SULFONAMIDES
Dr. Rajendra Nath
Professor
SULFONAMIDES
First effective chemotherapeutic agents
to be employed systemically for the
prevention & cure of bact. Infections in
humans.
The discovery of Penicillin & subsequ.
of other antib.s has diminished the
usefulness of the sulfonamides.
SULFONAMIDES
-Presently sulf. occupy small place in
therapeutic armamentarium of the
physician .
-In 1970s however the combination of
Trimethoprim &Sulfmethoxazole has
increased the use of sulf.s for the Tt.
& prophylaxis of specific microbial
SULFONAMIDES
diseases .
History –
Domagk tested the new comp. Azodye ( Prontosil ) & observed that mice
with Streptococcal & other inf.s could
be protected by prontosil ( active
metabolite was sulf.) & was very useful
SULFONAMIDES
in puerperal sepsis & in Meningococ.
Infection .
Subsequently Carbonic anhydrase inhi.
type of diuretics & Sulfonylurea hypoglycemic agents followed from observ.
made with sulf. antibiotics .
For the discovery of the therapeutic
SULFONAMIDES
value of prontosil Domagk was
awarded Nobel prize in medicine in
1938 .
Chemistry :
Sulf. is a generic name for derivatives
of Para – aminobenzene sulf.
( Sulfanilamide )
SULFONAMIDES
-Insoluble in water but sodium salts are
soluble.
-The paraNH2 gp. is essential for
activity .
H2N
SO2 NH2
SULFONAMIDES
Effect on Microbes:
-Wide range of AM activity against both
G+ve & G- ve bacteria.
- But now resist. strains have become
common & usefulness of these agents has
diminished .
- The Sulf. exert only bacteriostatic action .
- Cellular & humoral defense mech. of the
SULFONAMIDES
host are essential for final eradication of the
Infection.
Anti bact. Spectrum :
- Resistance is increasingly a problem
Still sensitive strains are-Most of the Strept. pyogenes ,
Haemophilus ducrei & influenzae , Vibrio
cholerae & Calymmatobacterium granulomatis.
SULFONAMIDES
Few strains of Staph. aureus ,
pneumococci, Meningococci & gonococci ,
E.coli & shigella are sensitive ( most of the
strains are resistant ).
- Anaerobes are not sensitive
- Chlamydiae (causing trachoma ,
lymphogranul.venereum ,inclusion
conjunctivitis), Actinomyces,
Nocardia & Toxoplasma are sensitive
-
SULFONAMIDES
Mech. of action :
Sulf.s are structural analogue & competit.
antagonists of Para- aminobenzoic acid
( PABA) .
SULFONAMIDES
- Prevent normal bact. utilization of PABA
for the synthesis of folic acid (Pterylgluta mic acid) .
- Specifically Sulf.s are competitive inhibitor
of dihydropteroate synthase ( bact. enz.
responsible for incorporation of PABA into
dihydropteroic acid ( immed. precursor of
folic acid )
SULFONAMIDES
- Sensitive org.s are those that must
synthesize their own folic acid & bact.s
that utilize preformed folate are not
affected .
- PABA competitively counteract Sulf.’ s
bacteriostatic action .
(Sulf.s do not affect mammalian cells
because they require preformed folic acid
SULFONAMIDES
and can not synthesize it ) .
Pteridine + PABA
Dihydropteroate synth.X
SULF.
Dihydropteroic acid
Dihydrofolic acid
NADPH
Glutamate
x DHFR NADP
Tetrahydrofolic acid
Trimethoprim
SULFONAMIDES
Synergists :
Most active agent that exerts a synergistic
effect with Sulf. is Trimethoprim
It is a potent & selective competitive
inhibitor of microbial dihydrofolate
reductase ( enz that reduces dihydrofol. to
tetrahydrofolate ).
Simultaneous administ. of Sulf. & Trimeth.
thus introduces Sequential Block in the
SULFONAMIDES
pathway & kill the bact.
Acquired bact. resist. to Sulf. :
- Originate by random mutation & selection
or by transfer of resist. by Plasmids ( this
type of resist. is persistent & irreversible)
May be due toi) Lower affinity for Sulf. by dihydropteroate
synthase .
SULFONAMIDES
ii) ↓ bact. permeability or active efflux of the
drug.
iii) Alternate metabolic pathway for synthesis
of essential metabolite.
iv) ↑ production of essen. metabolite or drug
antagonists.
↑ prod. of PABA is not a constant finding in
sulf. resist.. Bacteria & resist. mutants may
SULFONAMIDES
posses enz.s that are less readily inhibited
by sulfonamides
Pharmacokinetics:
-They are absorbed rapidly from GIT except
locally acting sulf.s .
