Aminoglycosides & Spectinomycin
description
Transcript of Aminoglycosides & Spectinomycin
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.
General propertiesGeneral properties
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.
General propertiesGeneral properties
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
General propertiesGeneral properties
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.
General propertiesGeneral properties
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.
General propertiesGeneral properties
• 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.
VancomycinsVancomycins
• 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.
VancomycinsVancomycins
• 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..
VancomycinsVancomycins
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.
Mechanism of actionMechanism of action
Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase
Gram (-)Gram (-) Gram (+)Gram (+)
porinporin
Mechanism of actionMechanism of action
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 actionMechanism of action
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.