bloodstream infections Linezolid OR (Daptomycin +/-
Carbapenem)
Complicated intraabdominal
infections
Linezolid OR Tigecycline
Complicated urinary tract
infections
Linezolid OR Daptomycin
Suggested
dosing of
antibiotics
Agent Adult dose Target Organism
Amikaci
n
Uncomplicated cystitis: 15
mg/kg IV as a single dose
Any clinical syndrome due to
CRPA susceptible to other
antimicrobial agents:15mg/kg
All other infections: 20
mg/kg IV once;
subsequent doses and dosing
interval based on
pharmacokinetic evaluation.
N.B., Use adjusted body
weight for patients
.120% of ideal body weight
for aminoglycoside
dosing.
ESBL-E, AmpC-E,
CRE, DTR-P.
aeruginosa
dosing of
antibiotics
Agent Adult dose Target Organism
Amikaci
n
Uncomplicated cystitis: 15
mg/kg IV as a single dose
Any clinical syndrome due to
CRPA susceptible to other
antimicrobial agents:15mg/kg
All other infections: 20
mg/kg IV once;
subsequent doses and dosing
interval based on
pharmacokinetic evaluation.
N.B., Use adjusted body
weight for patients
.120% of ideal body weight
for aminoglycoside
dosing.
ESBL-E, AmpC-E,
CRE, DTR-P.
aeruginosa
Ampicillin/sulb
actam
Agent Adult dose Target
Organis
m
Ampicillin/sulbac
tam
Total daily dose of 6-9 grams of
sulbactam
Potential infusion strategies
include the
following:
- 9 grams of ampicillin-
sulbactam (6 grams’
ampicillin, 3 grams sulbactam)
IV every 8 hours, infused over 4
hours
- 27 grams of ampicillin-
sulbactam (18 grams’
ampicillin, 9 grams sulbactam)
IV as a continuous infusion
CRAB
actam
Agent Adult dose Target
Organis
m
Ampicillin/sulbac
tam
Total daily dose of 6-9 grams of
sulbactam
Potential infusion strategies
include the
following:
- 9 grams of ampicillin-
sulbactam (6 grams’
ampicillin, 3 grams sulbactam)
IV every 8 hours, infused over 4
hours
- 27 grams of ampicillin-
sulbactam (18 grams’
ampicillin, 9 grams sulbactam)
IV as a continuous infusion
CRAB
Ampicillin/sulbactam
Agent Adult dose Target Organism
Ampicillin/sulbactam For mild infections caused by CRAB
isolates
susceptible to ampicillin-sulbactam,
particularly
if intolerance or toxicities preclude the use
of higher dosages.
- 3 grams of ampicillin-sulbactam (2
grams
ampicillin, 1-gram sulbactam) IV every 4
hours, infused over 30 minutes
Agent Adult dose Target Organism
Ampicillin/sulbactam For mild infections caused by CRAB
isolates
susceptible to ampicillin-sulbactam,
particularly
if intolerance or toxicities preclude the use
of higher dosages.
- 3 grams of ampicillin-sulbactam (2
grams
ampicillin, 1-gram sulbactam) IV every 4
hours, infused over 30 minutes
Cefepime
Agent Adult dose Target Organism
Cefepime Uncomplicated cystitis: 1gram IV
every 8
hours, infused over 30 minutes
All other infections: 2 grams IV
every 8 hours, infused
over 3 hours (if possible)
AmpC-E, CRPA
Agent Adult dose Target Organism
Cefepime Uncomplicated cystitis: 1gram IV
every 8
hours, infused over 30 minutes
All other infections: 2 grams IV
every 8 hours, infused
over 3 hours (if possible)
AmpC-E, CRPA
Agent
Adult dose
Target Organism
Aztreonam 2g IV over 3 h /6h DTR-PA
Ceftazidime Any clinical syndrome due to
CRPA susceptible to other
antimicrobial agents: 2 g IV
q8h
CRPA
Ceftazidime/avibactam 2.5 grams IV every 8 hours,
infused over 3 hours
CRE, DTR-P. aeruginosa
Ertapenem 1 gram IV every 24 hours,
infused over 30 minutes
ESBL-E, AmpC-E
Adult dose
Target Organism
Aztreonam 2g IV over 3 h /6h DTR-PA
Ceftazidime Any clinical syndrome due to
CRPA susceptible to other
antimicrobial agents: 2 g IV
q8h
CRPA
Ceftazidime/avibactam 2.5 grams IV every 8 hours,
infused over 3 hours
CRE, DTR-P. aeruginosa
Ertapenem 1 gram IV every 24 hours,
infused over 30 minutes
ESBL-E, AmpC-E
Agent Adult dose Target Organism
Ceftazidime/avibactam
PLUS Aztreonam
Ceftazidime-avibactam: 2.5
grams IV every 8 hours,
infused over 3 hours.
