Aminoglycosides & Spectinomycin. Part A Aminoglycosides.

Aminoglycosides & SpectinomycinAminoglycosides & Spectinomycin

Part APart A Aminoglycosides Aminoglycosides

• History and Source : History and Source : the research madthe research made by Waksman and coworks within 19e by Waksman and coworks within 1939-194339-1943

• Clinical Applications: Clinical Applications: for the treatmenfor the treatment of aerobic Gt of aerobic G-- bacterial infections and bacterial infections and tuberculosistuberculosis

• Two classes:Two classes: crude product and crude product and semisynthetic derivative semisynthetic derivative

OverviewOverview

1. 1. Antimicrobial activity:Antimicrobial activity:

i) rapidly bactericidal to resting bacterium i) rapidly bactericidal to resting bacterium

ii) broad-spectrumii) broad-spectrum ：： GG- - bacilli and coccibacilli and cocci ，， GG++ organisms organisms ，，TBTB

iii) more active at alkalineiii) more active at alkaline

iv) iv) concentration-dependent activityconcentration-dependent activity

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

vi) first exposure effect (FEE)vi) first exposure effect (FEE)

General propertiesGeneral properties

Blood Concentration

MIC

Peak Concentration

Time (h)

Bacterial growth is inhibited long after concentration below the MIC

2. 2. Mechanism of action:Mechanism of action:

• inhibit protein synthesis inhibit protein synthesis

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


Inhibiting protein synthesis: AminoglycosidesInhibiting protein synthesis: Aminoglycosides

PP AA

i) Interfering with the initiation complex of peptide fori) Interfering with the initiation complex of peptide for

mation.mation.

ii) Inducing misreading of mRNA, which causes the incii) Inducing misreading of mRNA, which causes the inc

orporation of incorrect amino acid into peptide, resulorporation of incorrect amino acid into peptide, resul

ting nonfunctional or toxic protein. ting nonfunctional or toxic protein.

iii) causing breakup of polysomes into nonfunctional iii) causing breakup of polysomes into nonfunctional monosomes.monosomes.

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

2.Mechanism of action -2.Mechanism of action - inhibit protein synthesisinhibit protein synthesis

3. Mechanism of resistance3. Mechanism of resistance

produces enzymesproduces enzymes

Altered ribosomal subunitAltered ribosomal subunit

Changes of PorinsChanges of Porins

i) The microorganism produces a transferase eni) The microorganism produces a transferase en

zyme or enzymes that inactivate the aminoglyczyme or enzymes that inactivate the aminoglyc

oside by adenylyation, acetylation, or phosphooside by adenylyation, acetylation, or phospho

rylation.rylation.

ii) Impaired entry of aminoglycoside into the cell.ii) Impaired entry of aminoglycoside into the cell.

iii) The receptor protein on the 30S ribosomal suiii) The receptor protein on the 30S ribosomal su

bunit may be deleted or altered as a result of bunit may be deleted or altered as a result of

mutation.mutation.

Mechanism of ResistanceMechanism of Resistance

ADMEADMEi) i) AAbsorption: not absorbed after po, but rapidly absorbbsorption: not absorbed after po, but rapidly absorb

ed after IM.ed after IM.

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

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


Clinical UsesClinical Uses

• be mostly used against be mostly used against aerobicaerobic GG-- bacteria bacteria

(bacilli, enteric) and in sepsis, be almost al(bacilli, enteric) and in sepsis, be almost al

ways used in combination withways used in combination with-lactam a-lactam a

ntibiotic and fluoroqunolonesntibiotic and fluoroqunolones

• TuberculosisTuberculosis


Adverse reactionsAdverse reactions

i) i) OtotoxicityOtotoxicity • involves progressive damage to and destructioinvolves progressive damage to and destructio

n of the sensory cells in the cochlea and vestibn of the sensory cells in the cochlea and vestibular organ in the ear (ular organ in the ear (irreversible!! Auditory and irreversible!! Auditory and vestibular damagevestibular damage).).

ii) ii) NephrotoxicityNephrotoxicity • consists of damage to the kidney tubules and bconsists of damage to the kidney tubules and b

e reversed if stop using.e reversed if stop using.


