Transcript A Map to Learn your Way around Antibioticland

The ABC’s of Antibiotics
Lourdes Irizarry, MD
Associate Professor of Medicine
Albuquerque VAMC & UNM SOM
Principles of Antimicrobial
Therapy

Site of action
 Individual patient
 Ecology of the institution
 Efficacy
 Toxicity
 Cost
Classes of Antibiotics

Beta lactams
 Monobactams
 Carbapenems
 Macrolides/Azalides/Lincosamides
 Aminoglycosides
 Fluoroquinolones
 Oxazolidinones
Antibiotic brands






50 penicillins
71 cephalosporins
12 tetracyclines
8 aminoglycosides
1 monobactam
3 carbapenems





9 macrolides
2 streptogramins
3 dihydrofolate
reductase inhibitors
1 oxazolidinone
5.5 quinolones
Inhibition of Cell Cell Wall
Synthesis
 Vancomycin,
teicoplanin
 Beta-lactams
 Monobactams
 Carbapenems
Inhibition of Protein Synthesis

50 S inhibitors
– macrolides

30 S inhibitors
– tetracycline
– chloramphenicol
– aminoglycosides
– clindamycin
– oxazolidinones
Interference with basic cell
functions

– quinolones

Folic acid
metabolism
DNA gyrase
– trimethoprim
– sulfonamides
Antibiotic Inactivation

Destruction or modification
– Ex: Beta-lactamase production

Alteration of the antibiotic target site(s)
– Ex: Abnormal PBPs

Prevention of access to target
– Ex: Efflux pump & Deletions of porins
Antibiotic Essentials’
Antibiotic
Gram
(+)
Gram.
(-)
Anaerobes
CNS
PCN
+
-
+/-
+
Neurosyphilis
Nafcillin
Ampicillin
Strep. A,
N.meingitidis
Listeria,
Eikenella
Enterococcus Pasteurella
(Not Staph.
Not PRSTP)
N.
meningitidis
MSSA
-
-
+
+
Enterococcus
+/-
+/-
+
(Not S. pyogenes,
Not Sthaph.)
E.coli,
Proteus
B-lactamase neg.
H.flu, Moraxella
Listeria
Antibiotic Essentials’ (2)
Antibiotic
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Ticarcillin
+
i.e. PCN
+++
+
+/-
Not
Enterococcus
Piperacillin
P.aeruginosa
(Not
Acitenobacter)
+
i.e. PCN
+++
+
+/-
+
i.e. PCN
Enterococcus
+++
+
+/-
E. faecalis
Mezlocillin
Antibiotic Essentials’ (3)
Antibiotic
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Ampicillin/
Sulbactam
+++
MSSA, MSSE
+
+++
-
+++
-
+++
-
Not PRSTP
i.e.
Ampicillin
H. flu,
Moraxella
Few Klebsiella
Ticarcillin/
+++
Clavulanic MSSA, MSSE
Not Enterococcus
acid
Piperacillin/
+++
Tazobactam MSSA, MSSE,
Enterococcus
+++
No increased
activity for
Pseudomonas
+++
No increased
activity for
Pseudomonas
Antibiotic Essentials’ (4)
Antibiotic
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
1st gen.
Cephalosporins
+
MSSA,
MSSE
+/-
-
-
Not STP
Not
Enterococcus
Not Blactamase
producers
Antibiotic Essentials’ (5)
3rd Gen
Cephalosporin
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Ceftazidime
-
+++
-
+++
-
+++
++
++
+++
++
++
+++
Antipseudomonal
Ceftriaxone
Cefotaxime
Ceftizoxime
+++
++
Not antiMSSA, MSSE,
pseudomonal
PRSTP
Not Enterococcus
+++
Not ideal for
Staph.
Not Enterococcus
Not antipseudomonal
Not ideal for
Staph.
Not Enterococcus
Not antipseudomonal
++
Antibiotic Essentials’ (6)
4th Generation
Cephalosporin
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Cefepeme
+++
MSSA, MSSE
Not
Enterococcus
+++
Antipseudomonal
-
+++
Antibiotic Essentials: (7)
Antibiotic
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Meropenem
Imipenem
+++
+++
+++
+
Not MRSA, Not
Enterococcus
Not.
Sternothrophomon
as
-
+++
-
+/-
Aztreonam
Antibiotic Essentials’: (9)
Antibiotic
Gram.
(+)
Gram.
(-)
Anaerobes
CNS
Azithromycin
Clarithromy
+
H. Flu
Moraxella
-
-
+/- H. flu &
Moraxella
-
-
Erythromycin
Not
Enterococcus
+/- SAU
+
Not
Enterococcus
+/-SAU
Macrolides

Erythromycin and Clarithromycin have
hepatic metabolism via cytochrome p-450
(Increase levels of theophylline, warfarin, triazolam,
bromocriptine, carbamazepine and cyclosporin)

Erythromycin iv from causes phlebitis,
not Azithromycin, no IV Clarithromycin
(too venous toxic)
Classification of Fuoroquinolones

First generation

– nalidixic acid

Third generation**
– gatifloxacin
 (sparfloxacin,
grepafloxacin)
Second generation
– norfloxacin
– ciprofloxacin*
– ofloxacin
– levofloxacin

