Syncope

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www.drsarma.in
Superbug
Dr. Sarma. R.V.S.N.
M.D., M.Sc.(Canada), FIMSA, Senior Consultant
Physician Cardio-Metabolic Specialist
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Antimicrobial Resistance
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Lancet Infect Dis 2010 10 597602
Published Online - August 11, 2010
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Worldwide Prevalence of MRSA
Grundmann H et al. Lancet 2006368874.
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Antibiotic Prescriptions
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No Major New Discoveries
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A Changing Landscape for Approved Antibacterials
Resistance
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. 2004381279-1286
• New antimicrobial agents. Antimicrob Agents
  Chemother. 2006501912

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Penicillin Cleavage by Penicillinase

• b Lactam Ring

• b - Lactamase

Inactive
Active
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Bacterium Resistant to Penicillin
Penicillinase
Plasmid
Gene for b - Lactamase
This organism can freely grow in the presence of
Penicillin
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The Busy Genome Elements of Horizontal Exchange
Genomic islands
e.g. Escherichia Coli Common 4.1 Mb K12 Islands
0.53 Mb 0157H7 Islands 1.34 Mb
Prophages
Conjugative Transposons (gram ve)
Minimal species Genomic backbone
Super Integrons (Mainly ? Protobacteria)
Insertion Sequences
Integrons
Transposons
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Acquisition of Hospital Infections
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Inappropriate Antibiotic Therapy

• 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

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Inappropriate Antibiotic Therapy

• 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

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Mechanism of Antibiotic Resistance

• 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

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Mechanism of Antibiotic Resistance

• Structurally modified antibiotic target site,
  resulting in
• Reduced antibiotic binding
• Formation of a new metabolic pathway preventing
  metabolism of the antibiotic

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Structurally Modified Antibiotic Target Site
Antibiotics normally bind to specific binding
proteins on the bacterial cell surface
Antibiotic
Target site
Binding
Cell wall
Interior of organism
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Structurally Modified Antibiotic Target Site
Antibiotics are no longer able to bind to
modified binding proteins on the bacterial cell
surface
Antibiotic
Modified target site
Cell wall
Interior of organism
Changed site blocked binding
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Altered Uptake Of Antibiotics Decreased
Permeability

• Altered uptake of antibiotics, resulting in
• Decreased permeability
• Increased efflux

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Altered Uptake Of Antibiotics Decreased
Permeability
Antibiotics normally enter bacterial cells via
porin channels in the cell wall
Antibiotic
Porin channel into organism
Cell wall
Interior of organism
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Altered Uptake Of Antibiotics Decreased
Permeability
New porin channels in the bacterial cell wall do
not allow antibiotics to enter the cells
New porin channel into organism
Antibiotic
Cell wall
Interior of organism
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Altered Uptake of Antibiotics Increased Efflux
Antibiotics enter bacterial cells via porin
channels in the cell wall
Porin channel through cell wall
Antibiotic
Entering
Entering
Cell wall
Interior of organism
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Altered Uptake of Antibiotics Increased Efflux
Once antibiotics enter bacterial cells, they are
immediately excluded from the cellsvia active
pumps
Antibiotic
Porin channel through cell wall
Entering
Exiting
Cell wall
Interior of organism
Active pump
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Antibiotics Inactivation (Cleavage)

• Antibiotic inactivation
• Bacteria acquire genes encoding enzymes that
  inactivate antibiotics
• Examples include
• ?-Lactamases
• Aminoglycoside-modifying enzymes
• Chloramphenicol acetyl transferase

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Antibiotics Inactivation (Cleavage)
Inactivating enzymes target antibiotics
Antibiotic
Enzyme
Target site
Binding
Cell wall
Interior of organism
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Antibiotics Inactivation (Cleavage)
Enzymes bind to antibiotic molecules
Enzymebinding
Antibiotic
Target site
Binding
Enzyme
Cell wall
Interior of organism
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Antibiotics Inactivation (Cleavage)
Enzymes destroy antibiotics or prevent binding to
target sites
Antibiotic altered, binding prevented
Antibioticdestroyed
Antibiotic
Target site
Enzyme
Cell wall
Interior of organism
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Multiple Mechanisms Of Antibacterial Resistance
Modified target
Altered uptake
Drug inactivation