- Peak plasma levels are achieved in 2-6 hrs
depending on the drug (100-200 µg / ml ).
- Small intestine is the major site of abs. but
SULFONAMIDES
Some of the drug absorbed through
stomach .
- Abs. from other site e.g.–vagina, resp.tract
or abraded skin is variable & cause toxic
reaction in susceptible person .
- All sulf.s are bound to plasma protein esp.
albumin & distributed throughout all
tissues of the body .
SULFONAMIDES
- They readily enter pleural , peritoneal ,
synovial ,ocular & similar body fluids .
- After systemic abs. of adequate doses ,
Sulfadiazine & Sulfisoxazole attain conc.
in CSF which may be effective in
meningeal infection .
- They reach the fetal circulation in placenta
in preg. mothers & can cause toxic
SULFONAMIDES
as well as antibacterial effect .
- They undergo metabolic alteration in vivo
esp. in liver . Major metabolite is N4 acetylated sulfonamide .
- Excreted from the body partly unchanched
& partly as metabolic prod.s .The largest
fraction excreted in urine .
- In acidic urine the older Sulf.s are insol. &
SULFONAMIDES
form crystalline deposits that can cause
urinary obstruction .
- Small fractions are eliminated in the feces
bile , milk etc.
Pharmacological properties: They are classified into four gps on the
basis of the rapidity with which they are
absorbed & excreted .
SULFONAMIDES
CLASS
SULFONAMIDE
1. Absorbed &
Excreted rapidly
SERUM H-½ in Hrs
Sulfisoxazole
Sulfamethoxazole
Sulfadiazine
5-6
11
10
Sulfasalazine
---
3. Topically used
Sulfacetamide
Silver sulfadiazine
-----
4. Long acting
Sulfadoxine
100 - 230
2. Poorly absorbedActive in bowel lumen
SULFONAMIDES
1. Agents that are absorbed & excreted
rapidly:
e.g. Sulfisoxazole & Sulfadiazine
Sulfisoxazole:
- having excellent AM activity
- high solubility eliminates much of the renal
toxicity.
- It is highly protein bound .approx. 95% of
SULFONAMIDES
a single dose is excreted by the kidney in 24
hrs., conc. in urine thus exceeds than in
blood & may be bactericidal .
- 1/3rd of the blood conc. reaches . CSF
Sulfamethoxazole : cong. of sulfisoxazole.
Enteric abs. & renal excrt. is slower. Given
orally & employed for both systemic &
urinary tract inf.s .Precaution must be taken
SULFONAMIDES
to avoid crystalluria (i.e. take plenty of water)
-Also marketed in fixed dose combination
with Trimethoprim.
Sulfadiazine :
Given orally , absorbed rapidly from GI
tract & peak conc. reaches in 3-6 hrs after
single dose. Fluid intake is must so that
SULFONAMIDES
1200 ml. urine output is maintained ( to
avoid crystalluria)
2.Poorly absorbed Sulf.s :
Sulfasalazine - poorly abs. from the GI tract
therefore used in the therapy of Ulcerative
colitis & Reigional Ileitis , but relapses
occurs ( Corticosteroids are better but in
mild to mod. form Sulfasalaz. is preferred .
SULFONAMIDES
-It is broken down by int. bact.s into
Sulfapyridine an active Sulf. + 5-aminosalicylic acid which reaches high levels in
feces
-5-aminosal. is the effective agent in
inflammatory bowel disease . Whereas
Sulfapyridine is respons. for toxicity e.g. –
Heinz body anemia , acute hemolysis in
pts of G6PO4 dehyd. enz. deficiency
SULFONAMIDES
(G6PD enzyme is required for regeneration of NADPH &
Which is required for reduction of oxidized glutathione.
Reduced glutathione protects –SH dependent enzyme
& other proteins against oxidation. Thus in presence of
pro-oxidants ( e.g.- Aspirin , Nitrofurantoin, Primaquine,
Chloroquine , Quinine , Sulfonamide, Vit. K etc. ) in a pt.
with deficiency of G6PD , there is no protection to RBCs
& so hemolysis occurs .)
SULFONAMIDES
agranulocytosis & may cause rev. infertility
in males .
3.Sulf. For Topical use :
Sulfacetamide – Sod. Salt of drug is
extensively employed in ophthalmic inf.s .
Advantages –high aquous conc. not irritating
to eyes .
- the drug penetrates in high
SULFONAMIDES
conc. into ocular fluids & tissues .
