SULFONAMIDES

Assoc. Prof. Iv. Lambev (itlambev@mail.bg)

G. Domagk
(1895–1964),
bacteriologist and
pathologist discovered
the first sulfonamide in
1935. Nobel prize for
Physiology and Medicine
in 1939.
Mechanism of action
•Unlike man, most bacteria cannot
utilize external folic acid, a nutrient
which is essential for growth, and they have
to synthesize it from para-aminobenzoic
acid (PABA). Sulfonamides are struc-
turally similar to PABA and inhibit the
enzyme dihydrofolate synthetase in the
biosynthetic pathway for folic acid.
•High concentrations of PABA antagonize
the effectiveness of sulfonamides.
PABA Sulfanilamide
DHF synthetase DHF reductase

PABA DHFA THFA Purines

() ()
Sulfonamides Trimethoprim
DNA
Dietary folate
in man
Proteins
Spectrum of activity
•Sulfonamides have a bacteriostatic action
on a wide range of Gram-positive and Gram-
negative microorganisms and also are active
against toxoplasma, nocardia species, and
chlamydia.
•Sulfonamides alone are usually reserved
for the treatment of nocardiosis and
toxоplasmosis.
•Resistance is common and due to the
production of dihydrofolate synthetase
with reduced affinity for binding of
sulfonamides, and is transmitted in
Gram-negative bacteria by plasmids.
•Resistant strains of Staphylococcus
aureus can synthesize more PABA
than normal.
Pharmacokinetics
•Most sulfonamides are well absorbed
orally. They are widely distributed in
the body and cross the BBB and placenta.
•Sulfonamides are metabolized in the liver,
initially by acetylation which shows
genetic polymorphism. The acetylated
product has no antimicrobial actions but
retains toxic potential.
A large number
of parent drugs and
N-acetyl metabolites
are excreted by the
kidney.
Unwanted effects
•Hypersensitivity reactions include rashes,
vasculitis, Stevens-Johnson syndrome.
•Haemolysis in patients with glucose-6-
phoshate-dehydrogenase deficiency.
•Crystalluria is a potential problem with
overdose of these drugs or with acid urine.
•Sulfonamides compete for bilirubin
binding sites on albumin and can cause
kernicterus in neonates.
Stevens–Johnson
syndrome after oral
intake of Co-trimoxazole
(Color Atlas and Synopsis
of Clinical Dermatology, 1999)

Lyell
syndrome
after oral
intake of
Co-trimoxazole
Clcr
DRUG PREPARATIONS
t1/2 8–16 h:
- sulfamethoxazolе
- sulfametrolе
t1/2 > 16 h:
- sulfadimethoxinе
- sulfalen
Sulfacetamidе
•collyrium 20% 10 ml

Sulfadicramide
For local
treatment
of bacterial
conjunctivitis
Low GI abssorption (30%)
- Sulfaguanidinе
in GI infections
Sulfasalazinе
(Salazopyrin )®

• colitis ulcerosa
Sulfamethoxazole/Trimethoprim:
Co-trimoxazolе (BAN)
•Biseptol® - tab. 480 mg
•Trimezol® - tab. 480 mg
•960 mg/12 h 7–10 days
Co-trimoxazolе (BAN)
 Trimethoprim inhibits dihydrofolate
reductase which converts dihydrofolate
to tetrahydrofolate:
DHF synthetase DHF reductase

PABA DHFA THFA Purines

() ()
Sulfamethoxazole Trimethoprim
The bacterial enzyme is inhibited at 50 000
times lower concentrations than the
mammalian equivalent.
The combination of trimethoprim with the
sulfonamide sulfamethoxazole (known as
co-trimoxazole – BAN) acts synergistically
to prevent folate synthesis by bacteria.
However, resistance to the sulfamethoxazole
component, and the incidence of unwanted
effects limit the value of this combination.
Trimethoprim has a wide spectrum of
activity against Gram-positive and Gram-
negative bacteria. The combination with
sulfamethoxazole is also effective against
Proteus and Pneumocystis carinii
(this is now its major indication).
Trimethoprim and sufamethoxazole are
well absorbed from the gut. Their t1/2 is
about 11 h. Trimethoprim is excreted
unchanged by the kidney. Co-trimoxazole
is availble for p.o. and i.v. use.
Adverse effects
Sulfamethoxazole/Trimethoprim…
•Nausea, vomiting, and
diarrhoea, which
are usually mild.
•Skin rashes.
•Folate deficiency leading to megaloblastic
changes in the bone marrow is rare except
in patients with depleted folate stores.
•Marrow depression with agranulocytosis.
ANTIMYCOBACTERIAL DRUGS
Basic antitubercular drugs
•Synthetic drugs (p.o.): Isoniazid,
Ethambutol, Pyrazinamide, Ethionamide
•Antibiotics: Rifampicin (p.o.), Rifamycin
(i.v. infusion), Rifabutin; Streptomycin
Drugs for treatment of leprosy
p.o.: Rifampicin, Clofazimine, Dapsone
 ANTITUBERCULAR DRUGS