?-lactam

Glycopeptide



Aminoglycoside


Tetracycline


Chloramphenicol

Macrolide


Sulphonamide


Trimethoprim


Quinolones
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?-Lactam Antibiotic Resistance Mechanisms

• Three mechanisms of ?-lactam antibiotic
  resistance are recognised
• Reduced permeability
• Inactivation with ?-lactamase enzymes
• Altered penicillin-binding proteins (PBPs)

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?-Lactam Antibiotic Resistance Mechanisms
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?-Lactam Antibiotic Resistance

• AmpC and Extended-Spectrum ?-lactamase (ESBL)
  production are the most important mechanisms of
  ?-lactam resistance in nosocomial infections
• The antimicrobial and clinical features of these
  resistance mechanisms are highlighted in the
  following slides

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?-Lactam Resistance AmpC Production

• 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
200219383388 Sader et al. Braz J Infect Dis
1999397110 Livermore et al. Int J Antimicrob
Agents 20032214-27
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?-Lactam Resistance ESBL Production

• An increasing global problem
• Found in a small, expanding group
  ofGram-negative bacilli, most commonly the
  Entero-bacteriaceae spp.
• Usually associated with large plasmids
• Enzymes are commonly mutants of TEM- and
  SHV-type ?-lactamases

Jones et al. Int J Antimicrob Agents
200220426431 Sader et al. Diagn Microbiol
Infect Dis 200244273280
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Antimicrobial Features of ESBLs

• Inhibited by ?-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

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Features of methicillin-resistant Staphylococcus
aureus (MRSA)

• 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 2550 in 1997

Jones. Chest 2001119397S404S
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Emergence of MRSA in the community

• 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, gt40 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
  200215407413
• Layton et al. Infect Control Hosp Epidemiol
  1995161217 Naimi et al. 20032902976-2984

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Antimicrobial features of MRSA (1)

• Mechanism involves altered target site
• new penicillin-binding protein PBP 2' (PBP 2a)
• encoded by chromosomally located mecA gene
• Confers resistance to all ?-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 20019486493
• Berger-Bachi Rohrer. Arch Microbiol
  2002178165171

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Antimicrobial features of MRSA (2)

• 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
  199740135136
• Hooper. Lancet Infect Dis 20022530538

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Glycopeptide resistance focus on vancomycin
resistance

• Vancomycin-resistant enterococci (VRE)
• Vancomycin-resistant S. aureus (VRSA)

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Features of quinolone resistance Gram-negative
organisms

• 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
• increasing prevalence of resistance during
  surveillance period

• Masterton. J Antimicrob Chemother 200249218220
  Thomson. J Antimicrob Chemother 199943(Suppl.
  A)3140

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Features of quinolone resistance Gram-positive
organisms

• 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 resistance
• emerging in many countries, including
  community-acquired resistance
• Hong Kong (12.1), Spain (5.3) and USA (lt1)
• marked cross-resistance with other frequently
  used antibiotics

• Hooper. Lancet Infect Dis 20022530538

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Summary

• Antibiotic resistance in the hospital setting is
  increasing at an alarming rateand 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 2002162185190

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Summary

• 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
  the appropriate duration
• changing antibiotic dosage or therapy based on
  resistance and pathogen information
• recognising that prior antimicrobial
  administration is a risk factor for the presence
  of resistant pathogens
• knowing the units antimicrobial resistance
  profile and choosing antibiotics accordingly

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• 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 gt 24 hours
• Keep the HOB elevated to at least 30 degrees
  unless medically contraindicated

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Outline of the talk

• Various Antibiotic Classes
• Mechanisms of action of Anti Bacterials
• Mechanisms of Bacterial Resistance
• Animation on Drug Resistance
• ? Lactamases Drug Resistance
• NDM1 Superbug Concerns
• Other Superbugs Global Issues
• How to prevent Drug Resistance
• Where we are heading in future

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• Various Antibiotic Classes
• Mechanisms of action of Anti Bacterials
• Mechanisms of Bacterial Resistance
• Animation on Drug Resistance
• ? Lactamases Drug Resistance
• NDM1 Superbug Concerns
• Other Superbugs Global Issues
• How to prevent Drug Resistance
• Where we are heading in future

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Bad Bugs, No Drugs1

• 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. 200642657-68.

