Aminoglycosides & Spectinomycin
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Aminoglycosides & Spectinomycin. Part A Aminoglycosides. Overview. History and Source : the research made by Waksman and coworks within 1939-1943 Clinical Applications: for the treatment of aerobic G - bacterial infections and tuberculosis

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Aminoglycosides & Spectinomycin


Part A Aminoglycosides


Overview

  • History and Source : the research made by Waksman and coworks within 1939-1943

  • Clinical Applications: for the treatment of aerobic G- bacterial infections and tuberculosis

  • Two classes: crude product and semisynthetic derivative


Peak Concentration

Blood

Concentration

Bacterial growth is inhibited long after concentration below the MIC

MIC

Time (h)

General properties

1. Antimicrobial activity:

i) rapidly bactericidal to resting bacterium

ii) broad-spectrum: G- bacilli and cocci,G+ organisms,TB

iii) more active at alkaline

iv) concentration-dependent activity

v) the duration of post antibiotic effect (PAE) is concentration- dependent (10 hours).

vi) first exposure effect (FEE)


General properties

2. Mechanism of action:

  • inhibit protein synthesis

  • act as Ionic-absorbent, act directly on permeability of the cell membrane of bacterium.


P

A

Inhibiting protein synthesis: Aminoglycosides


2.Mechanism of action -inhibit protein synthesis

i) Interfering with the initiation complex of peptide formation.

ii) Inducing misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein.

iii) causing breakup of polysomes into nonfunctional monosomes.

iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted.


3. Mechanism of resistance

produces enzymes

Changes of Porins

Altered ribosomal subunit


Mechanism of Resistance

i) The microorganism produces a transferase enzyme or enzymes that inactivate the aminoglycoside by adenylyation, acetylation, or phosphorylation.

ii) Impaired entry of aminoglycoside into the cell.

iii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation.


General properties

ADME

i) Absorption: not absorbed after po, but rapidly absorbed after IM.

ii) Distribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high concentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidney.

iii) Elimination: excreted mainly by glomerular filtration. If renal function is impaired, accumulation occurs with a increase in those toxic effects which are dose related.


General properties

Clinical Uses

  • be mostly used against aerobicG-bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with b-lactam antibiotic and fluoroqunolones

  • Tuberculosis


General properties

Adverse reactions

i) Ototoxicity

  • involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! Auditory and vestibular damage).

    ii) Nephrotoxicity

  • consists of damage to the kidney tubules and be reversed if stop using.


General properties

Adverse reactions

iii) Neuromuscular blockade (paralysis)

  • generally occurred after intra-pleural or intra-peritoneal instillation of large doses of an aminoglycosides

  • Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity.

    iv) Allergic reaction

  • skin rashes fever, eosinophiliay ,anaphylactic shock, etc.


Aminoglycosides

  • Streptomycin

  • Gentamicin

  • Tobramycin

  • Amikacin

  • Netilmicin

  • Neomycin

  • Kanamycin

  • Arbekacin

  • Dibekacin

  • Micronomicin

  • Sisomicin

  • Etilmicin

  • Isepamicin

  • Astromicin


Streptomycin

1. ADME

i) Absorption:IM

ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves therapeutic concentrations with inflamed meninges.

iii) Excretion:90%, kidney

2.Clinical uses

i) plague and tularemia: combination with an oral tetracycline.

ii) tuberculosis: as first-line agent

iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal.

3. Adverse reactions

i) Allergic reaction

skin rashes, fever, anaphylactic shock

ii) Ototoxicity: disturbance of vestibular function, deafness of newborn

iii) Nephrotoxicity

iv) Neuromuscular blockade (paralysis):Myasthenia Gravis, anesthetics, scoline


Gentamicin

1. ADME

Gentamicin can accumulate in cortex of the kidney .

2.Clinical use :

i) serious G- bacillary infections (sepsis, pneumonia, etc.).

ii) infection induced by enterococcal, viridans streptococcal, staphylococcal etc. (in combinationwith other antibiotics, e.g. b-lactams)

iii) prevent the infection induced by operation (e.g., gastrointestinal operation )

iv) local application or intrathecal administration (rarely use)

3. Adverse reactions

i) Nephrotoxicity (reversible and mild)

ii) Ototoxicity (irreversible!)

iii) Nausea and vomiting etc.


