Download Antibiotic Resistance by Dr Sarma

M.D., M.Sc.(Canada), FIMSA,
Senior Consultant Physician &
Cardio-Metabolic Specialist
Published Online - August 11, 2010
Grundmann H et al. Lancet 2006;368:874.
18
14
12
Resistance
Number of agents approved
16
10
8
6
4
2
0
0
1983-87
1988-92
1993-97
1998-02
2003-05
2008
Bars represent number of new antimicrobial agents approved by the FDA during that period
•Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;
•New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912
b – Lactam Ring
Active
b - Lactamase
Inactive
Penicillinase
Plasmid
Gene for b - Lactamase
This organism can freely grow
in the presence of Penicillin
Genomic islands
e.g. Escherichia Coli
Prophages
Common: 4.1 Mb
K12 Islands: 0.53 Mb
0157:H7 Islands: 1.34 Mb
Conjugative
Transposons (gram +ve)
Minimal species
Genomic backbone
Super Integrons
(Mainly  Protobacteria)
Insertion Sequences
Integrons
Transposons
Inappropriate empiric antibiotic therapy can lead to
increases in:
– mortality
– morbidity
– length of hospital stay
– cost burden
– resistance selection
A number of studies have demonstrated the benefits
of early use of appropriate empiric antibiotic therapy
for patients with nosocomial infections
Inappropriate antibiotic therapy can be defined
as one or more of the following:
– ineffective empiric treatment of bacterial
infection at the time of its identification
– the wrong choice, dose or duration of Rx.
– use of an antibiotic to which the pathogen is
resistant
Antibiotic resistance either arises as a result
of innate consequences or is acquired from
other sources
Bacteria acquire resistance by:
• Mutation: spontaneous single or multiple changes in
bacterial DNA
• Addition of new DNA: usually via plasmids, which can
transfer genes from one bacterium to another
• Transposons: short, specialised sequences of DNA
that can insert into plasmids or bacterial chromosomes
Structurally modified antibiotic target site,
resulting in:
– Reduced antibiotic binding
– Formation of a new metabolic pathway
preventing metabolism of the antibiotic
Antibiotics normally bind to specific binding
proteins on the bacterial cell surface
Antibiotic
Binding
Target site
Cell wall
Interior of organism
Antibiotics are no longer able to bind to modified
binding proteins on the bacterial cell surface
Antibiotic
Modified target site
Cell wall
Changed site: blocked binding
Interior of organism
Altered uptake of antibiotics, resulting in:
• Decreased permeability
• Increased efflux
Antibiotics normally enter bacterial cells via porin
channels in the cell wall
Antibiotic
Porin channel
into organism
Cell wall
Interior of organism
New porin channels in the bacterial cell wall do not
allow antibiotics to enter the cells
Antibiotic
New porin channel
into organism
Cell wall
Interior of organism
Antibiotics enter bacterial cells via
porin channels in the cell wall
Porin channel
Antibiotic
through cell wall
Entering
Entering
Cell wall
Interior of organism
Once antibiotics enter bacterial cells, they are
immediately excluded from the cells
via active pumps
Antibiotic
Porin channel
through cell wall
Entering
Exiting
Cell wall
Interior of organism
Active pump
Antibiotic inactivation
• Bacteria acquire genes encoding enzymes that
inactivate antibiotics
Examples include:
• b-Lactamases
• Aminoglycoside-modifying enzymes
• Chloramphenicol acetyl transferase
Inactivating enzymes target antibiotics
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Enzymes bind to antibiotic molecules
Enzyme
binding
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Enzymes destroy antibiotics or prevent binding to target sites
Antibiotic
destroyed
Antibiotic altered,
binding prevented
Antibiotic
Enzyme
Target site
Cell wall
Interior of organism
b-lactam
Glycopeptide
Aminoglycoside
Tetracycline
Chloramphenicol
Macrolide
Sulphonamide
Trimethoprim
Quinolones
Modified target
Altered uptake
Drug inactivation
+
+
–
–
+
++
+
+
–
++
++
++
++
–
–
–
+
+
Three mechanisms of b-lactam antibiotic
resistance are recognised:
• Reduced permeability
• Inactivation with b-lactamase enzymes
• Altered penicillin-binding proteins (PBPs)
AmpC and Extended-Spectrum b-lactamase
(ESBL) production are the most important
mechanisms of b-lactam resistance in
nosocomial infections
The antimicrobial and clinical features of
these resistance mechanisms are
highlighted in the following slides
Worldwide problem:
• Incidence increased from 17% to 23% between 1991
and 2001 in UK
Very common in Gram-negative bacilli
AmpC gene is usually sited on chromosomes, but
can be present on plasmids
Enzyme production is either constitutive (occurring
all the time) or inducible (only occurring in the
presence of the antibiotic)
Pfaller et al. Int J Antimicrob Agents 2002;19:383–388;
Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27
An increasing global problem
Found in a small, expanding group of
Gram-negative bacilli, most commonly
the Entero-bacteriaceae spp.