PLUS
Aztreonam: 2 grams IV every
6-8 hours (every 6-hour dosing
preferred if possible), infused
over 3 hours.
Administered at the same
time as ceftazidime
avibactam
Metallo-β-lactamase
producing
CRE
Ceftazidime/avibactam
PLUS Aztreonam
Ceftazidime-avibactam: 2.5
grams IV every 8 hours,
infused over 3 hours.
PLUS
Aztreonam: 2 grams IV every
6-8 hours (every 6-hour dosing
preferred if possible), infused
over 3 hours.
Administered at the same
time as ceftazidime
avibactam
Metallo-β-lactamase
producing
CRE
Agent Adult dose Target Organism
Ceftolozane/tazobactam Cystitis: 1.5 grams IV every 8
hours, infused
over 1 hour
All other infections: 3 grams
IV every 8 hours, infused over
3 hours
DTR-P. aeruginosa
ESBL-E
Ciprofloxacin Cystitis: 400 mg IV every 12
hours or 500 mg
PO every 12 hours
All other infections: 400 mg
IV every 8 hours
OR 750 mg PO every 12 hours
ESBL-E, AmpC-E,
CRPA
Ceftolozane/tazobactam Cystitis: 1.5 grams IV every 8
hours, infused
over 1 hour
All other infections: 3 grams
IV every 8 hours, infused over
3 hours
DTR-P. aeruginosa
ESBL-E
Ciprofloxacin Cystitis: 400 mg IV every 12
hours or 500 mg
PO every 12 hours
All other infections: 400 mg
IV every 8 hours
OR 750 mg PO every 12 hours
ESBL-E, AmpC-E,
CRPA
Agent Adult dose Target Organism
Colistin Colistin IV 2.5 mg/kg
Colistin Base Activity
(CBA) IV loading dose,
then 1.5 mg/kg CBA
over 1 hour IV /12 h
CRE,
DTR-P. aeruginosa,
CRAB
Colistin inhalation Colistin inhalation 75 to
150 mg CBA twice
daily.
Daptomycin IV 8-12mg/kg/day VRE
Colistin Colistin IV 2.5 mg/kg
Colistin Base Activity
(CBA) IV loading dose,
then 1.5 mg/kg CBA
over 1 hour IV /12 h
CRE,
DTR-P. aeruginosa,
CRAB
Colistin inhalation Colistin inhalation 75 to
150 mg CBA twice
daily.
Daptomycin IV 8-12mg/kg/day VRE
Agent Adult dose Target Organism
Gentamicin Uncomplicated cystitis: 5 mg/kg/dose IV as a
single dose
All other infections: 7 mg/kg IV once;
subsequent doses and dosing interval based on
pharmacokinetic evaluation.
ESBL-E, AmpC-E,
CRE, DTRP.
aeruginosa
Imipenem-cilastatin Uncomplicated cystitis (standard infusion):
500 mg IV every 6 hours, infused over 30
minutes.
All other ESBL-E or AmpC-E infections: 500
mg IV every 6 hours, infused over 30 minutes.
All other CRE and CRAB infections: 500 mg IV
every 6 hours, infused over 3 hours
ESBL-E, AmpC-E,
CRE, CRAB, DTR PA
Gentamicin Uncomplicated cystitis: 5 mg/kg/dose IV as a
single dose
All other infections: 7 mg/kg IV once;
subsequent doses and dosing interval based on
pharmacokinetic evaluation.
