Download Glycopeptides, Oxazolidinones, Streptogramins and

Glycopeptides, Oxazolidinones,
Streptogramins and
Aminoglycosides
Hail M. Al-Abdely, MD
Consultant, Adult Infectious Diseases
King Faisal Specialist Hospital and
Research Center
AIM OF THIS PRESENTATION
Practical use of these antibiotics
No sophisticated stuff!!
Driving forces behind Drug
development
 Good market
 Common NOT rare (pseudomonas versus
Burkhelderia)
 Common in the rich (HIV versus leishmania)
 Difficult to treat
 Emerging
new organisms (Fungi in immune
suppressed patients)
 Resistance in old organisms (several bacteria)
 Better kinetics and safety (Ampho B versus Azoles)

Basic Human need
Glycopeptides
Glycopeptides

Vancomycin
 Licensed

throughout the world
Teicoplanin
 Not
FDA approved
Vancomycin

Vancomycin is obtained from Nocardia
orientalis
Vancomycin has been used clinically since
1956
 Recent improvements in manufacturing
have increased its purity and reduced its
toxicity
 Pure gram positive spectrum

Vancomycin

Vancomycin is bactericidal (except enterococcus)



binds to the precursor units of bacterial cell walls
(peptidoglycans), inhibiting their synthesis.
In addition, RNA synthesis is inhibited
Work systemically, topically and locally



Systemic gram-positive infections
C. difficile colitis
Shunt infections/ventriculitis
When do you need Vancomycin
Nafcillin
Vancomycin
When do you need Vancomycin

Resistance to better drugs



MRSA, Coagulase-negative Staphylococi
Amp-resistant enterococcus,
Some corynebacteria and bacillus
Allergy to better drugs
 Toxicity of better drugs
 Empiric therapy for suspected resistance
 Special situations



Dosing intervals in OPD setting
Dialysis
Disadvantages of Vancomycin
Parentral
 Poor penetration to CSF
 Lower efficacy than penicillins
 Mild to moderate toxicity
 Resistance

 VRSA
 VRE
% Vancomycin-Resistant
Enterococci
Nosocomial Enterococci Reported as
Resistant to Vancomycin, by Year
30
25
20
15
10
5
0
89 90 91 92 93 94 95 96 97 98 99
*National Nosocomial Infections
Surveillance (NNIS) System
Data, 1989-1999.
Year
Vancomycin-resistant enterococci
Non-Intensive Care Unit Patients
30
25
20
15
10
5
00
20
99
19
98
19
97
19
96
19
95
19
94
19
93
19
92
19
91
19
90
19
89
0
19
Percent Resistance
Intensive Care Unit Patients
Source: National Nosocomial Infections Surveillance (NNIS) System
Due you need to measure levels

No except
 Pre-existing
renal impairment
 Rising creatinine
 Co-administered nephrotoxic drugs
 Assure therapeutic levels (serious infections)
Measure only trough levels (pre-dose)
 Dialysis patients: pre-dialysis level

 STOP
weekly vancomycin dosing in HD
patients
Teicoplanin
Similar to vancomycin in spectrum
 Once daily and I.M dosing
 May retain activity against vancomycinresistant Staphylococcus aureus
 More active against enterococcus than
vancomycin

When you may need Teicoplanin
Dosing advantages for out-patient
treatment
 VRSA
 Some strains of VRE

Lipopepetides
Daptomycin
Lipopepetides

Daptomycin



Approval by FDA September 2003 for treatment of
complicated skin and soft tissue infections
Mechanism of action: disruption of the plasma
membrane function.
Bacteriocidal against multidrug-resistant, grampositive bacteria




Methicillin-resistant Staphylococcus aureus
Vancomycin-resistant enterococci
Glycopeptide-intermediate and -resistant S. aureus.
Penicillin-resistant Streptococcus pneumoniae
Daptomycin
Fast bacteriocidal action
 Concentration-dependent killing
 Post antibiotic effect
 Once daily dosing
 Excreted mainly through kidneys