- Sensitivity react.s are rare
Silver Sulfadiazine; the comp. is used
topically to reduce microbial coloniz. & the
incidence of wounds from burns( one of the
agents of choice for the prev. of burn inf.) .
other is Mafenide .
SULFONAMIDES
4.Long acting Sulf.s :
e.g. – Sulfadoxine – having long half life ≈
7-9 days .
- It is used in comb. with Pyrimethamine
( 500 mg Sulfadoxine + 25 mg Pyrimeth.)
as Fansidar in prophylaxis & Tt of Malaria
caused by resist strains of Plasmodium
falciparum .
SULFONAMIDES
Sulfonamide Therapy :
- Various conditions for which the sulf.s are
therapeutically useful & constitute DOC
has been reduced sharply .
- The development of more effective AM
agents & gradual increase in resist. of no.
of bact. species to this class of drugs leads to
rare use of these agents
- The introduction of Trimethoprim &
SULFONAMIDES
Sulfamethoxazole combinations has revived
the use of sulf.s .
1. Urinary Tract Inf.s :
Sulf.s are no longer a therapeutic choice
in UTI . Preferred agents are –Trimethop.
+ Sulfamethoxazole , Quinolones ,
Trimethop. alone , Fosfomycin ,
Ampicillin & Cephalosporins
Sulfisoxazole may be used effectively
SULFONAMIDES
2. Nocardiosis – good response with Sulf.s
e.g.- Sulfisoxazole & Sulfadiazine
Dose – 6 - 8 Gm. / day continued for
several months .
second antb. along with sulf. is recomme.
in advanced cases e.g.- Ampicillin &
Erythromycin .
SULFONAMIDES
3. Toxoplasmosis :
Sulfadiazine( 1Gm.) + Pyrimethamine
(75 mg loading & 25 mg later on) is given
6 hrly x 3-6 weeks with folic acid 10 mg
orally .
4. Treatment & Prophy. of resist. Malaria :
Sulfadoxine + Pyrimethamine( Fansidar)
SULFONAMIDES
5. Use of Sulf.s for Prophylaxis :
They are as efficacious as Penicil.s in
prev. Streptococcal inf.s & recurrence of
Rheumatic fever .
6. Ophthalmic inf.s : topical –e.g.Sulfacetamide .
7. Infection of Burns :
e.g.- topical Silver sulfadiazine .
SULFONAMIDES
Adverse reactions :
1. Disturbance of urinary tract –
risk of crystalluria – high with older less
sol. Sulf.s but very less with more sol.
agents e.g.- Sulfisoxazole
-Fluid intake should be sufficient – daily
ensure urine out put of 1200ml.
- Alkalinization of urine is desirable .
SULFONAMIDES
2. Disorders of Hematopoietic system :
- Acute hemolytic anemia- sometimes
sensitization phenomenon & in others
erythrocytic def. of G6PO4 dehydrogenase
- Agranulocytosis – most pts recovered
spontaneously with supportive care
- Aplastic anemia –complete supp. of bone
marrow activity with anemia ,
SULFONAMIDES
granulocytopenia & thrombocytopenia.
3. Hypersensitivity reactions :
Skin & mucous memb. manifestationsurticarial rash , pemphigoid , perpurial &
petechial rashes , erythema nodosum
multiforme of Stevenson Jonhson’s type,
Exfoliative derm.& photosensitivity .
most often occurs after 1st wk. of therapy
SULFONAMIDES
It can occur with fever , malaise & pruritis
- Focal or diffuse necrosis of liver, fever,
headach ,hepatomegaly, jaundice –
leading to yellow atrophy of liver & death
Misce. :
Anorexia , nausia & vomiting -1-2%
in new borns – free bilirubin can deposit
in the basal ganglia & ant thalamic nuclei
SULFONAMIDES
of the brain causing encephalopathy called
Kern- icterus .
( Sulf.s are not given to pregnant women
near term because these drugs pass
through placenta & secret. in milk ).
Drug interaction :
with oral anticoagulant , sulfonylurea hypoglycemic agents & hydantoin --
SULFONAMIDES
In each case sulf.s can potentiate the effect
of the other drugs by inhibition of metabolis.
& possibly displacement from albumin .
SULFONAMIDES
TRIMETHOPRIM &SULFAMETHOXA.
• Constitutes important advance in the
dev.of clinically effective AM agents .
• If the drugs act on sequential steps in
the pathway of an obligatory
enzymatic reac. in bact. , the result of
their combination -
SULFONAMIDES
will be synergistic . This comb. is
known popularly as Cotrimoxazole .
