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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. Antimicrobial Resistance. Lancet Infect Dis 2010; 10: 597–602. Published Online - August 11, 2010. Worldwide Prevalence of MRSA.

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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: 597–602

Published Online - August 11, 2010


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Worldwide Prevalence of MRSA

Grundmann H et al. Lancet 2006;368:874.


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Antibiotic Prescriptions


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No Major New Discoveries


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A Changing Landscape for Approved Antibacterials

18

16

14

12

10

Number of agents approved

8

6

4

0

2

0

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. 2004;38:1279-1286;

  • New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912


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Penicillin Cleavage by Penicillinase

b – Lactam Ring

b - Lactamase

Active

Inactive


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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

0157:H7 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

Binding

Target site

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

Changed site: blocked binding

Interior of organism


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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

Binding

Target site

Cell wall

Interior of organism


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Antibiotics Inactivation (Cleavage)

Enzymesbindtoantibioticmolecules

Enzymebinding

Antibiotic

Binding

Target site

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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Three mechanisms of -lactam antibiotic resistance are recognised:

Reduced permeability

Inactivation with -lactamase enzymes

Altered penicillin-binding proteins (PBPs)

-Lactam Antibiotic Resistance Mechanisms


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-Lactam Antibiotic Resistance Mechanisms


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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

-Lactam Antibiotic Resistance


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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)

-Lactam Resistance: AmpC Production

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


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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

-Lactam Resistance: ESBL Production

Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. DiagnMicrobiol Infect Dis 2002;44:273–280


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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 Carbapenemsand Cephamycins

Often non-susceptible to fourth generation Cephalosporins

Antimicrobial Features of ESBLs


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Introduction of methicillin in 1959 was followed rapidly by reports of MRSA isolates

Recognizedhospital 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

Features of methicillin-resistant Staphylococcus aureus (MRSA)

Jones. Chest 2001;119:397S–404S


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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

Emergence of MRSA in the community

  • 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


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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

Antimicrobial features of MRSA (1)

  • Hiramatsu et al. Trends Microbiol 2001;9:486–493

  • Berger-Bachi & Rohrer. Arch Microbiol 2002;178:165–171


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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

Antimicrobial features of MRSA (2)

  • Hiramatsu et al. J Antimicrob Chemother 1997;40:135–136

  • Hooper. Lancet Infect Dis 2002;2:530–538


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Vancomycin-resistant enterococci (VRE)

Vancomycin-resistant S. aureus (VRSA)

Glycopeptide resistance: focus on vancomycin resistance


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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

Features of quinoloneresistance: Gram-negative organisms

  • Masterton. J Antimicrob Chemother 2002;49:218–220 Thomson. J Antimicrob Chemother 1999;43(Suppl. A):31–40


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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 (<1%)

marked cross-resistance with other frequently used antibiotics

Features of quinoloneresistance: Gram-positive organisms

  • Hooper. Lancet Infect Dis 2002;2:530–538


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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

Summary

  • Cosgrove et al. Arch Intern Med 2002;162:185–190


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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 unit’s antimicrobial resistance profile and choosing antibiotics accordingly

Summary


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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 > 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. 2006;42:657-68.


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Enterobacteriaceae

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


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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

Extended-Spectrum β-Lactamases


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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

CTX-M-type ESBLs

Livermore, DM J. Antimicrob. Chemother 2009


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Ability to hydrolyze penicillins,cephalosporins, monobactams, and carbapenems

Resilient against inhibition by all commercially viableß-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

Carbapenemases


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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 includescephalosporins and carbapenems


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K. pneumoniae carbapenemase-producing bacteria

  • Nordmann P et al. LID 2009


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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 (plasmid-mediated AmpC β-lactamases)

AmpC β-lactamases


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Emerging Metallo-β-Lactamaseswith Mobile Genetics(SENTRY Program 2001-2005)


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Ceftaroline

Ceftobiprole

Oral penem

Faropenem

Novel -lactams

  • 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

  • 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

  • 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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Dalbavancin

Once weekly IV dosing

Oritavancin

Telavancin

Versus vancomycin:

Additional mechanisms of action

Renal and hepatic excretion

No known nephrotoxicity or dose adjustments

Novel Glycopeptides

  • Malabarba A et al. J Antimicrob Chemother. 2005


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Spectrum of Activity

  • *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

  • Gotfried M et al. ICAAC. 2005. Lehoux D et al. ICAAC. 2007.


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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

Novel Fluoroquinolone

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


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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

Polymyxins


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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

Colistin


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Active:

Acinetobacter species,

Pseudomonas aeruginosa,

Enterobacteriaciae

Colistin


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160 mg (2 million IU) ever 8 h

240 mg (3 million IU) every 8 h for life-threatening infections

Colistin


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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)

Colistin


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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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Daptomycin’s 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


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