First line drugs:

Isoniazid

Rifampicin

Ethambutol

Pyrazinamide

Streptomycin

These drugs are use routinely.

They have high antitubercular efficacy,

and low toxicity.
Second line drugs
Antibiotics:
•Aminoglycosides: Kanamycin, Amikacin
•Other rifamicins: Rifabutin, Pifapentine
•Some macrolides: Azithromycin, Clarithromycin
•Other antibiotics: Capreomycin, Cycloserine
Synthetic drugs:
•Fluoroquinolones: Ciprofloxacin, Ofloxacin,
Levofloxacin, Moxifloxacin
•Ethionamide, Para-aminosalicylic acid
•Linezolid
These drugs are no more effective than the first-line agents.
Their toxicities are often more serious. They are active against
atypical strains of mycobacteria.
 Isoniazid (5 mg/kg/24 h p.o. )
inhibits production of long-chain
mycolic acids which are unique to the cell
wall of mycobacteria species. It is bacterio-
cidal against dividing microorganisms.
Resistance is due to random mutation.
It can be troublesome in the developing
countries.
Oral absorption of isoniazid is good, but
reduced by food. It diffuses well into the
body tissues, including the CSF, and pene-
trates into macrophages so that it is effe-
ctive against intracellular tubercle bacilli.
Isoniazid undergoes genetically controlled
polymorphic acetylation in the liver. A high
percentage of fast acetylators being found
in Japanese and Eskimo populations.
In European populations 40–50% are rapid
acetylators.
Unwanted effects of isoniazid

•Nausea and vomiting.

•Peripheral neuropathy in high
doses. This can be prevented
by prophylactic oral use of pyridoxine
(vit. B6). High risk patients are with diabetes,
alcoholism, chronic renal failure, malnutrition.
•Hepatotoxicity.
•Systemic lupus erythematosus-like syndrome.
(B6)
  Ethambutol impairs synthesis of the
cell wall of mycobacteria. It is primarily
bacteriostatic. Its oral bioavailability
is 77%. Only a small amount is metabo-
lized and most is eliminated unchanged
by the kidney. Unwanted effects:
•Headache, dizziness
•Optic neuritis (dose-related,
but usually reversible).
 Pyrazinamide has a bactericidal effect.
 Rifampicin (Rifampin – USAN)
This semisynthetically modified antibiotic product of
Streptomyces mediterranei has been an important
component of the treatment of tuberculosis in humans.
Rifampicin acts by inhibiting RNA polymerase, which
catalyzes the transcription of DNA to RNA. Rifampicin
is bactericidal and has a wide spectrum:
● Brucella, Staphiloccocus spp.
● Gram-positive and Gram-negative anaerobic bacteria are
inhibited at low concentrations, including Bacteroides fragilis.
● Chlamydia and Rickettsia are susceptible.
● Mycobacterium tuberculosis.
● Mycobacterium leprae.
Absorption from the gut is almost complete,
but is delayed by food. Peak plasma levels
reach 3 h after a single oral dose of
600 mg. The t1/2 is 3 h.
About 8590% of the drug is protein
bound in plasma but rifampicin penetrates
well into most tissues, cavities, and exuda-
tes. It is metabolized by deacetylation and
is excreted mainly in the bile. The drug
and its metabolite undergo prolonged
enterohepatic recirculation.
Rifampicin
Unwanted effects of rifampicin
•Sometimes influenza-like symptoms,
flushing, rashes.
•Hepatotoxicity, usually only producing a
transient rise of transaminases in plasma.
•Induction of drug-metabolizing enzymes
in the liver. Important interactions
include those with oral contraceptives,
phenytoin, warfarin, and sulphonylureas.
•Urine and tears become pink/red which
may be a useful guide to compliance.
 Streptomycin is an aminoglycoside
antibiotic. Its antibacterial activity is due
to its binding to the 30S subunit of the
bacterial ribosome and inhibiting of protein
synthesis. It has a wide spectrum of anti-
bacterial activity but it is primarily used to
treat mycobacterial infections (i.m.).
•The main problems are eighth nerve toxi-
city (vestibulotoxicity more than deaf-
ness), nephrotoxicity, allergic reactions,
resistance.
 DRUG TREATMENT
OF TUBERCULOSIS