Usually associated with large plasmids
Enzymes are commonly mutants of TEMand SHV-type b-lactamases
Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. Diagn Microbiol Infect Dis 2002;44:273–280
Inhibited by b-lactamase inhibitors
Usually confer resistance to:
• 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime
• Monobactams eg. Aztreonam
• Carboxypenicillins eg. Carbenicillin
Varied susceptibility to Piperacillin / Tazobactam
Typically susceptible to Carbapenems and Cephamycins
Often non-susceptible to fourth generation Cephalosporins
Introduction of methicillin in 1959 was followed
rapidly by reports of MRSA isolates
Recognized hospital pathogen since the 1960s
Major cause of nosocomial infections worldwide
• Contributes to 50% of infectious morbidity in ICUs
• Surveillance studies suggest prevalence has increased
worldwide, reaching 25–50% in 1997
Jones. Chest 2001;119:397S–404S
MRSA in hospitals leads to an associated rise in
incidence in the community
Community-acquired MRSA strains may be distinct from
those in hospitals
In a hospital-based study, >40% of MRSA infections
were acquired prior to admission
Risk factors for community acquisition included:
• Recent hospitalization; Previous antibiotic therapy
• Residence in a long-term care facility; Intravenous drug use
•Hiramatsu et al. Curr Opin Infect Dis 2002;15:407–413
•Layton et al. Infect Control Hosp Epidemiol 1995;16:12–17; Naimi et al. 2003;290:2976−2984
• Mechanism involves altered target site
– new penicillin-binding protein — PBP 2' (PBP 2a)
– encoded by chromosomally located mecA gene
• Confers resistance to all b-lactams
• Gene carried on a mobile genetic element — staphylococcal
cassette chromosome mec (SCCmec)
• Laboratory detection requires care
• Not all mecA-positive clones are resistant to methicillin
•Hiramatsu et al. Trends Microbiol 2001;9:486–493
• Cross-resistance common with many other antibiotics
• Ciprofloxacin resistance is a worldwide problem
in MRSA:
– involves ≥2 resistance mutations
– usually involves parC and gyrA genes
– renders organism highly resistant to ciprofloxacin, with
cross-resistance to other quinolones
• Intermediate resistance to glycopeptides
first reported in 1997
•Hiramatsu et al. J Antimicrob Chemother 1997;40:135–136
• Vancomycin-resistant enterococci (VRE)
• Vancomycin-resistant S. aureus (VRSA)
• Resistance most common in organisms associated with nosocomial
infections
– Pseudomonas aeruginosa
– Acinetobacter spp.
– also increasing among ESBL-producing strains
• Meropenem Yearly Susceptibility Test Information Collection
(MYSTIC) surveillance programme (1997―2000)
– 13.4% of Gram-negative strains resistant to ciprofloxacin
– P. aeruginosa and Acinetobacter baumannii are the most
prevalent resistant strains
•Masterton. J Antimicrob Chemother 2002;49:218–220
– increasing prevalence of
resistance
during surveillance
Thomson. J Antimicrob Chemother 1999;43(Suppl. A):31–40
MRSA
• S. aureus occurred in 22.9% of pneumonias
in hospitalised patients in USA and Canada
(1997 SENTRY data)
Enterococcus spp. resistance
• has developed rapidly, especially among
VRE
Streptococcus pneumoniae •Hooper.
resistance
Lancet Infect Dis 2002;2:530–538
Antibiotic resistance in the hospital
setting is increasing at an alarming rate
and is likely to have an important impact
on infection management
Steps must be taken now to control the
increase in antibiotic resistance
•Cosgrove et al. Arch Intern Med 2002;162:185–190
The Academy for Infection Management
supports the concept of using appropriate
antibiotics early in nosocomial infections
and proposes:
• selecting the most appropriate antibiotic
based on the patient,
risk factors, suspected infection and
resistance
• administering antibiotics at the right dose for
Hand washing plays an important role in
nosocomial pneumonias
Wash hands before and after suctioning,
touching ventilator equipment, and/or
coming into contact with respiratory
secretions.