Fourth generation***
– moxifloxacin
– trovafloxacin,
(clinafloxacin)
Activity of Fluoroquinolones Against
Gram Positive Bacteria
Species
Cipro.
Gati.
Levo.
Moxi.
Trova
Oflox
0.125-1
MSSA
0.5-.078 0.1-0.13 0.25
0.06
0.06
MRSA
3.13-32
0.2-16
4
4
S. epi
0.39-1
0.2-0.25 0.5-1
0.13
0.015-4 0.125-1
0.78-2
1-3.13
1
0.12-2
1-8
1.56-4
3.13-8
1-4
0.25-8
1-4
0.5
1-3.13
0.120.25
0.120.5
1-2
E.
1.56-4
faecalis
E.
3.13-16
faecium
S.
1.56-4
pneumo
16
Activity of Fluoroquinolones for
Gram Negative Bacteria
Species Cipro
E.cloac
E.coli
Amp.-R
Kleb.
Cefz.-R
Pseudo.
Gati
Levo
Moxi
Trova
Oflox
0.03-0.1 0.06-0.2 0.06
0.06
0.06
0.030.12
0.0160.5
16
0.0160.1
8
0.03
0.008
0.03-0.5
16
8
32
0.060.39
8
0.1-0.39 0.13
0.13
0.13-0.5
4
16
8
16
0.78-8
3.13-32
32
32
2-32
0.25-32
Activity of Fluoroquinolones
Against Anaerobes
Species
Cipro
Gati
Levo
Moxi
Trova
B. frag
2-128
0.25-1
2
0.12
0.25-2
C.difficile 16-32
1-2
8
-
1-2-16
Peptostre 0.5-8
1
3.13>4
2
0.25-0.5
6
Pneumococci With Reduced
Susceptibility to
Fluoroquinolones (%)
5
Ages 15-64
4
5
Age 65 and
older
4
3
3
2
2
1
1
0
0
88
89
90
91
92
93
Year
Chen DK, et al. N Engl J Med. 1999;341:233-239.
94
95
96
97
98
No. of Prescriptions per 100 Persons
Susceptibility of S.pneumoniae
to Fluoroquinolones
Activity of New
Fluoroquinolones Against
MRSA, VRE and PRSP
MRSA VRE
PRSP QTc change
Levofloxacin
+/-
+/-
++
4.6 msc
Gatifloxacin
+/-
+/-
++++
2.9 msc
Moxifloxacin
+/-
+/-
++++
6 msc
Gemifloxacin
+/-
+/-
++++
5 msc
Ciprofloxacin
+/---
+/---
+/---
?
Quinupristin/Dalfopristin
 S.
pneumoniae
 S.aureus
 E.
(MRSA)
faecium (VRE)
– No activity against E. faecalis
Others’...

Metronidazole anaerobic drug with excellent
CNS penetration
 Clindamycin: good for Gram.(+) and
anaerobes. Always include in the treatment of
Strep. skin & soft tissue infections. Great for
lung abscesses. (No CNS penetration)

Vancomycin: Inferior to B-lactams
against SAU
Other highlights...

Cross allergic reaction between Penicillins,
Cephalosporins and Carbapenems. Not
Aztreonam.
 Aztreonam cross allergy with Ceftazidime
 Cephalosporins and Metronidazole: Disulfiram
reaction
 Ticarcillin: bleeding in uremic patients
Drugs Under Development
PRSP, MRSA,VISA,VRE

Lipopetides (Daptomycin: narrow
therapeutic index)
 Glycyclines
 Glycopeptides (Vancomycin analogues)
 Fluoroquinolones
 Macrolides/Ketolides
 Evernimicin (trials on hold)
Antibiotics With
Immunomodulating Effects
 Macrolides
 Fluoroquinolones
 Quinupristin/dalfopristin
Future Directions on the
Treatment of Infections

Usage of immunomudalating agents
 Usage of non-antibiotics as adjuvant
therapy
 New approaches to rational drug design
– mapping
– binding
– genomics
“A collection of
anecdotes is not
data.”
Anonymous
“You have to run
towards where the
ball is going to be.”
Yogi Berra
very difficult,
particularly
about the
future.”
Neils Bohr
ABT-492

4th generation fluororoquinolone
 Trovafloxacin like activity
 Levofloxacin safety profile
 Little CNS or CV activity
 Iv & po
 Phase I trials 2,000
ABT-723

Ketolide
– ketone added to erythromycin
– quinoline ring increases activity

Phase II trials
 Phase III Fall 2,000
 S. pneumoniae activity 2-3x higher than
clarithromycin
Macrolides

Inhibits RNA dependent protein synthesis,
causing dissociation of peptidyl transfer
(tRNA) from the ribosome during
elongation phase
Fluoroquinolones
Mechanism of Action

Inhibit the activities of DNA gyrase (an
essential adenosine triphosphatehydrolizing topoisomerase) which in turn
inhibits bacterial DNA peplication and
transcription. Leading to bacterial death.
Mechanism of Action of
Quinolones (2)

To accommodate within bacterial cell,
organism’s DNA helix is coiled and twisted
in a direction opposite to the double helix
(negative supercoil). DNA gyrase catalyzes
the entry of these negative supercoils into
circular chromosomal DNA and plasmid
DNA
Mechanism of Action Quinolone
(3)

DNA gyrase consists of 2A and 2B
subunits. A interrupts supercoiling. After
fixing the negative supercoils in place, A
reseals the break.
 Quinolones trap the complex after strand
breakage preventing A from resealing the
breaks. DNA sythesis is halted.
Mechanisms of Resistance

Spontaneous mutations in bacterial
chromosomes
– Mutations in A subunit of bacterial DNA gyrase
that lowers affinity of drug at gyrase complex
– Mutations of chromosomally mediated drug
influx and efflux systems
– Selection for resistance dependent on quinolone
and organism