ESBL-E, AmpC-E,
CRE, DTRP.
aeruginosa
Imipenem-cilastatin Uncomplicated cystitis (standard infusion):
500 mg IV every 6 hours, infused over 30
minutes.
All other ESBL-E or AmpC-E infections: 500
mg IV every 6 hours, infused over 30 minutes.
All other CRE and CRAB infections: 500 mg IV
every 6 hours, infused over 3 hours
ESBL-E, AmpC-E,
CRE, CRAB, DTR PA
Agent Adult dose Target Organism
Levofloxacin 750 mg IV/PO every 24 hours. ESBL-E, AmpC-E,
S. maltophilia,
CRPA
Linezolid 600 mg IV every 12 hours. VRE
Metronidazole Complicated intraabdominal infections: 500 mg/
6h
Meropenem Uncomplicated cystitis (standard infusion): 1
grams IV every 8 hours, infused over 30
minutes.
All other ESBL-E or AmpC-E infections: 1–2 g
IV q8h, infused over 30 minutes.
All other CRE and CRAB infections: 2 g IV every
8 hours, infused over 3 hours
Levofloxacin 750 mg IV/PO every 24 hours. ESBL-E, AmpC-E,
S. maltophilia,
CRPA
Linezolid 600 mg IV every 12 hours. VRE
Metronidazole Complicated intraabdominal infections: 500 mg/
6h
Meropenem Uncomplicated cystitis (standard infusion): 1
grams IV every 8 hours, infused over 30
minutes.
All other ESBL-E or AmpC-E infections: 1–2 g
IV q8h, infused over 30 minutes.
All other CRE and CRAB infections: 2 g IV every
8 hours, infused over 3 hours
Agent Adult dose Target Organism
Nitrofurantoin Macrocrystal/monohydr
ate: 100 mg PO every
12 hours.
ESBL-E cystitis,
AmpC-E cystitis
Piperacillin-
tazobactam
Any clinical syndrome
due to CRPA susceptible
to other antimicrobial
agents: 4.5 g IV loading
over 30 minutes then, 4
hrs later, start 4.5gmIV
over 4 hours and then
repeat every 8 hours over
4 hours.
Nitrofurantoin Macrocrystal/monohydr
ate: 100 mg PO every
12 hours.
ESBL-E cystitis,
AmpC-E cystitis
Piperacillin-
tazobactam
Any clinical syndrome
due to CRPA susceptible
to other antimicrobial
agents: 4.5 g IV loading
over 30 minutes then, 4
hrs later, start 4.5gmIV
over 4 hours and then
repeat every 8 hours over
4 hours.
Agent Adult dose Target Organism
Tigecycline 200 mg IV as a single dose, then
100 mg IV
every 12 hours
CRE, CRAB, S.
maltophilia
Trimethoprim -
sulfamethoxazole
Cystitis: 160 mg (trimethoprim
component) PO
Q12h
Other infections: 8–12 mg/kg/day
(trimethoprim component) PO
divided every 8–
12 hours (consider maximum dose
of 960 mg
trimethoprim component per day).
ESBL-E, AmpC-E,
S. maltophilia
Tigecycline 200 mg IV as a single dose, then
100 mg IV
every 12 hours
CRE, CRAB, S.
maltophilia
Trimethoprim -
sulfamethoxazole
Cystitis: 160 mg (trimethoprim
component) PO
Q12h
Other infections: 8–12 mg/kg/day
(trimethoprim component) PO
divided every 8–
12 hours (consider maximum dose
of 960 mg
trimethoprim component per day).