Use a continuous subglottic suction ET tube
for intubations expected to be > 24 hours
Keep the HOB elevated to at least 30
degrees unless medically contraindicated
• Various Antibiotic Classes
• Mechanisms of action of Anti Bacterials
• Mechanisms of Bacterial Resistance
• Animation on Drug Resistance
• b Lactamases – Drug Resistance
• NDM1 – Superbug – Concerns
• Other Superbugs – Global Issues
• How to prevent Drug Resistance
• Where we are heading in future
• Various Antibiotic Classes
• Mechanisms of action of Anti Bacterials
• Mechanisms of Bacterial Resistance
• Animation on Drug Resistance
• b Lactamases – Drug Resistance
• NDM1 – Superbug – Concerns
• Other Superbugs – Global Issues
• How to prevent Drug Resistance
• Where we are heading in future
• The Antimicrobial Availability Task
Force of the IDSA1 identified as
particularly problematic pathogens
– A. baumannii and P. aeruginosa
– ESBL-producing
Enterobacteriaceae
– MRSA
– Vancomycin-resistant
enterococcus
• Declining research investments in
antimicrobial development2
•1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews.
http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.
• The rapid and disturbing spread of:
– extended-spectrum ß-lactamases
– AmpC enzymes
– carbapenem resistance
•
metallo-β-lactamases
•
KPC and OXA-48 β-lactamases
– quinolone resistance
• β-lactamases capable of conferring bacterial
resistance to
– the penicillins
– first-, second-, and third-generation cephalosporins
– aztreonam
– (but not the cephamycins or carbapenems)
• These enzymes are derived from group 2b β-
lactamases (TEM-1, TEM-2, and SHV-1)
– differ from their progenitors by as few as one AA
E. coli and Klebsiella ESBL Phenotype Rates by Country
(SENTRY Program)
65
60
55
Frequency (%)
50
45
40
35
30
25
20
15
10
5
0
Switzer Sweden
Spain
Ireland Germany
UK
France
Country
Klebsiella
E. coli
Italy
Israel
Turkey
Greece
Poland
• Until 2000, most ESBL producers were hospital Klebsiella
spp. with TEM and SHV mutant β-lactamases
• Now, the dominant ESBLs across most of Europe and Asia
are CTX-M enzymes, which originated as genetic escapes
from Kluyvera spp
• Currently recognized as the most widespread and threatening
mechanism of antibiotic resistance, both in clinical and
community settings
– 80% of ESBL-positive E. coli from bacteraemias in the UK and
Ireland are resistant to fluoroquinolones
– 40% are resistant to gentamicin
Livermore, DM J. Antimicrob. Chemother 2009
• Ability to hydrolyze penicillins, cephalosporins,
monobactams, and carbapenems
• Resilient against inhibition by all commercially viable ß-
lactamase inhibitors
– Subgroup 2df: OXA (23 and 48) carbapenemases
– Subgroup 2f : serine carbapenemases from
molecular class A: GES and KPC
– Subgroup 3b contains a smaller group of MBLs that
preferentially hydrolyze carbapenems
•
IMP and VIM enzymes that have appeared globally, most
frequently in non-fermentative bacteria but also in
• KPCs are the most prevalent of this group of
enzymes, found mostly on transferable plasmids
in K. pneumoniae
• Substrate hydrolysis spectrum includes cephalosporins
and carbapenems
•Nordmann P et al. LID 2009
• Once expressed at high levels, confer resistance to
many β-lactam antimicrobials (excluding cefepime
and carbapenems)
• In E. coli, constitutive over expression of AmpC β-
lactamases can occur because
– of mutations in the promoter and/or attenuator
region (AmpC hyperproducers)
– the acquisition of a transferable ampC gene on a
plasmid or other transferable elements (plasmidmediated AmpC β-lactamases)
Genetic group
Geographic origin
Characterized enzymes
imp
Japan
vim
spm
gim
vim
sim
Italy
Brazil
Germany
USA
Korea
IMP-1 through IMI-13a
IMP-14, and IMP-16a
VIM-1 through VIM-7a
SPM-1a
GIM-1a
VIM-7a,b
SIM-1
– Ceftaroline
– Ceftobiprole
• Oral penem
– Faropenem
•Hebeisen P et al. Antimicrob Agents Chemother. 2001.
Sader HS et al. Antimicrob Agents Chemother. 2005.
Granizo JJ et al. Clin Ther. 2006.
Schurek KN et al. Expert Rev Anti Infect Ther. 2007.
Organism
MIC90 (g/mL)
CTL
CBP
FAR
Pen-S
0.016
0.015
0.25
Pen-I
0.06
0.12
0.008
Pen-R
0.25
1
1
CTX-R*
0.5
1
ND‡
•*Multiple mutations in PBP1a, 2b, and 2x.
‡ MIC
90
of 2 mg/L vs. cefuroxime-resistant strain
•Davies TA et al. ICAAC. 2005.
Sahm DF et al. ICAAC. 2006.
Van Bambeke F et al. Drugs. 2007.
