2. Sulfonamides
Sulfonamides were the first antimicrobial agents (AMAs)
effective against pyogenic bacterial infections
Sulfonamido-chrysoidine (Prontosil Red) was one of the
dyes included by Domagk to treat experimental
streptococcal infection in mice and found it to be highly
effective.
Subsequently an infant was cured of staphylococcal
septicaemia (which was 100% fatal at that time) by
prontosil.
3. By 1937, it became clear that
prontosil was broken down in the
body to release sulfanilamide
which was the active
antibacterial agent.
Because of rapid emergence of
bacterial resistance and the
availability of many safer and
more effective antibiotics, their
current utility is limited, except
in combination with
trimethoprim (as cotrimoxazole)
or pyrimethamine (for malaria).
4. Sulphonamides
Sulfonamides that are still of clinical interest
are:
1) Short acting (4–8 hr): Sulfadiazine
2)Intermediate acting (8–12 hr):
Sulfamethoxazole
3. Long acting (~7 days): Sulfadoxine,
Sulfamethopyrazine
4. Special purpose sulfonamides: Sulfacetamide
sod., Mafenide, Silver sulfadiazine, Sulfasalazine
5. ANTIBACTERIAL SPECTRUM
Sulfonamides are primarily bacteriostatic against many gram-positive and
gram-negative bacteria like
Strepto. pyogenes, Staph. aureus,
Haemophilus influenzae, Escherichia coli,
H. ducreyi, Shigella
Vibrio cholerae.
gonococci, meningococci, pneumococci
Anaerobic bacteria are not susceptible.
Chlamydiae: trachoma, lymphogranuloma venereum, inclusion
conjunctivitis, are sensitive, as are Actinomyces, Nocardia and
Toxoplasma
6. Mechanism of action
Sulfonamides competitively inhibit the union of PABA with pteridine
residue to form dihydropteroic acid which conjugates with glutamic
acid to produce dihydrofolic acid.
Woods and Fildes (1940) proposed the hypothesis that sulfonamides,
being structural analogues of PABA, inhibit bacterial folate synthase →
FA is not formed and a number of essential metabolic reactions suffer
Many bacteria synthesize their own folic acid (FA) of which p-
aminobenzoic acid (PABA) is a constituent, and is taken up from the
medium.
8. Resistance to
sulfonamides
Most bacteria are capable of developing
resistance to sulfonamides like
gonococci, pneumococci, Staph. aureus,
meningococci, E. coli, Shigella and some
Strep. pyogenes, Strep. viridans and
anaerobes.
The resistant mutants either:
(a) produce increased amounts of PABA,
or
(b) their folate synthase enzyme has low
affinity for sulfonamides, or
(c) adopt an alternative pathway in
folate metabolism.
9. PHARMACOKINETICS
Sulfonamides are rapidly and nearly
completely absorbed from g.i.t
The highly protein bound members are
longer acting
The primary pathway of metabolism of
sulfonamides is acetylation at N4 by
nonmicrosomal acetyl transferase,
primarily in liver
10. Sulfadiazine
It is the prototype of the general
purpose sulfonamides that is rapidly
absorbed orally and rapidly excreted in
urine.
Plasma protein binding is 50%, and it is
20–40% acetylated.
The acetylated derivative is less soluble
in urine, crystalluria is likely.
It has good penetrability in brain and
CSF—was the preferred compound for
meningitis.
Dose: 0.5 g QID to 2 g TDS; SULFADIAZINE
0.5 g tab
11. Sulfamethoxazole
It has slower oral absorption and
urinary excretion resulting in
intermediate duration of action;
It is the preferred compound for
combining with trimethoprim because
the t½ (10hr)of both is similar.
However, a high fraction is acetylated,
which is relatively insoluble—
crystalluria can occur.
Dose: 1 g BD for 2 days, then 0.5 g BD.
GANTANOL 0.5 g tab
12. Sulfadoxine, Sulfamethopyrazine
They are used in combination with
pyrimethamine in the treatment of malaria
,Pneumocystis jiroveci (pneumonia in AIDS
patients )and in toxoplasmosis
These are ultralong acting compounds, action
lasting > 1 week because of high plasma protein
binding and slow renal excretion (t½ 5–9 days).
13. Sulfacetamide
sod.
It is a highly soluble compound yielding
neutral solution which is only mildly
irritating to the eye in concentrations up
to 30%.
It is used topically for ocular infections
due to susceptible bacteria and
chlamydia, including ophthalmia
neonatorum caused by Ch.
oculogenitalis.
It attains high concentrations in anterior
segment and aqueous humour after
topical instillation.
LOCULA, ALBUCID 10%, 20%, 30% eye
drops, 6% eye oint
14. Silver sulfadiazine
Used topically as 1% cream, it is active against a large number of
bacteria and fungi, even those resistant to other sulfonamides, e.g.