ESBL-E, AmpC-E,
S. maltophilia
NP (HAP and/or VAP):
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftolozane/tazobacta
m
HAP and VAP
Dosage: 3 g (2/1) every 8 h
(h), 1-h IV infusion,
(Note: double dose compared to
other indications)
Duration: 8–14 days (d)
complicate intra-
abdominal infection
cUTIs (including acute
pyelonephritis)
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftolozane/tazobacta
m
HAP and VAP
Dosage: 3 g (2/1) every 8 h
(h), 1-h IV infusion,
(Note: double dose compared to
other indications)
Duration: 8–14 days (d)
complicate intra-
abdominal infection
cUTIs (including acute
pyelonephritis)
NP (HAP and/or VAP):
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftazidime/aviba
ctam
HAP and VAP, including
bacteraemic cases
(bacteraemia associated with
or suspected to be associated
with HAP/VAP)
Dosage: 2.5 g (2/0.5) every
8 h, 2-h IV infusion
Duration: 7–14 d
cIAI (in combination with
metronidazole),
cUTI (including
pyelonephritis),
Bacteraemia associated with
or suspected to be associated
with cIAI or cUTI
Infections due to aerobic
Gram-negative organisms in
patients with limited
treatment options
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftazidime/aviba
ctam
HAP and VAP, including
bacteraemic cases
(bacteraemia associated with
or suspected to be associated
with HAP/VAP)
Dosage: 2.5 g (2/0.5) every
8 h, 2-h IV infusion
Duration: 7–14 d
cIAI (in combination with
metronidazole),
cUTI (including
pyelonephritis),
Bacteraemia associated with
or suspected to be associated
with cIAI or cUTI
Infections due to aerobic
Gram-negative organisms in
patients with limited
treatment options
NP (HAP and/or VAP):
Dosage and Treatment
Duration for NP
Other Approved Indications
Meropenem/v
aborbactam
HAP and VAP, including
bacteraemic cases
(bacteraemia associated
with or suspected to be
associated with HAP/VAP)
1
Dosage: 4 g (2/2) every 8
h, 3-h IV infusion
Duration: 7–14 d
cIAI
cUTI (including
pyelonephritis),
Bacteraemia associated
with or suspected to be
associated with cIAI or cUTI
Infections due to aerobic
Gram-negative organisms in
patients with limited
treatment option
Dosage and Treatment
Duration for NP
Other Approved Indications
Meropenem/v
aborbactam
HAP and VAP, including
bacteraemic cases
(bacteraemia associated
with or suspected to be
associated with HAP/VAP)
1
Dosage: 4 g (2/2) every 8
h, 3-h IV infusion
Duration: 7–14 d
cIAI
cUTI (including
pyelonephritis),
Bacteraemia associated
with or suspected to be
associated with cIAI or cUTI
Infections due to aerobic
Gram-negative organisms in
patients with limited
treatment option
NP (HAP and/or VAP):
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftobiprole
medocaril
HAP (not for VAP)
1
Dosage: 500 mg every 8 h,
2-h IV infusion
Duration: 7–14 d
CAP
Dosage and Treatment
Duration for NP
Other Approved
Indications
Ceftobiprole
medocaril
HAP (not for VAP)
1
Dosage: 500 mg every 8 h,
2-h IV infusion
Duration: 7–14 d
CAP
NP (HAP and/or VAP):
Dosage and Treatment
Duration for NP
Other Approved Indications
Telavancin HAP and VAP caused by S.
aureus including
bacteraemic cases (when no
alternative treatment
available)
2
Dosage: 10 mg/kg every 24
h, 1-h IV infusion
Duration: 7–21 d
complicated skin and skin
structures infection caused by S.
aureus including bacteraemic
cases (when no alternative
treatment available)
Dosage and Treatment
Duration for NP
Other Approved Indications
Telavancin HAP and VAP caused by S.
aureus including
bacteraemic cases (when no
alternative treatment
available)
2
Dosage: 10 mg/kg every 24
h, 1-h IV infusion
Duration: 7–21 d
complicated skin and skin
structures infection caused by S.
aureus including bacteraemic
cases (when no alternative
treatment available)
No action today means
no cure tomorrow.
no cure tomorrow.
Prevention is
better than
treatment
better than
treatment
The five
moments
for hand
hygiene
moments
for hand
hygiene
Prescribing antibiotics when they
are truly needed
Appropriate evaluation requires obtaining a culture from these sites only when indicated,
without contamination by the collection protocol itself (superficial swab cultures and
cultures of drains and sinus tracts are inappropriate),
Avoiding antibiotic treatment of a “positive”
culture result without symptoms and signs of
active infection.
are truly needed
Appropriate evaluation requires obtaining a culture from these sites only when indicated,
without contamination by the collection protocol itself (superficial swab cultures and
cultures of drains and sinus tracts are inappropriate),
Avoiding antibiotic treatment of a “positive”
culture result without symptoms and signs of
active infection.