Tobramycin

1.antimicrobial activity & pharmacokinetics: very similar to those of gentamicin; has cross-resistance to gentamicin.

2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin).


Netilmicin

1. similar to gentamicin & tobramycin in its pharmacokinetic properties.

2. broad spectrum, against aerobic G- bacilli.

3. tolerance to many aminoglycosides (gentamicin, tobramycin) - inactivating enzymes.

4. less toxic


Amikacin

1.Antibacterial activity: the broadest in the group.

2.Clinical uses :

  • Treatment of G-bacillary infections which resistance to gentamicin and tobramycin.

  • Most strains resistance to amikacin found is also resistance to other aminoglycosides.

  • combination with b-lactams, produce a synergistic bactericidal.

    3. Adverse reactions

    i) Ototoxicity

    ii) Nephrotoxicity

    iii) Neuromuscular blockade (paralysis)

    iv) skin rashes, fever, nausea and vomiting etc.


Macrolides and lincomycin


Structure


Representative drugs

Erythromycin

Dirithromycin

Meleumycin

Josamycin

Acetylspiramycin

Midecamycin

Penicillin-resistant Staphylococcus

Penicillin-allergic patients

First generation

Rokitamycin

Roxithromycin

Clarithromycin

Azithromycin

Acetylmidecamycin

flurithromycin

Second generation

Penicillin-resistant Staphylococcus

Penicillin-allergic patients


  • Antibacterial spectrum

  • board bactericidal or bacteriostatic drugs

  • G+ and G- bacteria, cocci, Neisseria gonorrhea, gram-positive bacilli, and spirochetes, mycoplasma,rickettsiosis

  • 2. Mechanisms

  • Inhibition of protein synthesis

  • (1) reversible binding to 50S subunit of

  • ribosome (23S rRNA)

  • (2) L22 protein binding in 50S subunit,

  • lead to disruption of ribosome


3. Clinical Usage

(1) Streptococci infection

(2) Legionella pneumophila

(3) infection from spirochetes, mycoplasma,rickettsiosis

4. Adverse reaction

(1) GI

(2) hepatic damage

(3) superinfection: infection that occurs while treating another infection.

e.g. oral fungal infection

(4) Ototoxicity

(5) allergic reaction


  • Lincomycin & Clindamycin

  • Antibacterial spectrum

  • (1) board bactericidal or bacteriostatic drugs, similar to the macrolides

  • (2) Anaerobic G+ and G- bacteria

  • 2. Mechanisms

  • Inhibition of protein synthesis

  • L16 protein binding in 50S subunit,

  • lead to disruption of ribosome. Avoid to using with erythromycin

  • (same binding sites), antagonistic effects.


3. Clinical Usage

(1) Aerobic bacteria

(2) anaerobic bactreria

(3) infection from staphylcoccus in bone tissues (osteomyelitis )

4. Adverse reaction

(1) GI

(2) hepatic damage

(3) allergic reaction


Tetracyclins and chloramphenicol


Chlortetracycline

Oxytetracycline

tetracycline

Natural products

Doxycycline

Methacycline

minocycline

Semisynthesis


  • Antibacterial spectrum

  • board bacteriostatic drugs

  • G+ and G- bacteria, cocci, spirochetes, mycoplasma,rickettsiosis,

  • chlamydia.