Pseudomonas.
It slowly releases silver ions which appear to be largely responsible
for the antimicrobial action.
Uses: for preventing infection of burnt surfaces and chronic ulcers.
SILVIRIN 1% cream, ARGENEX 1% cream with chlorhexidine 0.2%.
Sulfasalazine used in ulcerative colitis and rheumatoid arthritis.
15. ADVERSE
EFFECTS
• Nausea, vomiting and epigastric pain.
• Crystalluria is dose related, but
infrequent now. Precipitation in urine can
be minimized by taking plenty of fluids and
by alkalinizing the urine.
• Hypersensitivity reactions occur in 2–5%
patients. Like rashes, urticaria and drug
fever. Photosensitization is reported.
• Hepatitis, unrelated to dose, occurs in
0.1% patients
16. USES
Systemic use of sulfonamides alone (not
combined with trimethoprim or
pyrimethamine) is rare now.
Combined with trimethoprim (as
cotrimoxazole) sulfamethoxazole is used
for many bacterial infections, P. jiroveci
and nocardiosis .
Along with pyrimethamine, certain
sulfonamides are used for malaria and
toxoplasmosis
Ocular sulfacetamide sod. (10–30%) is
alternative in trachoma/inclusion
conjunctivitis.
17. COTRIMOXAZOLE
The fixed dose combination of trimethoprim and
sulfamethoxazole is called cotrimoxazole.
Trimethoprim is a diaminopyrimidine which selectively
inhibits bacterial dihydrofolate reductase (DHFRase).
Cotrimoxazole introduced in 1969 causes sequential
block of folate metabolism as depicted in Fig.
Trimethoprim is >50,000 times more active against
bacterial DHFRase than against the mammalian enzyme.
Thus, human folate metabolism is not interfered
Individually, both sulfonamide and trimethoprim are
bacteriostatic, but the combination becomes cidal
against many organisms.
18.
19. Spectrum
of action
Organisms covered by the combination are—
Salmonella typhi,
Serratia,
Klebsiella,
Enterobacter,
Yersinia enterocolitica,
Pneumocystis jiroveci and
many sulfonamide-resistant strains of
Staph. aureus,
Strep. pyogenes,
Shigella, enteropathogenic
E. coli, H.influenzae,
gonococci and
meningococci.
20. Adverse
effects
• Nausea, vomiting, stomatitis, headache
and rashes are the usual manifestations.
• Folate deficiency (megaloblastic anaemia)
is infrequent, occurs only in patients with
marginal folate levels
Cotrimoxazole should not be given
during pregnancy. Trimethoprim being an
antifolate, there is teratogenic risk
22. Cotrimazine
Cotrimazine It is a combination of trimethoprim with
sulfadiazine. Its utility is similar to that of
cotrimoxazole.
Trimethoprim Sulfadiazine
90 mg + 410 mg: AUBRIL tab, 2
tab BD for 2 days,
180 mg + 820 mg: TRIGLOBE
FORTE tab.
23. Uses
1. Urinary tract infections: Single dose
therapy with 4 tablets of cotrimoxazole has
been used successfully for acute cystitis.
Cotrimoxazole is especially valuable for
chronic or recurrent cases or in
prostatitis, because trimethoprim is
concentrated in prostate.
2. Respiratory tract infections: Both upper
and lower respiratory tract infections,
including chronic bronchitis and
faciomaxillary infections, otitis media.
24. Uses
3. Bacterial diarrhoeas and dysentery
Cotrimoxazole may be used for severe and
invasive infections by E. coli, Shigella,
nontyphoid Salmonella, and Y.
enterocolitica
4. Pneumocystis jiroveci causes severe
pneumonia in neutropenic and AIDS
patients. Cotrimoxazole has prophylactic as
well as therapeutic value.
One DS tablet 4–6 times/day for 2–3 weeks
25. QUINOLONES
These are synthetic antimicrobials
having a quinolone structure that
are active primarily against gram-
negative bacteria, though the
newer fluorinated compounds also
inhibit gram-positive ones.
The first member Nalidixic acid
introduced in mid-1960s was useful
to treat urinary and g.i. tract
infections ,have limited use
because of low potency, modest
blood and tissue levels, restricted
spectrum and high frequency of
bacterial resistance.
26. Fluoroquinolones
A breakthrough was achieved in the
early 1980s by fluorination of the
quinolone structure at position 6 and
introduction of a piperazine substitution
at position 7 resulting in derivatives
called fluoroquinolones with high
potency, expanded spectrum, slow
development of resistance, better tissue
penetration and good tolerability
27.
28. Nalidixic
acid
It is active against gram-negative
bacteria, especially coliforms: E. coli,
Proteus, Klebsiella, Enterobacter,
Shigella.