Adverse reactionsAdverse reactions

iii) iii) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis)

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

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

iv) iv) Allergic reactionAllergic reaction • skin rashes fever, eosinophiliay skin rashes fever, eosinophiliay ,, anaphylactic shockanaphylactic shock,,

etc.etc.


• StreptomycinStreptomycin• GentamicinGentamicin• TobramycinTobramycin• AmikacinAmikacin• NetilmicinNetilmicin• NeomycinNeomycin• Kanamycin

AminoglycosidesAminoglycosides

• Arbekacin • Dibekacin • Micronomicin• Sisomicin• Etilmicin• Isepamicin• Astromicin

1. ADME1. ADMEi) Ai) Absorption:bsorption: IMIMii) Dii) Distribution: mainly at extracellular fluid, istribution: mainly at extracellular fluid, crosses the BBB and achieves tcrosses the BBB and achieves t

herapeutic concentrations with inflamed meningesherapeutic concentrations with inflamed meninges.. iii) Eiii) Excretion:xcretion: 90%, kidney90%, kidney

2.Clinical uses2.Clinical usesi) i) plague and tularemiaplague and tularemia: combination with an oral tetracycline.: combination with an oral tetracycline.ii) ii) tuberculosis: as first-line agenttuberculosis: as first-line agentiii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptiii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), strept

omycin and penicillin produce a synergistic bactericidal.omycin and penicillin produce a synergistic bactericidal.

3. Adverse reactions3. Adverse reactionsi) i) Allergic reactionAllergic reaction skin rashes, fever, skin rashes, fever, anaphylactic shockanaphylactic shockii) ii) Ototoxicity: disturbance of vestibular function, deafness of newbornOtotoxicity: disturbance of vestibular function, deafness of newborniii) iii) NephrotoxicityNephrotoxicityiv) iv) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis) ：： Myasthenia Gravis, anesthetics, sMyasthenia Gravis, anesthetics, s

colinecoline

StreptomycinStreptomycin

1. ADME1. ADME Gentamicin can accumulate in cortex of the kidney .Gentamicin can accumulate in cortex of the kidney .

2.Clinical use : 2.Clinical use :

i) serious Gi) serious G-- bacillary infections (sepsis, pneumonia, bacillary infections (sepsis, pneumonia, etcetc.)..). ii) infection induced by ii) infection induced by enterococcalenterococcal, , viridans streptococcalviridans streptococcal, , staphstaph

ylococcal etc. ylococcal etc. (in combination(in combination with other antibiotics, e.g. with other antibiotics, e.g. -lacta-lactams) ms)

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

iv) local application or intrathecal administration (rarely use)iv) local application or intrathecal administration (rarely use)

3. Adverse reactions3. Adverse reactionsi) i) Nephrotoxicity Nephrotoxicity (reversible and mild)(reversible and mild)ii) ii) Ototoxicity Ototoxicity (irreversible!) (irreversible!) iii) Nausea and vomitingiii) Nausea and vomiting etc etc..

GentamicinGentamicin

1.1. antimicrobial activity & pharmacokineantimicrobial activity & pharmacokineticstics: very : very similar to those of gentamicisimilar to those of gentamicin; has cross-resistance to gentamicin.n; has cross-resistance to gentamicin.

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

TobramycinTobramycin

1. similar to gentamicin & tobramycin in its pharmac1. similar to gentamicin & tobramycin in its pharmacokinetic properties.okinetic properties.

2. broad spectrum, against aerobic G2. broad spectrum, against aerobic G-- bacilli. bacilli. 3. tolerance to many aminoglycosides (gentamicin, t3. tolerance to many aminoglycosides (gentamicin, t

obramycin) - inactivating enzymes.obramycin) - inactivating enzymes.

4. less toxic4. less toxic

NetilmicinNetilmicin

1.Antibacterial activity:1.Antibacterial activity: the the broadest broadest in the group.in the group.

2.Clinical uses : 2.Clinical uses : • Treatment of GTreatment of G--bacillary infections which bacillary infections which resistance to gentamicin resistance to gentamicin

and tobramycinand tobramycin. . • Most strains resistance to amikacin found is also resistance to othMost strains resistance to amikacin found is also resistance to oth

er aminoglycosides. er aminoglycosides. • combination with combination with -lactams-lactams, produce a synergistic bactericidal., produce a synergistic bactericidal.