- Trimethoprim also comes in single
entity prepration .
Chemistry :
Trimethoprim is Di-aminopyrimidine
SULFONAMIDES
Spectrum :
is equivalent to Sulfamethoxazole ,
although Trimeth. is 20 -100 times
more potent.
- Most G+ve & G-ve micro-org. are
sensitive ( resist. occurs when used
alone ) .
SULFONAMIDES
Pseudomonas aeruginosa ,Bact.fragilis
& Enterococci are resist.
Efficacy of combination :
Additional micro-org. covered by this
combination –
Klebsiella , S. typhi , Serratia , Yersinia
enterocolitica , Enterobacter, Brucella
SULFONAMIDES
abortus, Proteus mirabils , Pseudomonas , Klebsiella , Brucella abortus ,
Pneumocystis jiroveci .
-Many sulfonamide resistant strains of
S. pyogenes , Staph. aureus, Shigella,
E.coli , H. influenzae , meningococci
& gonococci becomes sensitive .
SULFONAMIDES
Max. degree of synergism occurs
when micro-org. are sensitive to both
component .
Mech. of action :
Sequential block in Folic acid synthesis
occurs.
Trimeth. is selective inhibitor of DHFR
enzym. of lower org.s, about 100,000
SULFONAMIDES
times more drug is required to↓ human
reductase than bact. enz.
( Optimal synergy exhibited at a conc. ratio of sulfamethoxazole 20:
Trimethoprim 1 . This ratio is obtained in the plasma when the two are
given in a dose ratio of 5 : 1
).
Bact. Resist. :
It is a rapidly increasing problem but
lower than the resistance to either drug
SULFONAMIDES
alone.( due to acquisition of a plasmid
that codes for an altered DHFR enz. ).
However, resist. to the combination has
been slow to develop compared to
either drug alone
Absorption ,Distribution &Excretion:
Constant ratio of 20: 1 in their conc.
SULFONAMIDES
in blood & tissues is not perfectly
matched by the two drugs .The ratio in
blood is often greater than 20:1 & that
in tissues is frequently less.
-After single oral dose of the comb.
prep. Trimeth. is absorbed more
rapidly than Sulfamethoxazole.
SULFONAMIDES
Half life of trimeth. & sulfmethox. is
11 & 10 hrs respectively.
(800 mg. of Sulfamethox +160 mg. of
Trimeth. is the comb. dose) .
-The drug readily enters in CSF &
sputum .
- High conc. is also found in bile .
SULFONAMIDES
-About 60% of administ. Trimeth . & 2550% of Sulfamethox. are excret. in
urine.
Uses :
1. UTI (uncomplic.) – more efficac.
in chronic & recurrent inf. of the UT.
small doses / day or usual dose
SULFONAMIDES
once or twice a wk. appears to be
effective in reducing the no. of recurrt.
UTI in adult female .
( Enterobacteriace surrounding the
urethral orifice may be eliminated or
markedly red. in no..Thus diminishing
the chance of ascending reinfection .)
SULFONAMIDES
- Also effective in bact. prostatitis .
2.Resp. tract inf. :
-effective in acute exacerbation of chr.
bronchitis ( 1 tab. BD is sufficient to
↓ sputum , fever & purulence ) .
- Effective in acute otitis media in
children & acute maxillary sinusitis in
SULFONAMIDES
adults caused by H. influenzae & S.
pneumoniae.
3. GIT :
- Alternative to Fluoroquinolones for
Shigellosis .
- Second line drug for Typhoid fever
(1st line drug is Ceftriaxone or fluroq.)
SULFONAMIDES
- Also effective in carriers of S. typhi .
4. Inf. by Pneumocystis jiroveci :
high dose is effective for this severe
inf. in pts of AIDS ≡ Pentamidine .
5. Prophy. in Neutropenic pts.
6. Miscellaneous :
Nocardia , Brucellosis & Methicil.
SULFONAMIDES
resist. Strains of S. aureus (MRSA) .
Adverse Effects :
More or less same as Sulf.s
-Folate def. in normal person may prod.
megaloblastosis , leukopenia or
thrombocytopenia.
- 75% of ADRs involves skin –
SULFONAMIDES
exf. dermatitis , Stevenson Johnson’s
syndrome & toxic epidermal necrolysis
( Lyell’s syndrome) .
GIT-Nausea, vomiting ,diarrhea is rare
glossitis , stomatitis & aller.cholest.
hepatitis ( Jaundice) .
CNS –headache ,depression & halluci.