McGee L et al; Morrissey I et al. ICAAC. 2007.
ABx Route
In vivo Efficacy
CTL
IV
Good lung
penetration in
rabbit model
CBP
IV
Equal to CTX in
murine model
FAR
PO
Eradication of S.
pneumoniae; NI to
AMX  CLV, CPX
CrossResistance
Limitations
None - all
active
against
MDR
strains
Presumed or
reported crosshypersensitivity
to b-lactams
•Boswell FJ et al; Jones RN et al. J Antimicrob Chemother. 2002.
Azoulay-Dupuis E et al. Antimicrob Agents Chemother. 2004.
Echols R et al; Kowalsky S et al; Lentnek A et al; Drehobl M et al. ICAAC. 2005.
Jacqueline C et al; Young C et al; Rubino CM et al. ICAAC. 2006.
• Dalbavancin
– Once weekly IV dosing
• Oritavancin
• Telavancin
• Versus vancomycin:
– Additional mechanisms of action
– Renal and hepatic excretion
– No known nephrotoxicity or dose adjustments
•Malabarba A et al. J Antimicrob Chemother. 2005
Organism
Pen-S
Pen-NS
MDR
MIC90 (g/mL)
VAN
DAL*‡
ORI*‡
TEL*‡
0.5
0.03
0.004
0.03
0.25-2
0.03
0.008
0.015
ND
ND
0.008
0.03
•*Rapidly bactericidal
‡ Also
active against macrolide- and FQ-resistant strains
•Streit JM et al. Diag Micro Infect Dis. 2004.
Lin G et al. ICAAC. 2005.
Thornsberry C et al. ICAAC. 2006.
Draghi DC et al; Grover PK et al; Fritsche TR et al. ICAAC. 2007.
ABx Route
In vivo Efficacy
DAL
IV
Animal model of PCNresistant NBPP
ORI
IV
High AUC:MIC ratios in
ELF and plasma in
murine NBPP
TEL
IV
Good penetration into
ELF and AMs in human
volunteers; Phase III trial
pending
CrossResistance
AEs
Partial with
vancomycin;
clinical
significance
unclear
Redman
syndrome
with TEL;
Rare  in
platelets
•Gotfried M et al. ICAAC. 2005.
Lehoux D et al. ICAAC. 2007.
• Garenoxacin (PO/IV)
– Bactericidal
– MIC90 = 0.06 g/mL for
penicillin-, macrolide-, and 
6 drug- resistant S.
pneumoniae
– MIC90 = 1 g/mL for CIPand LEV- resistant S.
pneumoniae
•Wu P et al. Antimicrob Agents Chemother. 2001.
Jones RN et al. Diag Micro Infect Dis. 2007.
• a group of polypeptide antibiotics that consists of 5
chemically different compounds (polymyxins A-E),
were discovered in 1947
• Only polymyxin B and polymyxin E (colistin) have
been used in clinical practice
• the primary route of excretion is renal
•65
• The target of antimicrobial activity of colistin is the
bacterial cell membrane
• Colistin has also potent anti-endotoxin activity
– The endotoxin of G-N bacteria is the lipid A portion of
LPS molecules, and colistin binds and neutralizes
LPS
•66
• Active:
– Acinetobacter species,
– Pseudomonas aeruginosa,
– Enterobacteriaciae
•67
• 160 mg (2 million IU) ever 8 h
• 240 mg (3 million IU) every 8 h for life-threatening
infections
•68
• Dose adjustment for renal failure
• Adverse effects:
– nephrotoxicity (acute tubular necrosis)
– neurotoxicity (dizziness, weakness, facial
paresthesia, vertigo, visual disturbances, confusion,
ataxia, and neuromuscular blockade, which can lead
to respiratory failure or apnea)
•69
June 30, 2008 -- Health Canada has authorised
the marketing of ceftobiprole medocaril for
injection (Zeftera and marketed by Janssen
Ortho) for the treatment of complicated skin
and soft tissue infections including diabetic
foot infections
On September 24, 2007, Health Canada approved
daptomycin intravenous infusion (Cubicin, Cubist
Pharmaceuticals, Inc, and marketed by Oryx
Pharmaceuticals, Inc) for the treatment of complicated
skin and skin structure infections caused by certain
gram-positive infections and for bloodstream
infections, including right-sided infective endocarditis,
caused by S. aureus.
• Irreversibly binds to cell
membrane of Grampositive bacteria
– Calcium-dependent
membrane insertion of
molecule
• Rapidly depolarizes the
cell membrane
– Efflux of potassium
– Destroys ion-concentration
gradient
• Mechanism of action of Anti bacterials
• Mechanism of Bacterial Resistance
– Second level
•
Third level
– Fourth level
• Fifth level