•Mycobacterium tuberculosis readily deve-

lops resistance to monotherapy. Three or
four drugs are used for the first 2 months,
and then the treatment is continued with
2 drugs for a further 4–7 months.
A standard regimen in the UK includes
rifampicin and isoniazid for 6 months
with ethambutol and pyrazinamide for
the first 2 months only.
 PRINCIPLES OF RATIONAL
ANTIBACTERIAL
CHEMOTHERAPY
(Adapted from Laurence et al., 1997 & others)
The following principles, many of which
apply to drug therapy in general, are a
guide to good clinical practice
with antimicrobial agents.
(1) Make a diagnosis precisely:
– defining the site of action;
– defining the microorganism(s) responsible
and their sensitivity to drugs;
– biological samples for laboratory must be
taken before treatment is begun.
(2) Aims of therapy
The goal of antibacterial therapy is to help the body
eliminate infectious organisms without toxicity to the
host. It is important to recognize that the natural defense
mechanisms of a patient are of primary importance in
preventing and controlling infection. Examples of
natural defenses against bacterial invasion are:
are
● the mucociliary escalator in the respiratory tract
● the flushing effect of urination
● the normal flora in the GIT.
All such mechanisms can be affected by disease or
therapeutic interventions.
Once microbial invasion occurs, various host
responses serve to combat the invading organisms,
including:
● the inflammatory response
● cellular migration and phagocytosis
● the complement system
● antibody production.
production
The difficulty of controlling infections in immunocom-
promised patients emphasizes that antibacterial therapy
is most effective when it supplements endogenous
defense mechanisms rather than when acting as the
sole means of control.
(3) Consider factors affecting the success
of antibacterial therapy
•Bacterial susceptibility
Various factors need to be considered in susceptibility
testing. The minimum inhibitory concentration (MIC)
is the concentration of drug that must be attained at
the infection site to achieve inhibition of bacterial
replication. In general, if bacteria are not susceptible to a drug
in vitro they will be resistant in vivo.
•Distribution to the site of infection
To be effective, an antibacterial agent must be distributed to the
site of infection and come into contact with the infecting organism
in adequate concentrations of the active drug form.
Bacteria that locate intracellularly (Bartonella,
Brucella, Chlamydoia, Mycobacterium, Rickettsia)
will not be affected by antibacterial agents that remain in
the extracellular space. Staphylococcus is facultatively
intracellular and may sometimes resist treatment
because of intracellular survival.
Drugs that accumulate in leukocytes and other cells
include fluoroquinolones, lincosamides,
sulfonaides and macrolides but aminoglycosides
and β-lactams do not achieve effective
intracellular concentrations.
An infectious/inflammatory process often adversely
affects the distribution of a drug in vivo. An exception
is inflammation of the meninges (meningitis), which
reduces the normal barrier between blood and CSF,
so that antibacterial agents that normally cannot cross
this barrier reach the CSF.
This breakdown of barriers by inflammation does not
occur to an appreciable extent with the blood–prostate
barrier and blood–bronchus barrier.
Effective antibacterial concentrations may not be achieved
in poorly vascularized tissues, e.g. the extremities during
shock, sequestered bone fragments or heart valves.
(4) Remove barriers to cure (e.g. lack of free
drainage of abscesses, obstruction in the
urinary or respiratory tracts).
(5) Decide whether therapy is necessary.
As a general rule, acute infections require
chemotherapy whilst chronic infections
may not. Chronic abscess or empyema
respond poorly. Even some acute infections
such as gastroenteritis are better managed
symptomatically than by antimicrobials.
(6) Choose the most suitable route of
administration of antibacterial drug(s)
Often there is a choice of routes of administration,
although some drugs (such as aminoglycosides) must be
given parenterally if systemic activity is desired. Other
factors influencing route selection include the
characteristics of the disease being treated, likely
treatment duration, the patient’s temperament and
owner’s capability.
● Topical administration is valuable for disorders of
eye and ear and some skin or gut infections. High
drug concentration may be achieved locally in this
way and some drugs too toxic for routine systemic
administration (bacitracin, neomycin, polymyxins)
can be useful topically.
● Oral administration is adequate in most infections
and is usually preferable for home treatment. Some
owners find it easier to administer drugs orally with
food but the potential ADRs of ingesta on systemic
drug availability should be considered.
If in doubt, administration on an empty
stomach (no food for 1–2 h before and after dosing)
is recommended, as the most common outcome
of drug–ingesta interactions is impaired systemic
drug availability.
● Parenteral administration is not routinely
advantageous but can be useful for fractious,
unconscious or vomiting patients, or those with
oral/pharyngeal/esophageal pain or dysfunction.
(7) Select the best drugs. This involves
consideration of:
– specificity (the antimicrobial activity of a
drug must cover the infecting organisms);
– pharmacokinetic factors (the chosen drug
must reach the site of infection (e.g. by
crossing BBB);
– the patients (who may previously had
allergic reactions to antimicrobials or
whose routes of drug elimination may be
impaired, e.g. by renal disease).
In some infections the choice of antimicro-
bials follows automatically from the clinic-
cal diagnosis because the causative organ-
nism is always the same, and is virtually
always sensitive to the same drug, e.g.
segmental pneumonia in a young person
which is almost always caused by S. pneu-
monia (benzylpenicillin), some haemolytic
streptococcal infections, e.g. scarlet
fever and erysipelas (benzylpenicillin),
typhus (tetracycline), leprosy, lues.
In the other cases the infecting organism is
identified by the clinical diagnosis, but no
assumption can be made as to its sensitivity
to any one antimicrobial, e.g. tuberculosis.
In the most cases the infecting organism is
not identified by the clinical diagnosis, e.g.
in urinary tract infections, meningitis, etc.
In the last two categories the choice of
antimicrobial drug may be guided by:
– knowledge of the likely pathogens
– simple staining and sensitivity tests.
8. Compliance