SULFONAMIDES
Hematological –
Aplastic ,hemolytic & microcytic anem.
coagul. disorder , granulocytopenia ,
agranulocytosis & perpura .
-Pts with AIDS have increased chances
of hypersensitivity reaction .
SULFONAMIDES
ICLAPRIM ( a Trimethoprim analogue with improved
activity )
- Recently introduced
- Given I.V.
- More effective & better tolerated than Trimethoprim
- ≡ Linezolid
- Effective in Pts. Suffering from skin & soft tissue
infection caused by MRSA .
- Highly effective against Vancomycin resist. Staph.
Aureus (VRSA )
- In Streptococcal Pneumonia .(Phase III trials are going on for oral
use )
QUINOLONES
- First Quinolone , Nalidixic acid was
isolated as a byproduct of the synth.
of Chloroquine & mainly used for UTI.
(Bactericidal against most G-ve organisms except Pseudomonas
Less active against G+ ve organisms . There is rapid development
of resistance. It acts by ↓ DNA gyrase & is bactericidal .
QUINOLONES
It is mainly used as a urinary antiseptic as a second line
Drug .
Nitrofurantoin is not given simultaneously as antagonism
Occurs .
It is also given in diarrhea caused by Proteus , E. coli ,
Shigella & Salmonella infections.
FLUOROQUINOLONES
Introduction of Fluorinated 4- Quino
lones e.g.- First generation FQs Ciprofloxacin ,Norfloxacin ,
,Ofloxacin , Pefloxacin .
Second generation FQsGatifloxacin, Lomefloxacin ,
Sparfloxacin, Levofloxacin etc.
FLUOROQUINOLONES
Gemifloxacin , Moxifloxacin,
Trovafloxacin , Alatrofloxacin &
Finafloxacin (some books describe Gemiflox.,
Gatifloxacin & Sparfloxacin as 3rd generation &
Rest as 4th generation FQs )
FLUOROQUINOLONES
FLUOROQUINOLONES
represents a particularly important
therapeut. advancement because these
agents have broad spectrum of AM
activity & effective after oral administ.
for the Tt of wide variety of infectious
diseases .
- Microbial resist. does not dev. rapidly.
FLUOROQUINOLONES
Chemistry :
Quinolones contain a carboxylic acid
moiety at pos.-3 of the primary
ring struct. Fluoroquinolones also
contain a fluorine substituent at pos.6 & piperazine moiety at pos. – 7 &
this is a breakthrough which confers
FLUOROQUINOLONES
High potency , expanded spectrum ,
slow development of resistance , better
tissue penetration and good tolerability
to these agents .
FLUOROQUINOLONES
Structure:
7
N
F
(6)
COOH ( 3 )
O
FLUOROQUINOLONES
FLUOROQUINOLONES
FLUOROQUINOLONES
Mech. of action :
-Target is Bact. DNA Gyrase &
Topoisomerase IV enzyme .
- For most of the G +ve bact. e.g.S. aureus , Topoisomerase IV is the
primary enz. inhibited by the Quinol.s
- In contrast many G-ve bact. DNA Gyr.
FLUOROQUINOLONES
is the primary Quinol. target .
-Individual strand of double helical
DNA must be separated to permit DNA
replication & transcription .
-DNA Gyrase is respons. for combating
mechanical obstacle prod. by overwind
or excessive post. supercoiling of the
FLUOROQUINOLONES
DNA in front of the point of separation
by continuous introd. of negative super
coils into DNA .
- The DNA Gyrase of E.coli consists of
two subunits A & B . The A subunit
which carry out the strand cutting
function of the gyrase is the site of
FLUOROQUINOLONES
FLUOROQUINOLONES
FLUOROQUINOLONES
FLUOROQUINOLONES
FLUOROQUINOLONES
action of the quinolone . Mutation of
the gene that encode subunit A
polypeptide can cause resist.
- Topoisomerase IV consists of 4subut.
they separates interlinked daughter
DNA mol.s that are prod. of DNA repl.
(Eukaryotic cells have similar type II
FLUOROQUINOLONES
variant of Topoisomerase & quinol.s
suppress it in comparatively much
higher conc.s ).
Spectrum :
Bactericidal against E.coli ,Salmonella
Shigella ,Enterobacter,Campylobact.
and Neisseria, Klebsiella ,V. cholera
FLUOROQUINOLONES
(Ciproflox. is active against P. aereug.,
Staphylococcus but not against Methicil
resist. strains ).
Some intracellular bact.s are also inhib.
e.g. – Chlamydia , Mycoplasma,
Legionella , Brucella & M.tuberculos.