  • 2. Mechanisms

  • (1) Cell membrane transportation

  • (2) Inhibition of protein synthesis

  • 30S subunit of ribosome

  • (3) permeability


3. Clinical Usage

(1) spirochetes

(2) mycoplasma

(3) rickettsiosis,

(4) chlamydia

(5) bacteria

4. Adverse reaction

(1) GI

(2) hepatic damage

(3) superinfection: infection that occurs while treating another infection.

e.g. oral fungal infection

(4) teeth and bone

(5) renal toxicity

(6) photosensitized reaction

(7) ototoxicity


chloramphenicol


  • Antibacterial spectrum

  • board bacteriostatic bactericidal drugs

  • G+ and G- bacteria, spirochetes, mycoplasma,rickettsiosis,

  • 2. Mechanisms

  • Inhibition of protein synthesis

  • 70S ribosome complex, 50S

  • hematopoietic stromal cellin bone marrow,

  • mammary70S is similar to baterial 70S, lead to bone marrow suppression


3. Clinical Usage

(1) bacterial meningitis, purulent Meningitis in Children

(2) Corynebacterium diphtheriae infection

(3) eye infection (bacteria)

(4) anaerobic infection

4. Adverse reaction

(1) GI

(2) Gray baby syndrome: disturb the ribosome function in mitochondria

ability of detoxication via glucuronic acidconjugation

ability of renal excretion

(3) bone marrow suppresion:

AA, anemia, granulocytopenia, thrombopenia


Vancomycins

  • Antibacterial Mechanism

  • Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan penta-peptide.

  • Resistance

  • occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser.


Fig. Antibacterial Mechanism of Vancomycins


Vancomycins

  • ADME

  • Oral administration (poorly absorbed).

  • Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired).

  • Widely distributed in the body, including CSF when the meninges is inflamed.


Vancomycins

  • Clinical Uses

  • 1) severe infection caused by MRSA etc.

  • 2) alternative for b-lactam

  • 3) enterococcal or staphyococcal endocarditis (combination with gentamicin).

  • 4) pseudomembranous colitis

  • ***Overuse should be avoided, in view of limited options for treatment of resistant gram positive infections.


Vancomycins

  • Adverse Reactions

  • 1) Hypersensitive reaction

  • (e.g. red man syndrome)

  • 2) Ototoxicity

  • 3) Nephrotoxicity

  • 4) Gl effects, Phlebitis etc.


Part B

Synthetic antimicrobial agents


Generation Example time

1 Nalidixic acid 1962

2 Pipemidic acid 1973

3 Norfloxacin1980’s

4 Clinfloxacin 1990’s

Synthetic antimicrobial agents

  • Quinolones

  • Sulfonamides

  • Other Synthetic antimicrobial

  • Trimethoprim, Nitrofurans


From chloroquine to nalidixic acid


5

4

R

6

3

1

2

R

7

R

First generation fluoroquinolones


From ofloxacin to levofloxacin


Fluoroquinolones


General properties of Quinolones

Antimicrobial activity & spectrum:

(1) bactericidal and have significant PAE.

(2) aerobic G- bacteria, Pesudomonas, aerobic G+bacteria, Chlamydia spp., Legionella pneumophila , anaerobic bacteria, mycobacteria, multiple-resistance strains.


DNA gyrase

Topoisomerase

Mechanism of action

Key enzymes in DNA replication: bacterial DNA is supercoiled.


porin

DNA gyrase

Topo

isomerase

Gram (-)

Gram (+)

Mechanism of action


DNA gyrase

Catalytic subunite

Fluoroquinolones:

4 stacked molecules

DNA gyrase

ATP binding subunite

Mechanism of action


decreased

permeability

active efflux

system

porin

DNA gyrase

Topo

isomerase

mutation of

the enzymes

Gram (-)

Gram (+)

Mechanism of resistance


ADME of fluoroquinolones

  • Absorption: well absorbed; bound by divalent cations

    • Do not administer with iron, magnesium, calcium

  • Distribution: all distribute widely (even in CSF), and most concentrate in urine

  • Metabolism:

    • hepatic metabolism diminishes the activity of norfloxacin and ciprofloxacin

    • Several have predominately hepatic clearance (Grepafloxacin, Sparfloxacin, Trovafloxacin)

  • Excretion: urinary excretion predominates for the first generation fluoroquinolones


Clinical Uses

  • Urinary tract infections.

  • GI and abdominal infections.

  • Respiratory tract infections.

  • Bone, joint and soft tissues infections, Osteomyelitis.

