Transcript Ab-Resist_07ho

Resistance to antibiotics

Intrinsic resistance (examples)
• penG does not enter gram negative bacteria well

why? doesn’t penetrate--ampicillin does
• rifampin doesn’t kill fungi

why? doesn’t get in---weaken barrier with amphotericin and then it does
• isoniazid does not kill bugs that don’t require synthesis of mycolic
acids
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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
2006 Antibiogram Harborview/UW
Acquired Drug Resistance
1. enzymatic inactivation (b-lactams, aminoglyc. chloramph)
Bacteria keep up with big pharma in the b-lactam antibiotic
arms race
bacteria can often express more than one b-lactamase
Inactivation of
aminoglycosides by
acetylation,
phosphorylation, and
adenylation in drugresistant organisms
Acquired Drug Resistance
1. enzymatic inactivation (b-lactams, aminoglyc. chloramph)
2. rapid efflux of drug out of cell (tetracyclines, ciprofloxacin)
Drug export systems in Gram +
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/competitor (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.)
Vancomycin resistance: mechanism
Vancomycin resistance: mechanism
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
Plasmid-mediated drug resistance
tetracycline
chloramphenicol
sulfonamide
aminoglycoside
Problems with Antibiotic resistance

more than 50% of antibiotics used in domestic animals for subtherapeutic 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.
Antibiotics given to pigs as of 2000
 “KFC
does not purchase poultry treated
nontherapeutically with medically important
antibiotics.” – Letter to “Keep Antibiotics
Working,” August 28, 2002
 McDonald’s
‘We’ve 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
McDonald’s. – Walt Riker, McDonald’s,
“Chickens Fed With Antibiotics McGone,”
Chicago Sun-Times, February 12, 2002
Prospects for new antibiotics?
 new
antibiotic development slowed in 80’s/90’s
 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
active against Strep pneumoniae
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
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Qnr proteins
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
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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
PREVALENCE OF PLASMID-MEDIATED RESISTANCE TO
QUINOLONES IN Escherichia coli

1% QnrA+ isolates among ciprofloxacin-resistant E.coli
from different countries [AAC (2003) 47:559]
 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]
TB drug development
 no
new TB drugs in
past 40 years
 multi-drug resistant
TB prevalent
 Johnson & Johnson


R207910
targets
mycobacterium ATP
synthetase
b-Lactam Antibiotic development
 spectrum
of action
 resistance to b-lactamase
 specific b-lactamase
inhibitors
Ampicillin
Penicillin G
Amoxicillin
Methicillin
Dicloxacillin
R
b-lactam antibiotics-1
Group
Spectrum
b-lactamase
sensitivity
Natural penicillins
Pen G/Pen V
narrow spectrum
gram positive
sensitive
Penicillinase resistant
-methicillin
-dicloxacillin
narrow spectrum
resistant
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
b-lactam antibiotics-1
Group
Spectrum
b-lactamase
sensitivity
Natural penicillins
Pen G/Pen V
narrow spectrum
gram positive
sensitive
Penicillinase resistant
methicillin
dicloxacillin
Aminopenicillins
ampicillin
amoxicillin
Antipseudomonal
ticarcillin
piperacillin
narrow spectrum
resistant
gram negative
sensitive
gram negative including
pseudomonas
sensitive
Cephalosporins
Brody’s Human Pharmacology
b-lactam antibiotics-2
Group
Spectrum
b-lactamase
sensitivity
Cephalosporins
cefaclor
ceftriaxone
broad spectrum
variable
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
b-lactamase
inhibitors
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)
Activity of available b-lactamase inhibitors against clinically
important b-lactamases