3. Adverse reactions3. Adverse reactions

i) i) OtotoxicityOtotoxicity

ii) ii) NephrotoxicityNephrotoxicity

iii) iii) Neuromuscular blockade (paralysis)Neuromuscular blockade (paralysis)

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

AmikacinAmikacin

Macrolides and lincomycin

Structure

ErythromycinDirithromycinMeleumycinJosamycinAcetylspiramycinMidecamycin

Penicillin-resistant StaphylococcusPenicillin-allergic patients

RokitamycinRoxithromycinClarithromycinAzithromycinAcetylmidecamycinflurithromycin

Penicillin-resistant StaphylococcusPenicillin-allergic patients

First generation

Second generation

Representative drugs

1.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 pneumophilaLegionella 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 bactreriaanaerobic bactreria (3) infection from staphylcoccus in bone tissues (osteomyelitis )

4. Adverse reaction (1) GI (2) hepatic damage (3) allergic reaction

Tetracyclins and chloramphenicol

ChlortetracyclineOxytetracyclinetetracycline

DoxycyclineMethacyclineminocycline

Natural products

Semisynthesis

1. 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

1. 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 cell in bone marrow, mammary 70S 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 acid conjugation ability of renal excretion (3) bone marrow suppresion: AA, anemia, granulocytopenia, thrombopenia

• Antibacterial MechanismAntibacterial Mechanism

Inhibiting cell wall synthesis by bindinInhibiting cell wall synthesis by binding to the g to the DD-Ala--Ala-DD-Ala terminus of nasc-Ala terminus of nascent peptidoglycan penta-peptide. ent peptidoglycan penta-peptide.

• Resistance Resistance occurred because of the alteration of occurred because of the alteration of

DD-Ala--Ala-DD-Ala to the -Ala to the DD-Ala--Ala-DD-Ser. -Ser.

VancomycinsVancomycins

Fig. Antibacterial MechanismFig. Antibacterial Mechanism of Vancomycins of Vancomycins

• ADMEADME

• Oral administration (poorly absorbed).Oral administration (poorly absorbed).

• Intravenous administration, is excreted by glIntravenous administration, is excreted by gl

omerular filtration (accumulates when renal fuomerular filtration (accumulates when renal fu

nction is impaired).nction is impaired).

• Widely distributed in the body, including CSF Widely distributed in the body, including CSF

when the meninges is inflamed. when the meninges is inflamed.


• Clinical UsesClinical Uses1) severe infection caused by MRSA 1) severe infection caused by MRSA etcetc..

2) alternative for 2) alternative for -lactam -lactam

3) enterococcal or staphyococcal endocarditis (3) enterococcal or staphyococcal endocarditis (

combination with gentamicin).combination with gentamicin).

4) pseudomembranous colitis4) pseudomembranous colitis***Overuse should be avoided, in view of limited options for t***Overuse should be avoided, in view of limited options for t

reatment of resistant gram positive infections.reatment of resistant gram positive infections.


• Adverse ReactionsAdverse Reactions

1) Hypersensitive reaction1) Hypersensitive reaction (e.g. red man syndrome)(e.g. red man syndrome)2) Ototoxicity2) Ototoxicity3) Nephrotoxicity3) Nephrotoxicity4) G4) Gl effects, Phlebitis l effects, Phlebitis etcetc..


Part BPart B

Synthetic antimicrobial agentsSynthetic antimicrobial agents

• QuinolonesQuinolones

Synthetic antimicrobial agentsSynthetic antimicrobial agents

Generation Example timeGeneration Example time

1 Nalidixic acid 19621 Nalidixic acid 1962

2 Pipemidic acid 19732 Pipemidic acid 1973

3 3 NorfloxacinNorfloxacin 1980’s1980’s

4 Clinfloxacin 1990’s4 Clinfloxacin 1990’s

• SulfonamidesSulfonamides• Other Synthetic antimicrobialOther Synthetic antimicrobial Trimethoprim, NitrofuransTrimethoprim, Nitrofurans

From chloroquine to nalidixic acidFrom chloroquine to nalidixic acid

First generation fluoroquinolonesFirst generation fluoroquinolones

R

R

R

4

123

56

7８

From ofloxacin to levofloxacinFrom ofloxacin to levofloxacin

Fluoroquinolones

Antimicrobial activity & spectrum: Antimicrobial activity & spectrum:

(1) bactericidal and have significant PAE. (1) bactericidal and have significant PAE.