  • Meningitis

  • STD: Neisseria gonorrhea and Chlamydia (Quinolone

    resistance in gonorrhea increasing)

    Adverse reactions

  • Gastrointestinal effects.

  • CNS side effects.

  • Allergic reaction.

  • Hepatotoxicity, nephrotoxicity.

  • Joint/cartilage toxicity, Tendinopathy

  • Achilles tendon rupture

  • Limited FDA approval for children (under 18)


Fluoroquinolones agents

  • Norfloxacin

  • Ciprofloxacin

  • Ofloxacin

  • Levofloxacin

  • Lomefloxacin

  • Fleroxacin

  • Sparfloxacin

  • Clinafloxacin

  • Gatifloxacin


Gerhard Domagk

Nobel Laureate 1939

Sulfonamides : Inhibitors of Folate Synthesis

2,4-Diaminoazobenzen-4’-sulfonamide

Prontosil

  • Antimicrobial activity:

  • A wide antimicrobial spectrum.

  • Exerting onlybacteriostatic effect.


Pteridine+PABA

Dihydropteroate

synthase

Blocked by

sulfonamides

Dihydropteroic acid

glutamate

Dihydrofolic acid

NADPH

Dihydrofolate

reductase

Blocked by trimethoprim

NADPH

Tetrahydrofolic acid

Mechanism of action


Mechanism of Resistance

  • A lower affinity for sulfonamides by the dihydropteroate synthase

  • Decreased cell permeability or active efflux of the drug

  • An alternative pathwayto synthesis the essential metabolites

  • An increased production of essential metabolites


Classification & Clinical uses :

  • Oral absorbable agents (Systemic infections)

  • Short-acting agents: Sulfafurazole (SIZ)

  • Medium-acting agents:

    Sulfadiazine (SD) [Co: pyrimethamine → toxoplasmosis]

    best in the CSF and brain→ → meningitis

    Sulfamethoxazole (SMZ) [Co: trimethoprim, named

    trimoxazole / TMP-SMZ

  • Long-acting agents: Sulfadoxine (SDM) [Co: pyrimethamine → malaria]

  • Oral nonabsorbable agents (Intestinal infections) Sulfasalazine

  • Topical agents (Infections of burn and wound)

    Mafenide (SML)

    Sulfadiazine sliver

    Sulfacetamide (SA)


ADME of sulfonamides

  • Approximately 70%-100% of an oral dose is absorbed.

  • Distributing throughout all tissues of the body,even in CSF ( sulfadiazine and sulfisoxazole, may be effective in meningeal infections) ;readily passing through the placenta.

  • Metabolized in the liver by acetylation.

  • Eliminated mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated may precipitate, thus induced renal disturbance.


Adverse reactions

  • Hypersensitivity reaction

  • Urinary tract disturbances: Sulfonamide crystalluria

  • Hematopoietic system disturbances

  • Kernicterus

  • Hepatitis

  • GI effects

    Drugs interactions

  • All sulfonamides are bound in varying degree to plasma protein.


Combination agents: Co-trimoxazole

1) Features

  • Trimethoprim in combination with Sulfamethoxazole (1:5,eg,160mg:800mg for p.o.) exerts asynergistic effects (bacteriocidal effect ).

  • Co-block essential enzymes offolate metabolism.

  • The ADME of the two agents is similar.


Pteridine+PABA

Dihydropteroate

synthase

Blocked by

sulfonamides

Dihydropteroic acid

glutamate

Dihydrofolic acid

NADPH

Dihydrofolate

reductase

Blocked by trimethoprim

NADPH

Tetrahydrofolic acid


2)Clinical Uses

  • Chronic and recurrent infections in the urinary tract

  • Bacterial respiratory infections

  • GI infections (e.g. induced by Salmonella)

  • pneumocystis carinii pneumonia

    3)Adverse reactions

  • There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.

  • Trimethoprim(TMP): megaloblastic anemia

  • Sulfamethoxazole (SMZ): all adverse reactions mentioned

  • HIV patients (fever, rashes, leukopenia, diarrhea, hyperkalemia)

  • Drug interactions: warfarin, phenytoin, etc.


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