•As with all drug therapy, antibacterials will not

be effective unless administered correctly to
the patient.
•It is very important for the successful treatment
to keep a compliance from patients.
(9) Indications for combination therapy:
– to avoid the development of resistance
in chronic infections (e.g. FIV, HIV, tuberculosis).
– to broaden the antibacterial spectrum:
a) in a known mixed infection;
b) unusual pathogens, including Mycobacterium,
Rhodococcus and fungi.
c) if the microorganism cannot be predicted
(septicemia complicating neutropenia);
– to obtain potentation (e.g. penicillin
plus gentamicin for enterococcal
endocarditis)
(10) Antimicrobial therapy and pregnancy
or lactation

PRC B have:
•Azithromycine
•Erythromycine
•Penicillins
•Most
cephalosporines
PRCs LRCs
A: controlled studies L1: safest (Ibuprofen,
show no risk (Vit. B9) Paracetamol)
B: no evidence of risk in L2: safer (Cephalosporins,
humans (Penicillins) Omeprazole)
C: risk cannot be ruled L3: moderately safe
out (Bisoprolol) (Acarbose, Aspirin)
D: positive evidence of L4: possibly hazardous
risk (Diazepam) (Diazepam, Lithium)
X: contraindicated in L5: contraindicated
pregnancy (Estrogens) (ACE inhibitors)
(11) Administer the drug in optimum dose
and frequency
– Inadequate dose may encourage the
development of microbial resistance.
– Intermittent dosing is preffered to
continual infusion.
– Plasma concentration monitoring can be
applied to optimize therapy with aminoglyco-
sides, fluoroquinolones, cephalosporins,
etc. in patients with kidney disease.
(12) Continue therapy until apparent
cure has been achieved.
– Most acute infections are treated for
5 to 10 days. There are many exceptions
to this, such as typhoid fever, tuberculo-
sis, and infective endocarditis, in which
relapse is possible long after apparent
clinical cure and so the drugs are
continued for a long time, determined
by clinical experience.
(13) Test for cure. In some infections, microbio-
logical proof of cure is desirable because
disappearance of symptoms and signs
occurs before the microorganisms are
eradicated, e.g. urinary tract infections
(examinations must be done after
withdrawal of chemotherapy).
(14) Prophylactic chemotherapy for surgical
and dental procedures should be of very limited
duration. It should be started at the time of
surgery to reduce the risk of producing
resistant microorganisms.
(15) Remeber that the most important carriers
of cross infections are your 10 fingers.