(2) aerobic G(2) aerobic G-- bacteria, bacteria, PesudomonasPesudomonas, , aeroaerobic Gbic G++ bacteria, bacteria, ChlamydiaChlamydia spp., Legionell spp., Legionella pneumophila , anaerobic bacteria, mycoa pneumophila , anaerobic bacteria, mycobacteria, multiple-resistance strains.bacteria, multiple-resistance strains.

General properties of General properties of QuinolonesQuinolones

Mechanism of actionMechanism of action

Topoisomerase Topoisomerase

DNA gyrase DNA gyrase

Key enzymes in DNA replication: bacterial DNA is supercoiled.Key enzymes in DNA replication: bacterial DNA is supercoiled.


Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin


Fluoroquinolones:Fluoroquinolones:4 stacked molecules4 stacked molecules

DNA gyraseDNA gyraseCatalytic subuniteCatalytic subunite

DNA gyraseDNA gyraseATP binding subuniteATP binding subunite

Mechanism of resistanceMechanism of resistance

Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin

mutation of mutation of the enzymesthe enzymes

active effluxactive effluxsystemsystem

decreaseddecreasedpermeabilitypermeability

• AAbsorption: well absorbed; bound by divalent cationsbsorption: well absorbed; bound by divalent cations– Do not administer with iron, magnesium, calciumDo not administer with iron, magnesium, calcium

• DDistribution: all distribute widely (istribution: all distribute widely (even in CSF)even in CSF), and most , and most concentrate in urineconcentrate in urine

• MMetabolism: etabolism: – hepatic metabolism diminishes the activity of norfloxacin hepatic metabolism diminishes the activity of norfloxacin

and ciprofloxacinand ciprofloxacin– Several have predominately hepatic clearance Several have predominately hepatic clearance

(Grepafloxacin, Sparfloxacin, Trovafloxacin) (Grepafloxacin, Sparfloxacin, Trovafloxacin) • EExcretion: urinary excretion predominates for the first xcretion: urinary excretion predominates for the first

generation generation fluoroquinolonesfluoroquinolones

ADME of fluoroquinolonesADME of fluoroquinolones

Clinical UsesClinical Uses •Urinary tract infections.Urinary tract infections.•GI and abdominal infections.GI and abdominal infections.•Respiratory tract infections.Respiratory tract infections.•Bone, joint and soft tissues infections, Bone, joint and soft tissues infections, OsteomyelitisOsteomyelitis..•MeningitisMeningitis•STD: STD: Neisseria gonorrhea Neisseria gonorrhea and and ChlamydiaChlamydia (Quinolone (Quinolone resistance in resistance in gonorrheagonorrhea increasing) increasing)

Adverse reactionsAdverse reactions •Gastrointestinal effects. Gastrointestinal effects. •CNS side effects.CNS side effects.•Allergic reaction.Allergic reaction.•Hepatotoxicity, nephrotoxicity. Hepatotoxicity, nephrotoxicity. •Joint/cartilage toxicity, TendinopathyJoint/cartilage toxicity, Tendinopathy–Achilles tendon rupture–Limited FDA approval for children (under 18)

• NorfloxacinNorfloxacin • Ciprofloxacin Ciprofloxacin • Ofloxacin Ofloxacin • Levofloxacin Levofloxacin • LomefloxacinLomefloxacin • Fleroxacin Fleroxacin • Sparfloxacin Sparfloxacin • Clinafloxacin Clinafloxacin

• Gatifloxacin Gatifloxacin

Fluoroquinolones agentsFluoroquinolones agents

SulfonamidesSulfonamides : Inhibitors of Folate Synthesis

2,4-Diaminoazobenzen-4’-sulfonamideProntosil

Gerhard DomagkNobel Laureate 1939

Antimicrobial activity:Antimicrobial activity:•A wide antimicrobial spectrum.A wide antimicrobial spectrum.•Exerting onlyExerting only bacteriostatic effect.bacteriostatic effect.

Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADPH

Dihydropteroatesynthase

Dihydrofolatereductase


Mechanism of ResistanceMechanism of Resistance • A lower affinityA lower affinity for sulfonamides by the dih for sulfonamides by the dih

ydropteroate synthaseydropteroate synthase• Decreased cell permeabilityDecreased cell permeability or active efflux or active efflux

of the drugof the drug• An alternative pathwayAn alternative pathway to synthesisto synthesis the es the es

sential metabolitessential metabolites• An increased productionAn increased production of essential meta of essential meta

bolitesbolites

Classification & Classification & Clinical usesClinical uses : :

• Oral absorbable agents (Oral absorbable agents (Systemic infectionsSystemic infections))─ Short-acting agents: Short-acting agents: Sulfafurazole Sulfafurazole (SIZ)(SIZ)─ Medium-acting agents: Medium-acting agents: Sulfadiazine (SD) [Co: pyrimethamine Sulfadiazine (SD) [Co: pyrimethamine →→ toxoplasmosis] toxoplasmosis] best in the CSF and brainbest in the CSF and brain → → meningitis→ → meningitis Sulfamethoxazole (SMZ) [Co: trimethoprim, named Sulfamethoxazole (SMZ) [Co: trimethoprim, named

trimoxazole / TMP-SMZtrimoxazole / TMP-SMZ ─ Long-acting agents: Long-acting agents: Sulfadoxine Sulfadoxine (SDM) (SDM) [Co: pyrimetha[Co: pyrimetha

mine mine →→ malaria] malaria]• Oral nonabsorbable agents (Oral nonabsorbable agents (Intestinal Intestinal infectionsinfections) )

SulfasalazineSulfasalazine• Topical agents (Topical agents (Infections of burn and woundInfections of burn and wound) ) Mafenide Mafenide (SML)(SML)

Sulfadiazine sliver Sulfadiazine sliver Sulfacetamide Sulfacetamide (SA)(SA)

ADME of sulfonamidesADME of sulfonamides

• AApproximately 70%-100% of an oral dose is absorbepproximately 70%-100% of an oral dose is absorbed.d.

• DDistributing throughout all tissues of the body,istributing throughout all tissues of the body, even even inin CSF CSF ( sulfadiazine and sulfisoxazole, may be effec( sulfadiazine and sulfisoxazole, may be effective in meningeal infections) ;readily passing througtive in meningeal infections) ;readily passing through h the placentathe placenta..

• MMetabolized etabolized in the liverin the liver by acetylation. by acetylation.• EEliminated mainly liminated mainly in the urinein the urine as the unchanged dru as the unchanged dru

g and metabolic product. In acid urine, the eliminateg and metabolic product. In acid urine, the eliminated may precipitate, thus induced d may precipitate, thus induced renal disturbance. renal disturbance.

Adverse reactionsAdverse reactions• Hypersensitivity reactionHypersensitivity reaction• Urinary tract disturbances: Urinary tract disturbances: Sulfonamide crys

talluria

• Hematopoietic system disturbancesHematopoietic system disturbances• Kernicterus Kernicterus • HepatitisHepatitis• GI effectsGI effects

Drugs interactionsDrugs interactions• All sulfonamides are bound in varying deAll sulfonamides are bound in varying de

gree to gree to plasma protein.plasma protein.

Combination agents: Combination agents: Co-trimoxazoleCo-trimoxazole 1) Features 1) Features • Trimethoprim in combination with SulfamethTrimethoprim in combination with Sulfameth

oxazole (1:5,eg,160mg:800mg for p.o.) exertoxazole (1:5,eg,160mg:800mg for p.o.) exertss a a synergistic effects (bacteriocidal effect ). synergistic effects (bacteriocidal effect ).

• Co-block essential enzymes ofCo-block essential enzymes of folate metabfolate metabolism. olism.

• The ADME of the two agents is similar.The ADME of the two agents is similar.

Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADPH

Dihydropteroatesynthase

Dihydrofolatereductase

2)Clinical Uses 2)Clinical Uses • Chronic and recurrent infections in the urinary tractChronic and recurrent infections in the urinary tract• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (e.g. induced by GI infections (e.g. induced by SalmonellaSalmonella))• pneumocystis carinii pneumocystis carinii pneumoniapneumonia

3)Adverse reactions• There is no evidence that co-trimoxazole, when given in recom

mended 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.

Aminoglycosides & Spectinomycin. Part A Aminoglycosides.

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Transcript of Aminoglycosides & Spectinomycin. Part A Aminoglycosides.