Selecting the most appropriate antibiotic(s)
for a specific patient
for a specific patient
Optimization of th Dosing Regimens in
MDR Infections
Prolonged/Continuous Infusion of Beta-Lactams
The prolonged IV administration of antibiotics can increase the time above the MIC target.
Furthermore, the continuous administration of BL such as piperacillin/tazobactam and
meropenem showed a reduction in clinical failures compared to an intermittent
administration.
MDR Infections
Prolonged/Continuous Infusion of Beta-Lactams
The prolonged IV administration of antibiotics can increase the time above the MIC target.
Furthermore, the continuous administration of BL such as piperacillin/tazobactam and
meropenem showed a reduction in clinical failures compared to an intermittent
administration.
Combination Therapy
Faster bacterial clearance, prevention of the development of bacterial resistance and
synergistic or additive effects have been advocated to support the combination therapy,
In the presence of A. baumannii, the combination of colistin and
amikacin was most effective for the eradication of persister cells
potential side effects like increased toxicity and higher costs are possible drawbacks.
Faster bacterial clearance, prevention of the development of bacterial resistance and
synergistic or additive effects have been advocated to support the combination therapy,
In the presence of A. baumannii, the combination of colistin and
amikacin was most effective for the eradication of persister cells
potential side effects like increased toxicity and higher costs are possible drawbacks.
Handle antibiotics
Value of Antibiograms
Antibiograms represent an important tool to provide
empirical antibiotics recommendations and are a core
element of antimicrobial stewardship programs by increasing
the likelihood of appropriate initial antimicrobial coverage.
Regional cumulative antibiograms have been shown to be
feasible and may inform an empirical antibiotic selection for
institutions where local surveillance data are missing. They
may also be valuable to assist targeted antimicrobial
stewardship interventions.
Antibiograms represent an important tool to provide
empirical antibiotics recommendations and are a core
element of antimicrobial stewardship programs by increasing
the likelihood of appropriate initial antimicrobial coverage.
Regional cumulative antibiograms have been shown to be
feasible and may inform an empirical antibiotic selection for
institutions where local surveillance data are missing. They
may also be valuable to assist targeted antimicrobial
stewardship interventions.
Oral antibiotic administration has been shown to decrease the cost and length of
hospitalization.
The general guidance for the timing of intravenous-to-oral switching of antibiotics provided
the gastrointestinal tract is functional, and clinical improvement with or without
improvement in laboratory markers.
the switch to oral antibiotics should not lead to an antibiotic therapy which is longer than
that used for parenteral therapy.
Actually, it is increasingly evident that prescribing oral antibiotics could influence gut
microbiome dynamics, promoting more strongly AMR
hospitalization.
The general guidance for the timing of intravenous-to-oral switching of antibiotics provided
the gastrointestinal tract is functional, and clinical improvement with or without
improvement in laboratory markers.
the switch to oral antibiotics should not lead to an antibiotic therapy which is longer than
that used for parenteral therapy.
Actually, it is increasingly evident that prescribing oral antibiotics could influence gut
microbiome dynamics, promoting more strongly AMR
Achieving source control by identifying
and eliminating the source of the
infection or reducing the bacterial load
and eliminating the source of the
infection or reducing the bacterial load
vaccines, antibodies, pattern recognition receptors (PRRs),
probiotics, bacteriophages, peptides, phytochemicals, metals
and antimicrobial enzymes
probiotics, bacteriophages, peptides, phytochemicals, metals
and antimicrobial enzymes
TAKE HOME MESSAGE
Appropriate use of antibiotics should be integral to good clinical
practice and standards of care.
Inappropriate antibiotic use are contributing to the development
and spread of AMR.
Antibiotics should be treated as a global public good on the
limit of shortage;
Infections, especially those with MDR bacteria, compromise the
success of all medical practitioners, including surgeons.
Appropriate use of antibiotics should be integral to good clinical
practice and standards of care.
Inappropriate antibiotic use are contributing to the development
and spread of AMR.
Antibiotics should be treated as a global public good on the
limit of shortage;
Infections, especially those with MDR bacteria, compromise the
success of all medical practitioners, including surgeons.
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