Vancomycin Vancomycin has become increasingly important in the treatment of - PowerPoint Presentation

Slide1

Vancomycin

Vancomycin

has become increasingly important in the treatment of

life-threatening infections

.

MRSA infections.

Methicillin

-resistant Staphylococcus

epidermidis

(MRSE) infections

Enterococcal

infections.

Slide2

Daptomycin

Telavancin

Fosfomycin

Polymyxins

Slide3

Protein Synthesis Inhibitors

Slide4

Protein Synthesis Inhibitors

Antibiotics exert their antimicrobial effects by

targeting bacterial ribosomes and inhibiting bacterial protein synthesis

.

Bacterial ribosomes

composed of

30S and 50S subunits

.

Mammalian ribosomes

have

40S and 60S subunits.

Selectivity minimizes potential adverse

Structure of

mitochondrial ribosomes

more closely resembles bacterial ribosomes.

High concentration…side effect(

tetracyclines

and chloramphenicol).

Slide5

Tetracyclines

Mechanism of action:

Slide6

Slide7

Absorption

Administration with

dairy products

or other substances that contain

divalent

and

trivalent

cations

(magnesium, aluminum antacids or iron supplements)

decreases absorption

particularly for

tetracycline

.

Slide8

Tetracyclines

Bacteriostatic

including

gram-positive and gram-negative bacteria.

Resistance to

tetracyclines

is

:

Efflux pump that expels drug out of the cell

Enzymatic inactivation of the drug.

Production of bacterial proteins that prevent

tetracyclines

from binding to the ribosome

.

Slide9

Contraindications:

The

tetracyclines

should not be used in pregnant.

Breast-feeding women.

Children less than 8 years of age

.

Slide10

Slide11

Protein Synthesis Inhibitors

Tigecycline

: a

derivative of

minocycline

, is the first available member of the

glycylcycline

antimicrobial class

.

Complicated skin and soft tissue infections.

Complicated intra-abdominal infection.

Bacteriostatic

action.

Broad-spectrum

activity.

The primary route of elimination is

biliary

/fecal.

Nausea and vomiting

.

Slide12

Aminoglycosides

The term “aminoglycoside” stems from their structure—two

amino sugars joined by a

glycosidic

linkage to a central hexose nucleus.

Treat serious infections/aerobic gram-negative bacilli.

Their clinical

utility is limited by serious toxicities.

Aminoglycosides are derived from either:

Streptomyces sp. (have –

mycin

suffixes)

Micromonospora

sp. (end in -

micin

).

Slide13

Aminoglycides

The

bactericidal

effect of aminoglycosides is

concentration dependent

; that is, efficacy is dependent on the

maximum concentration (

Cmax

)

of drug above the minimum inhibitory concentration (MIC) of the organism.

Aminoglycosides target

Cmax

is

eight to ten times the MIC

.

Exhibit a

postantibiotic

effect (PAE),

which is continued bacterial suppression after drug levels fall below the MIC.

The larger the dose the longer the PAE.

Because of these properties

extended interval dosing

(a single large dose given once daily)

is now more commonly utilized than divided daily doses

.

This

reduces the risk of

nephrotoxicity and increases convenience.

Slide14

Aminoglycosides

The

aminoglycosides

are effective for the majority of

aerobic

gram negative bacilli

, including those that may be

multidrug resistant.

Aminoglycosides

are often combined with a β-

lactam

antibiotic to employ a synergistic effect

.

Amikacin

Gentamicin

Tobramycin

Streptomycin

Slide15

Resistance

Resistance to

aminoglycosides

occurs via:

Efflux pumps

Decreased uptake

Modification and

inactivation by plasmid-associated synthesis of enzymes.

Each of these enzymes has its own

aminoglycoside

specificity; therefore,

cross-resistance cannot be presumed

.

Amikacin

is less vulnerable to these enzymes than other

antibiotics in

this group.

Slide16

Aminoglycosides

The

highly polar,

polycationic

structure of the

aminoglycosides

prevents adequate absorption after

oral

administration.

All

aminoglycosides

except

neomycin

must be given

parenterally

to achieve adequate serum levels.

Neomycin

is not given

parenterally

due to

severe

nephrotoxicity

.

It is administered

topically

for skin infections

or

orally

for bowel preparation prior to colorectal surgery.

Concentrations in CSF are inadequate even in the presence of inflamed

meninges

.

All

aminoglycosides

cross the placental barrier

and may accumulate in fetal plasma and amniotic fluid.

More than 90% of the

parenteral

aminoglycosides

are excreted unchanged in the urine

Slide17

Adverse Effects

Otoxicity

:

(vestibular and auditory) is directly

related to high peak plasma levels and the duration of treatment.