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Enterobacteriaceae

• The rapid and disturbing spread of
• extended-spectrum ß-lactamases
• AmpC enzymes
• carbapenem resistance
• metallo-ß-lactamases
• KPC and OXA-48 ß-lactamases
• quinolone resistance

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Extended-Spectrum ß-Lactamases

• ß-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
  ß-lactamases (TEM-1, TEM-2, and SHV-1)
• differ from their progenitors by as few as one AA

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CTX-M-type ESBLs

• Until 2000, most ESBL producers were hospital
  Klebsiella spp. with TEM and SHV mutant
  ß-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
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Carbapenemases

• 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 Enterobacteriaceae

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KPC (K. pneumoniae carbapenemase)

• 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

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K. pneumoniae carbapenemase-producing bacteria

• Nordmann P et al. LID 2009

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AmpC ß-lactamases

• Once expressed at high levels, confer resistance
  to many ß-lactam antimicrobials (excluding
  cefepime and carbapenems)
• In E. coli, constitutive over expression of AmpC
  ß-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
  (plasmid-mediated AmpC ß-lactamases)

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Emerging Metallo-ß-Lactamaseswith Mobile
Genetics(SENTRY Program 2001-2005)
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Novel ?-lactams

• 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.

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Spectrum of Activity
Organism MIC90 (?g/mL) MIC90 (?g/mL) MIC90 (?g/mL) MIC90 (?g/mL)
Organism 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

• 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.

• Multiple mutations in PBP1a, 2b, and 2x.
  MIC90 of 2 mg/L vs. cefuroxime-resistant
  strain

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Clinical Utility
ABx Route In vivo Efficacy Cross-Resistance Limitations
CTL IV Good lung penetration in rabbit model None - all active against MDR strains Presumed or reported cross-hypersensitivity to ?-lactams
CBP IV Equal to CTX in murine model None - all active against MDR strains Presumed or reported cross-hypersensitivity to ?-lactams
FAR PO Eradication of S. pneumoniae NI to AMX ? CLV, CPX None - all active against MDR strains Presumed or reported cross-hypersensitivity to ?-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.

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Novel Glycopeptides

• 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

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Spectrum of Activity
Organism MIC90 (?g/mL) MIC90 (?g/mL) MIC90 (?g/mL) MIC90 (?g/mL)
Organism VAN DAL ORI TEL
Pen-S 0.5 0.03 0.004 0.03
Pen-NS 0.25-2 0.03 0.008 0.015
MDR 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.

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Clinical Utility
ABx Route In vivo Efficacy Cross-Resistance AEs
DAL IV Animal model of PCN-resistant NBPP Partial with vancomycin clinical significance unclear Redman syndrome with TEL Rare ? in platelets
ORI IV High AUCMIC ratios in ELF and plasma in murine NBPP Partial with vancomycin clinical significance unclear Redman syndrome with TEL Rare ? in platelets
TEL IV Good penetration into ELF and AMs in human volunteers Phase III trial pending 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.

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Novel Fluoroquinolone

• Garenoxacin (PO/IV)
• Bactericidal
• MIC90 0.06 ?g/mL for penicillin-, macrolide-,
  and ? 6 drug- resistant S. pneumoniae
• MIC90 1 ?g/mL for CIP- and LEV- resistant S.
  pneumoniae
• More potent than MOX

• Wu P et al. Antimicrob Agents Chemother. 2001.
  Jones RN et al. Diag Micro Infect Dis. 2007.

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Polymyxins

• 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

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Colistin

• 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

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Colistin

• Active
• Acinetobacter species,
• Pseudomonas aeruginosa,
• Enterobacteriaciae

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Colistin

• 160 mg (2 million IU) ever 8 h
• 240 mg (3 million IU) every 8 h for
  life-threatening infections

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Colistin

• 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)

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Ceftobiprole (Zeftera)

• 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

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Daptomycin (Cubicin)

• 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.

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Daptomycins Mechanism of Action

• Irreversibly binds to cell membrane of
  Gram-positive bacteria
• Calcium-dependent membrane insertion of molecule
• Rapidly depolarizes the cell membrane
• Efflux of potassium
• Destroys ion-concentrationgradient

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• Mechanism of action of Anti bacterials
• Mechanism of Bacterial Resistance
• Second level
• Third level
• Fourth level
• Fifth level