Resistance to antibiotics

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Resistance to antibiotics

• Intrinsic resistance (examples)
• penG does not enter gram negative bacteria well
• why? doesnt penetrate--ampicillin does
• rifampin doesnt kill fungi
• why? doesnt get in---weaken barrier with
  amphotericin and then it does
• isoniazid does not kill bugs that dont require
  synthesis of mycolic acids
• Environmental resistance
• e.g. sulfonamide resistance if high purines,
  methionine, thymidine available (such as in an
  abscess)
• e.g. aminoglycosides not effective in anaerobic
  environment
• Acquired Resistance
• genetic changes, plasmids with new genes

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2006 Antibiogram Harborview/UW
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Acquired Drug Resistance

• 1. enzymatic inactivation (b-lactams, aminoglyc.
  chloramph)

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Bacteria keep up with big pharma in the b-lactam
antibiotic arms race
bacteria can often express more than one
?-lactamase
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Inactivation of aminoglycosides by acetylation,
phosphorylation, and adenylation in
drug-resistant organisms
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Acquired Drug Resistance

• 1. enzymatic inactivation (b-lactams, aminoglyc.
  chloramph)

• 2. rapid efflux of drug out of cell
  (tetracyclines, ciprofloxacin)

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Drug export systems in Gram
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Acquired Drug Resistance

• 1. enzymatic inactivation (b-lactams, aminoglyc.
  chloramph)

• 2. rapid efflux of drug out of cell
  (tetracyclines, ciprofloxacin)

• 3. decreased conversion to active form (isoniazid)

• 4. increased concentration of antagonist/competito
  r (sulfonamide
• resistance with increased PABA synthesis).

• 5. altered amount of receptor (trimethoprim-DHFR
  amplification)

• 6. altered structure of target to reduce binding
  (methicillin
• resistance, vancomycin resistance, ciprofloxacin
  res.)

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Vancomycin resistance mechanism
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Vancomycin resistance mechanism
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Resistance can be transferred between bacteria

• phage transduction
• transposable elements
• plasmid transfer during conjugation
• plasmids can contain multiple resistance genes
• transfer can occur between non-pathogen and
  pathogens

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Plasmid-mediated drug resistance
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Problems with Antibiotic resistance

• more than 50 of antibiotics used in domestic
  animals for sub-therapeutic effect breeding
  ground for resistance

There are 7.5 billion chickens, 292 million
turkeys, 109 million cattle and 92 million pigs
in the United States.
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Antibiotics given to pigs as of 2000
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• KFC does not purchase poultry treated
  nontherapeutically with medically important
  antibiotics. Letter to Keep Antibiotics
  Working, August 28, 2002
• McDonalds
• Weve listened to the concerns, studied the
  issue, and the bottom line was we thought it was
  the right thing to do to discontinue the use of
  fluoroquinolone antibiotics in poultry, said
  Walt Riker, spokesman for Oak Brook-based
  McDonalds. Walt Riker, McDonalds, Chickens
  Fed With Antibiotics McGone, Chicago Sun-Times,
  February 12, 2002

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Prospects for new antibiotics?

• new antibiotic development slowed in 80s/90s
• selective drugs have lower market value
• 5-15 yr time frame to get new drugs to physicians
• recent increase in new antibiotic development is
  encouraging

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active against Strep pneumoniae
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Plasmid Mediated Quinolone Resistance (PMQR)

• First reported in a strain of K. pneumoniae
• QnrA protein 218 aa protein
• Protects DNA gyrase and topoisomerase IV from the
  inhibitory activity of quinolones--exact
  mechanism is not known yet
• Qnr proteins
• QnrA2 K. oxytoca (China)
• QnrB - E. coli, K. pneumoniae, E. cloacae, C.
  koseri (USA and India) - 40 aa identity with
  QnrA
• QnrS S. flexneri (Japan) - 59 aa identity
  with QnrA
• The presence of other mechanisms of resistance
  may increase plasmid-mediated quinolone resistance

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PREVALENCE OF PLASMID-MEDIATED RESISTANCE TO
QUINOLONES IN Escherichia coli

• 1 QnrA isolates among ciprofloxacin-resistant
  E.coli from different countries AAC (2003)
  47559
• 11 QnrA isolates among ciprofloxacin-resistant
  K. pneumoniae and 0 in E.coli from USA AAC
  (2004) 48 1295
• 7.7 QnrA isolates among ciprofloxacin-resistant
  E. coli in Shanghai (China) AAC (2003) 47 2242
• 0.4 QnrA isolates among nalidixic acid-
  resistant Escherichia coli (France) AAC (2005)
  49 3091

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TB drug development

• no new TB drugs in past 40 years
• multi-drug resistant TB prevalent
• Johnson Johnson
• R207910
• targets mycobacterium ATP synthetase

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b-Lactam Antibiotic development

• spectrum of action
• resistance to b-lactamase
• specific b-lactamase inhibitors

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Ampicillin
R
Penicillin G
Amoxicillin
Methicillin
Dicloxacillin
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b-lactam antibiotics-1
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Methicillin resistance

• caused by unique peptidyl transferase that does
  not bind b-lactams
• had been largely confined to hospital acquired
  infections
• more recently--outbreaks in athletic teams, iv
  drug users, school children, gay community,
  general population
• 900 cases in LA county jails (2002)

Structure of PBP2a
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b-lactam antibiotics-1
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Cephalosporins
Brodys Human Pharmacology
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b-lactam antibiotics-2
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Newer b-lactams

• aztreonam (monobactam)
• gram- specific
• resistant to b-lactamase
• Carbapenems imipenem, meropenem
• broad spectrum (gram,gram-)
• resistant to b-lactamase
• penetrates CSF
• imipenem a substrate for dehydropeptidase I in
  kidney, meropenem is not

Brenner
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b-lactamase inhibitors
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b-lactamase inhibitors

• Clavulanic acid (suicide inhibitor for most
  lactamases)
• little antibiotic action on its own
• combine with amoxicillin to get Augmentin (oral
  activity)
• combine with ticarcillin to get Timentin
• Sulbactam (similar inhibitor)
• combine with ampicillin to get Unasyn (given iv
  or im)

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Activity of available b-lactamase inhibitors
against clinically important b-lactamases