 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
 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

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)

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.)

 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 sulfonamide chloramphenicol aminoglycoside


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.

 “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

 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



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

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]

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

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

Ampicillin
Penicillin G
Amoxicillin
Methicillin
Dicloxacillin
R

Group
Natural penicillins
Pen G/Pen V b
-lactam antibiotics-1
Spectrum b
-lactamase sensitivity narrow spectrum gram positive sensitive
Penicillinase resistant
-methicillin
-dicloxacillin narrow spectrum resistant




 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

Group b
-lactam antibiotics-1
Natural penicillins
Pen G/Pen V
Spectrum narrow spectrum gram positive b -lactamase sensitivity sensitive
Penicillinase resistant methicillin dicloxacillin
Aminopenicillins ampicillin amoxicillin
Antipseudomonal ticarcillin piperacillin narrow spectrum gram negative gram negative including pseudomonas resistant sensitive sensitive

Brody’s Human Pharmacology

Group
Cephalosporins cefaclor ceftriaxone b
-lactam antibiotics-2
Spectrum broad spectrum b -lactamase sensitivity variable

b
 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

b
 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