FLUOROQUINOLONES
Absorption ,Fate & Excretion :
• Quinolones are well abs. after oral
administration & distributed widely
in body tissues .
(Metal cations e.g.- Al , Mg , Ca, Fe & Zn
form insoluble salts with
Fluoroquinolones & inhibit
absorption )
the
FLUOROQUINOLONES
)
Doses :
First generation FQs - Norfloxacin – 400mg BD. ,
Ciprofloxacin – 500mg BD. , Ofloxacin - 200-400mg BD.
Pefloxacin .
Second generation FQs -( with additional fluoro substit.s further
extending AM activity to Gram +ve cocci & anaerobes & having longer t
½)
Levofloxacin - 500mg OD. , Gatifloxacin -200-400mg OD ,
Lomifloxacin ,Sparfloxacin -400 mg 1st day then 200 mg OD ,
Moxifloxacin – 400 mg OD ,Trovafloxacin, Alatrofloxacin ( Prodrug for Trovaflox. Given I.V.) & Finafloxacin
FLUOROQUINOLONES
- Most quinolones are cleared
predominantly by the kidney
(doses must be adjusted for renal
failure) except Pefloxacin &Moxiflox.
which are mainly metabolized by liver.
Therapeutic Uses :
1. UTI – Nalidixic acid only used in
FLUOROQUINOLONES
susc. organism .Fluoroquinolones are
more potent & having much broad
spectrum of AM activity .
2. Prostatitis
3.Sexually Transmit. Disease (STD):
( e.g.-Gonorrhoea , L. venereum, Chancroid but FQs lack
activity against T. pallidum causing syphilis)
- single oral dose of a Fluorq. e.g.-
FLUOROQUINOLONES
Ofloxacin , Ciprofloxacin is effective for
sens. strains of N. gonorrhoeae
(but resist. led to Ceftriaxone as 1st
choice)
-Pelvic Inflammatory Disease ( PID)
4. Gastro- int & abdominal inf.s:
- In Traveller’s diarrhoea (by E. coli )
FLUOROQUINOLONES
- Shigellosis
- Cholera ( Norflox. is better than
Tetracycline in ↓duration of diarrh.)
- Enteric fever by S. typhi ( Cipro, Oflo
& Levoflox.) .It also clears chr. fecal
carriage.
- Peritonitis (in pts on peritoneal dialy.)
FLUOROQUINOLONES
5.Resp. tract inf.s :
Poor activity against comm. acquired
pneumonia & bronchitis ( newer
Flqnl.s e.g.- Gatifloxacin have excel.
activity against S.pneumonia ≡ β lact.)
other sens. org. for RT inf. are H. infl.
M. catarrh., S. aureus , M. pneum.
FLUOROQUINOLONES
& Legionella.
6.Bone , Joint & Soft tissue inf.s:
-For chr. osteomylitis (Tt need wks to
months ) prod. by S.aureus & G-ve
rods .
- Diabetic foot infection
- In anaerobic inf. it is given along with
FLUOROQUINOLONES
Metronidazole.
7. Other inf.s :
Ciproflox. – prophylax. of Anthrax (It is in
news for used as a weapon of Bioterrorism )
& Tt of Tularemia .
- for MDR cases of Tuberculosis &
for atypical mycobact. inf.s caused by
Mycobact. Avium compl. in AIDS pts.
FLUOROQUINOLONES
- Ciproflox + Amoxycil. + Clavulinic
acid has been shown to be effective
as oral therapy for fever in low sens.
Pts with granulocytopenia .
(Pefloxacin- methyl derivative of Norfloxacin, penetrates tissue better
CSF conc. is better than other fluorq.s therefore preferred drug for
meningeal inf., also used for gonorrhea & typhoid ) .
FLUOROQUINOLONES
Ofloxacin - more potent than Ciprofloxacin for G +ve org.s, inhibits
Mycobact. tuberculosis & M. leprae & used as alternative in MDR
regimen .
Levofloxacin – levo - isomer of Ofloxacin , better activity against
S. pneumoniae , also used in pyelonephritis , ch. bronchitis ,sinusitis
& other related inf.s of soft tissues . Can be administered just once a
day.
Gatifloxacin -spectrum same as other fluoroq.s , Gatifloxacin ophthal.
sol. is the first FDA approved fluoroq.
Sparfloxacin – difluorinated quinolone effective against G +ve bact.,
anaerobes & mycobacteria . Used in the treatment of pneumonia ,
ch. bronchitis , sinusitis etc. Causes QT –prolongation in ECG .