The

antibiotic accumulates

in the

endolymph

and

perilymph

of the

inner ear

.

Deafness may be irreversible

and has been known to affect

developing fetuses.

Nephrotoxicity

:

kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible, acute tubular necrosis.

Neuromuscular

parpalysis

:

high doses infused over a short period.

Allergic reaction:

contact dermatitis

is a common reaction to topically applied neomycin.

Slide18

Macrolides

Macrocyclic

lactone

structure to which one or more

deoxy

sugars are attached.

The

macrolides bind irreversibly

to a site on the

50S subunit

of the bacterial ribosome, thus inhibiting translocation steps of protein synthesis.

Generally considered to be

bacteriostatic

they may be

bactericidal

at higher doses

.

Slide19

Macrolides

Erythromycin

was the

first of these drugs to find clinical application

/ an

alternative to penicillin in individuals with an allergy to

β-

lactam

antibiotics

.

Clarithromycin

(a

methylated

form of erythromycin)

Azithromycin

(

having a larger

lactone

ring)

Telithromycin

a

semisynthetic

derivative of erythromycin

, is the first “

ketolide

” antimicrobial agent.

Ketolides

and

macrolides

have similar antimicrobial coverage.

Ketolides

are active against many

macrolide

-resistant gram-positive strains

Slide20

Antibacterial spectrum

Erythromycin:

This drug is effective against many of the same organisms as penicillin G it may be used in patients with penicillin allergy.

Clarithromycin

:

Clarithromycin

has activity similar to erythromycin,

Helicobacter pylori

, is higher than that of erythromycin.

Azithromycin

:

Although less active against streptococci and staphylococci than erythromycin,

azithromycin

is far

more active against respiratory infections

due to

H.

influenzae

and

Moraxella

catarrhalis

.

Telithromycin

:

This drug has an antimicrobial spectrum similar to that of

azithromycin

. Moreover, the

structural modification

within

ketolides

neutralizes the most common resistance mechanisms

Slide21

Resistance

Inability of the organism to take up the antibiotic

Presence of efflux pumps

Decreased affinity of the 50S ribosomal subunit for the

antibiotic RNA

in gram-positive organisms.

Presence of plasmid associated erythromycin

esterases

in gram-negative organisms

Slide22

Pharmacokinetics

Erythromycin is destroyed by gastric acid.

Enteric-coated tablets

Esterified

forms of the antibiotic.

All are adequately absorbed upon oral administration

Clarithromycin

,

azithromycin

, and

telithromycin

are stable in stomach acid and are readily absorbed.

Food

interferes with the absorption of erythromycin and

azithromycin

but can

increase that of

clarithromycin

.

Erythromycin

and

azithromycin

are available in

IV

formulations.

Slide23

Slide24

Drug interactions

Erythromycin

,

telithromycin

, and

clarithromycin

inhibit the hepatic metabolism of a number of drugs

, which can lead to

toxic accumulation

of these compounds.

An interaction with

digoxin

may occur. In this case, the

antibiotic eliminates a

species of intestinal flora

that ordinarily

inactivates

digoxin

, thus leading to

greater

reabsorption

of the drug from the

enterohepatic

circulation

.

Slide25

Clindamycin

Clindamycin

and

erythromycin

mechanism of action and resistance are similar.

Clindamycin is available in both

IV and oral

formulations, but use of the

oral form

is limited by

gastrointestinal intolerance

.

Slide26

Slide27

Chloramphenicol

Broad-spectrum

antibiotic is restricted to life-threatening infections for which no alternatives exist.

Chloramphenicol

binds reversibly to the bacterial

50S

ribosomal subunit and inhibits protein synthesis.

Due to some similarity of mammalian mitochondrial

ribosomes

to those of bacteria, protein and ATP synthesis in these organelles may be inhibited at high circulating

chloramphenicol

levels, producing

bone marrow toxicity

.

Slide28

Chloramphenicol

Resistance:

is conferred by the presence of

enzymes that inactivate chloramphenicol.

Mechanisms include

decreased ability to penetrate

the organism and

ribosomal binding site alterations

.

Drug interactions:

Chloramphenicol

inhibits some of the hepatic mixed-function oxidases

and, thus,

blocks the metabolism

of drugs such as

warfarin

and

phenytoin

,

thereby elevating their concentrations and potentiating their effects.

Slide29

Adverse effects

Anemias

: Patients may experience dose-related anemia, hemolytic

Gray baby syndrome:

Neonates have a low capacity to

glucuronidate

the antibiotic, and they have underdeveloped renal function.

Neonates

have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial

ribosomes

.

This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term

“gray baby

”), and death

.