It acts by inhibiting bacterial DNA gyrase
and is bactericidal. Resistance to
nalidixic acid develops rather rapidly
Adverse effects These are relatively
infrequent, consist mostly of g.i. upset
and rashes.
Most important toxicity is neurological—
headache, drowsiness, vertigo, visual
disturbances, occasionally seizures
29. Nalidixic acid is contraindicated in infants.
Dose: 0.5–1 g TDS or QID; GRAMONEG 0.5 g tab, 0.3 g/5
ml susp, DIARLOP 0.3 g/5 ml susp
Uses
1. Nalidixic acid is primarily used as a urinary antiseptic,
generally as a second line drug in recurrent cases or on
the basis of sensitivity reports.
2. It has also been employed in diarrhoea caused by
Proteus, E. coli, Shigella or Salmonella, but
norfloxacin/ciproloxacin are more commonly used now
31. Mechanism
of action
The FQs inhibit the enzyme bacterial
DNA gyrase.
The DNA gyrase consists of two A and
two B subunits: FQs bind to A subunit
with high affinity and interfere with its
strand cutting and resealing function.
In gram-positive bacteria the major
target of FQ action is a similar enzyme
topoisomerase IV
32. Ciprofloxacin
(prototype)
It is the most potent first generation FQ
The MIC of ciprofloxacin against these bacteria is
usually < 0.1 µg/ml,
Highly susceptible are
E. coli Neisseria
gonorrhoeae
K. pneumoniae N. meningitidis
Enterobacter H. influenzae
Salmonella typhi H. ducreyi
Nontyphoid Salmonella Campylobacter
jejuni
Shigella Yersinia
enterocolitica
Proteus Vibrio cholerae
33. Uses
1. Urinary tract infections
2. Gonorrhoea: Initially a single 500 mg dose was nearly 100% curative
3. Chancroid: 500 mg BD for 3 days is a second line alternative drug to
ceftriaxone/ azithromycin
4. Bacterial gastroenteritis:
5. Typhoid: Ciprofloxacin is one of the first choice drugs in typhoid
Ciprofloxacin given in a dose of 750 mg BD for 10 days is recommended.
6. Bone, soft tissue, gynaecological and wound infections: caused by
resistant Staph. and gram-negative bacteria respond to ciprofloxacin
7. Respiratory infections
8. Tuberculosis It is a second line drug which can be used as a component
of combination chemotherapy against multidrug resistant tuberculosis.
9. Gram-negative septicaemias: Parenteral ciprofloxacin may be
combined with a third generation cephalosporin or an aminoglycoside
10. Meningitis: ciprofloxacin has been successfully used in gram-negative
bacterial meningitis, in immunocompromised patients.
34. Norfloxacin
It is less potent than ciprofloxacin: MIC
values for most gram -ve bacteria are 2–
4 times higher.
Norfloxacin is primarily used for urinary
and genital tract infections.
Given for 8–12 weeks, it can treat
chronic UTI.
It is also good for bacterial diarrhoeas,
NORBACTIN, NORFLOX 200, 400, 800 mg
tab, 3 mg/ml eye drops; UROFLOX,
NORILET 200, 400 mg tab. BACIGYL 400
mg tab, 100 mg/5 ml susp.
35. FQ Uses, Action Brands
Perflovacin It is the methyl derivative of
norfloxacin
PELOX, 200, 400 mg tab, to be taken
with meals; 400 mg/5 ml inj
Ofloxacin 1)drug for nonspecific urethritis,
cervicitis and atypical pneumonia
2)can be used in resistant cases of
TB.
3) High activity is exhibited against
M. leprae
4) chronic bronchitis and other
respiratory or ENT infections.
ZANOCIN, TARIVID 100, 200, 400 mg
tab; 200 mg/100 ml i.v. infusion,
ZENFLOX also 50 mg/5 ml susp.
ZANOCIN, OFLOX, EXOCIN 0.3% eye
drops.
Levofloxacin It is the active levo(s) isomer of
ofloxacin having improved activity
against Strep. pneumoniae
TAVANIC, GLEVO 500 mg tab, 500
mg/100 ml inj. LOXOF, GLEVO,
LEVOFLOX, LEVODAY 250, 500, 750
mg tabs, 500 mg/100 ml inj; GLEVO
0.5% eye drops.
36. FQ Uses, Action BRANDS
Lomefloxacin second generation
difluorinated quinolone,
equal in activity to
ciprofloxacin but more
active against some
gram-negative bacteria
and chlamydia
higher incidence of
phototoxicity and Q-T
prolongation, it has
been withdrawn in USA
Gatifloxacin • 2nd generation FQ
with higher affinity
for bacterial
topoisomerase IV
• respiratory and ENT
infections
ADR:Q-T prolongation,
arrhythmias,
phototoxicity,
unpredictable
hypoglycaemia,
banned in India since
March 2011.