FLUOROQUINOLONES
Moxifloxacin –having high activity against Strep. pneumoniae. & other
G +ve org.s . Indicated mainly in bronchitis , pneumonia , sinusitis &
otitis media , also used as eye drops .
Trovafloxacin – It is more active than other fluoroq.s against strept.pneumoniae & other G +ve bacteria. But due to its hepatotoxicity it is
recomm. only in life threatening inf.s . )
Alatrofloxacin – It is a pro-drug for Trovaflox. usually given I.V., both
have an extended spectrum against anaerobes .
Finafloxacin – More efficacious in tissues & body compartments
having acidic pH with high safety profile & widest spectrum . Once
daily dosing , oral / I.V. ( undergoing phase III clinical trial )
FLUOROQUINOLONES
Adverse Effects :
Quinol.s & Fluoroql. are generally well
tolerated, most common GI adv. reac.
are – mild nausea , vomiting and /or
abd. discomfort.
CNS-S/E –mild headache & dizziness.
-Rarely halluc., delirium & seizures can
FLUOROQUINOLONES
occur predominantly in pts who also
are taking theophylline or NSAIDs
simultaneously .
-Ciproflox. & Peflox. ↓ the metabol. of
theophylline so toxicity can occur with
elevated levels of theophylline.
-Rashes can occur including phototox.
FLUOROQUINOLONES
reactions .
-Achilles tendon rupture & tendinitis can
occur rarely .
-All these agents can prod. arthropathy
(joint erosions) & reversible arthralgia
in several sp. of animals & especial.
in children (therefore the use of quinol.s has been
C/I in developing age & preg.)
FLUOROQUINOLONES
- In some cases can be used where benefits
may overweighs the risk of quinol. therapy
in children.
- Leukopenia , Eosinophilia & mild elevation
in Transaminases enz.s which occur
rarely.
- QT prolongation can occur with
Sparfloxacin & to a lesser extent
FLUOROQUINOLONES
with Gatifloxacin & Moxifloxacin
therefore quinol.s should be used with
caution in pts on class III (Amiodarone)
& class IA ( Quinidine, Procainamide)
antiarrhythmics .
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
• The urinary tract antiseptics ↓ the
growth of many species of bacteria .
• They can not be used to treat syst.
inf.s because effective conc.s are not
reached in plasma with safe doses.
• However because they are concen. in
the renal tubules they can be
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
administered orally to Tt inf.s of U.tract
• Tt with these agents is effective as
a local therapy only in the kidney ,
ureter & bladder inf.s.
1. Methenamine: Urinary tract antisep.
& a prodrug that owes its activity to
generate formaldehyde .
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
- Acidification of the urine promotes the
formald. dependent antibacterial action
NH4 (CH2)6 + 6H2O + 4H+ → 4NH4
+ 6HCHO .
-React.is slow &≈ 3hr. are required
to reach 90% completion .
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
AM activity – all bacteria are sensitive
to free formald. at conc. of about
20μg/ml ( Proteus sp. raise the pH
of the urine & thus ↓ the release of
formald.).
Microbial org. do not develop resist. to
formald.
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
Pharmacology :
Absorbed orally (10-30% decompose
in gastric juice unless drug is given as
enteric coated tabs )
- Ammonia is prod. so C/I in hepatic
insufficiency .
-Excreted in urine ( when
urinary pH is 6
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
& daily urine output is1to 1.5L , a daily
dose of 2 G will yield 16-60 μg/ml of
formalde. sufficient to kill micro-org).
-Bacteriostatic only at low pH ,along
with acids act as bactericidal (acids
used are Mandelic acid & Hippuric
acid) .
• GI disturbance if dose > 500 mg QID
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
• Painful micturition , hematuria,
albuminuria & rashes occur at 48gm /day doses for 5 wks or more.
• Renal insuffic. does not constitute
a C/I for Methenamine alone but the
acid given concurrent. is detrimental
• Crystalluria ( from mandelic moiety)
can occur
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
• With Sulf.s mutual antagonism can
occur.
Therapeutic Uses :
-Not a primary drug for acute UTI
(Value in chronic suppressive Tt.)
- most effective when org. is E.coli
(also against other common G+ve org.s
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
e.g.-S. aureus & S. epidermidis.)
2.Nitrofurantoin ( Furadantin ) :
Synthetic nitrofuran that is used for
the prev.& Tt of UTI .(Nitrofurazone -used in burns
& skin grafts , Furazolidone – used in diarrhea , Giardiasis )
AM activity :
Enz capable of reducing NF appear to
be crucial for its activation
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
→ highly reactive intermediates are
formed→ damage DNA of bact.