Streptogramins
quinupristin
dalfopristin
Streptogramins







Isolated from Streptomyces pristinaespiralis
Used as oral agents in France since the 1960s
Dalfopristin and quinupristin are the only parentral
agents
The combination product (Synercid®) has up to 16
times the activity of each agent alone
Streptogramins inhibit bacterial protein synthesis by
irreversibly blocking ribosome functioning
Each component is bacteriostatic but the combination is
bacteriocidal
The main reason for development and approval is VRE
Synercid™
Combination of dalfopristin and
quinupristin
 administered by intravenous infusion
 Metabolism is not dependent on
cytochrome P450. But a major inhibitor of
the activity of cytochrome P450 3A4
isoenzyme
 Elimination through fecal excretion

When you may ask for Synercid™

Serious VRE infection

MRSA infection for which you can not use
vancomycin +/- linezolid
Safety of Synercid™
Safe with no major toxicities
 Thrombophlebitis, GI
 Mostly given through a CVL

Oxazolidinones
Oxazolidinones
Synthetic antibiotics
 One approved (Linezolid), some are still
investigational (Eperezolid, furazolidone)

Linezolid
Linezolid
Approved for use in adults April 2000 and for
pediatrics December 2002
 Works against aerobic gram-positive organisms
 Linezolid inhibits bacterial protein synthesis by
interfering with translation
 binds to a site on the bacterial 23S ribosomal
RNA of the 50S subunit; this action prevents the
formation of a functional 70S initiation complex,
an essential step in the bacterial translation
process

Linezolid






Linezolid is administered by intravenous infusion
or orally
oral bioavailability for linezolid is 100%.
have significant penetration into bone, fat,
muscle, and hematoma fluid
metabolism is non-enzymatic and does not
involve CYP450
does not inhibit or induce CYP450 isoenzymes.
Non-renal clearance accounts for 65% of an
administered linezolid dosage (no adjustment in
renal failure)
Indications of Linezolid
Mainly developed because of VRE
 first new antibiotic approved to target
methicillin-resistant staphylococci in 35
years

Resistance to Linezolid

linezolid-resistant VRE organisms were
being discovered in various institutions

Also some MRSA
Safety of Linezolid

linezolid is a non-selective inhibitor of
monoamine oxidase (MAO)
AMINOGLYCOSIDES
AMINOGLYCOSIDES
Members of the Group
Streptomycin
Neomycin
Kanamycin
Gentamycin
Tobramycin
Amikacin
Arbikacin
Dibekacin
Netilmicin
Sisomycin
Aminosidine
Paromomycin
Spectinomycin
AMINOGLYCOSIDES

Mechanism of Action



interfere with protein synthesis
active transport mechanism
Mode of Action
 bactericidal
AMINOGLYCOSIDES

Antibacterial activity

Spectrum:





aerobic gram (-) bacteria
mycobacteria
Brucella
gram (+) bacteria
Characteristics


Highly polar cations  limited distribution
Low activity in low PH
AMINOGLYCOSIDES

Pharmacodynamics
 Concentration
dependent killing
 Postantibiotic effect
Once
daily dosing
Similar efficacy
Low nephrotoxicity
AMINOGLYCOSIDES
Pharmacokinetics
Absorption
very poorly absorbed
parenteral
Distribution negligible binding to plasma proteins
excluded from most cells
VD = ECF
in renal cortex / inner ear
Excretion
GF
AMINOGLYCOSIDES
Mechanisms of Resistance

inactivation by microbial enzymes






Plasmid-mediated
Acetylases, adnylases, phosphorylases
Amikacin is the most stable
impaired intracellular transport / failure of
permeation
altered ribosomal binding site / low affinity of the
drug
Enterococcus: In cases of high level resistance to
gentamicin, you can only use streptomycin
PROBLEMS OF AMINOGLYCOSIDES

Adverse Effects
 Ototoxicity
 Nephrotoxicity

Monitoring
 Neurotoxicity

Distribution
 Combined with other
agents

Resistance  Alternatives
Monitoring levels of Aminoglycosides
Trough levels correlate with nephrotoxicity
and a lesser extent ototoxicity
 High peak levels in elderly can be
associated with nephrotoxicity and
ototoxicity
 If dosing once daily, check trough levels.
They should be non-detectable
 Close monitoring is essential in renal
impairment

Final Statement

Microbes are going to stay with us no mater
what we do to them
 Those who are going to stay with us are those
that are most resilient (i.e. resistant) ones that
can adapt to all of our weapons
 So, let’s try to keep facing the less resilient ones;
those that we can treat effectively
 We do that by a “wise” management of the battle
with microbes through judicious use of
antimicrobials.