( It also blocks bact. carbohydrate metabol. by ↓ AcetylCo- A synthesis )
•
•
Bact. reduces NF more rapidly than
mammalian cells & this is the cause of
selective AMA.
Bact.s which are susceptible rarely
become resist.
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
- Active against many strains of E.coli,
Enterococci ( most sp. of proteus ,
Pseudomonas , enterobacter &
Klebsiella are resistant ) .
• NF is bacteriostatic for most
suscep. micro-org at conc. of 30μg/
ml. or less & bactericidal at conc. of
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
100μg/ml .
• Antibact. activity is more in acidic
urine.
Pharmacology :
• It is abs. rapidly & completely from
GIT.
• Anti bact. conc. are not achieved in
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
plasma at recomm. doses as drug is
eliminated rapidly .
• Plasma half life is 0.3 -1 hrs
• In pts of impaired renal func. the effi.
of drug is↓ & syst. toxicity ↑ .
• It colors the urine brown.
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
S/E – Nausea , vomiting & diarrhoea .
- H/senst. react. e.g.- chills , fever
leucopenia , granulocytopenia ,
hemolytic anemia ( ass. with G6PO4 dehyd. enz deficiency )
-Cholestatic jaundice & hepatic cell.
damage can occur.
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
-
-
-
Acute pneumonitis with fever , chills
cough & dyspnea can occur( more
in elderly ) .
Headache , vertigo ,dizziness ,
musc. aches & nystagmus are
readily reversible .
Neuropathies are more in pts
having ↓ renal function.
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
Doses :
adults- 50-100mg QID. with meals &
at bed time . A single 50-100mg dose
at bed time is sufficient to prev. recurr.
( children- 5-7 mg/kg ).
- only approved for Tt of UTI susc. to
this drug (also not recommended for
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
prostatitis & pyelonephritis .)
but effective for prophyl. of recurrent
UTI .
3. Phenazopyridine :
Phenaz. HCl ( Pyridium) is not a
urinary antiseptic but has analgesic
action on the urinary tract & reduces
ANTISEPTIC & ANALGESIC
AGENTS FOR UTI
sympt.s of dysuria ,frequency , burning
& urgency ) .
Dose – 200mg TDS daily .
It is an Azo –dye which colors urine
red / orange .
GI upset can be reduced by giving it
with meals .
URINARY TRACT INFECTION
• In active UTI ,there are more than
100,000 bact. / ml i.e. more than 10 /
hpf.
• It may be acute or chronic ,acute inf.
is usually by one organism while in
chronic inf. there may be two or more
organisms .
URINARY TRACT INFECTION
• Common infective org.s in UTI are
E.coli , Proteus , Pseudomonas ,
Klebsiella & enterococci .
• Recurrence with same org. is referred
as relapse & with other org . / with long
interval is referred as reinfection .
(Renal inf. not treated properly may lead to loss of renal
URINARY TRACT INFECTION
function .For soft tissue inf. e.g. – pyelonephritis ,
& prostatitis Tt is usually required for 3-4 wks , whereas
for mucosal inf. e.g. cystitis require 1-3 days treatment.
Furthermore urine lacks natural defense like lysozymes &
immunoglobulins which are protective in tears & saliva .
Organisms reach urinary tract by ascending inf. from
urethra . In women , urethra is short & vagina is colonized
with org.s .
Free flow ,large urinary volume , complete emptying &
acidic pH are anti bacterial defense .
URINARY TRACT INFECTION
Manifestations :
Lower urinary tract involvement leads
- Frequency
- Urgency
- Dysuria
-Lower abdominal discomfort .
Upper tract involvement leads to -
URINARY TRACT INFECTION
Headache
Malaise
Vomiting
Fever with chills
Abdominal pain .
-Presence of pus cells/ bacteria / RBCs
in plain urine & +ve urine culture
URINARY TRACT INFECTION
confirms the diagnosis .
-Untreated inf. may progress to ch.pyelonephritis ,hypertension & renal
failure .
General management :
- Prophylaxis for recurrent infection.
- High fluid intake
URINARY TRACT INFECTION
- Analgesic for brief period , urinary
analgesic e.g. Phenazopyridine .
- Urinary antiseptic e.g. –Nitrofurantoin
or Methenamine .
- Systemic antimicrobials
Bibliography
1.Goodman & Gilman’s ,The Pharmacological
Basis of Therapeutics (12th Edition).
2. Clinical Pharmacology by Lawrence (Latest
edition)
3. Pharmacology by G.M. Brenner & C. W.
Stevens ( Latest Edition )
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