CHAPTER 84 SULFONAMIDES AND TRIMETHOPRIN

Broad spectrum antimicrobial drugs that disrupt the synthesis of tetrahydrofolic acid

I. SULFONAMIDES
- available for systemic treatment of bacterial infections
- with the advent of newer antimicrobial drugs, use of sulfonamides has
greatly declined; however,
sulfonamides still have an important therapeutic role, primarily in
the treatment of urinary tract
infections
- suppress bacterial growth by inhibiting synthesis of folic acid which is
required by all cells for
biosynthesis of DNA, RNA, and proteins
- active against a broad spectrum of microbes

1. Therapeutic Uses - once employed widely, application is now limited

- declination in use due to:
• introduction of bactericidal antibiotics that have less
toxicity
• development of bacterial resistance
- urinary tract infection is the principal indication
- sulfisoxazole is generally favored
- high solubility in urine - effective concentrations w/in
the urinary tract
- less expensive than other sulfonamides
- when infection is recurrent, or when urinary tract obstruction is
present, treatment with a
sulfonamide alone may not be sufficient

2. Pharmacokinetics – well absorbed following oral administration

- applied topically to the skin or mucous membranes
- absorbed in sufficient amounts to cause systemic effects
- well distributed to all tissues
- readily crosses the placenta
- levels achieved in the fetus are sufficient to produce both
antimicrobial effects and
toxicity
- metabolized in the liver - principal reaction is acetylation
- acetylation may decrease solubility, increasing the risk of
renal damage from crystal
formation
- excreted primarily by the kidneys

3. Adverse Effects
- hypersensitivity reactions = mild reactions to include rash, drug
fever, and photosensitivity
- especially frequent with topical applications, which are no
longer employed routinely
- reserved for ophthalmic infections, burns, and vaginitis
 - most severe is Stevens-Johnson Syndrome
- a life-threatening skin disease that causes rashes, skin
peeling and sores on
the mucous membranes
- a person with SJS suffers blistering of mucous
membranes, typically in the
mouth, eyes, and genitals, and patchy areas of
rash
- symptoms include widespread lesions of the skin and
mucous membranes,
together with fever, malaise, and toxemia
- hematologic effects = blood dyscrasias, hemolytic anemia
- red cell lysis can produce fever, pallor, and jaundice
- can cause agranulocytosis, leucopenia, thrombocytopenia,
and very rarely, aplastic
anemia
- kernicterus = disorder in newborns caused by deposition of
bilirubin in the brain
- bilirubin is neurotoxic and can cause severe neurologic
deficits and even death
- promoted by displacing bilirubin from plasma proteins
- should not be administered to infants under the age of 2
months not pregnant women
near term or to mothers who are breast-feeding
- renal damage from crystalluria (forming crystalline aggregates)
with older sulfonamides
- caused irritation and obstruction result in anuria and even
death
- patients should maintain a daily urine output of 1200 ml
(accomplished by consuming
8 – 10 glasses of water a day)

4. Drug Interactions – can intensify the effects of warfarin, phytoin, and

sulfonylurea-type oral hypoglycemics (tolbutamide)
- principal mechanism of inhibition of hepatic metabolism

5. Preparations
a. Systemic Sulfonamides
- short-acting agents are used primarily to treat infections of
the urinary tract

i. Sulfisoxazole – preferred agent for urinary tract

infections
- less expensive
- because of its high water solubility, poses a
minimal risk of
crystalluria
- useful against a variety of systemic infections
(nocardiosis,
melioidosis, chancroid)
 - may be administered orally (preferred method) or
by injection

ii. Sulfamethoxazole – trade name Gantanol

- indications are the same as sulfisoxazole
- can be administered less frequently than short
acting agents
- presents a greater risk of injury to kidneys
- employed primarily in fixed-dose combination
with trimethoprim
- administered orally

iii. Sulfadiazine – short acting agent

- high urine flow must be maintained
- crosses the blood brain barrier with ease,
allowing it to be the best
sulfonamide for prophylaxis of meningitis
- when combined with pyrimethamine, is useful
against toxoplasmosis
- administered orally

b. Topical Sulfonamides
- associated with high incidence of hypersensitivity reactions
and are not routinely used

i. Sulfacetamide – trade names Isopto Cetamide and

Sodium Sulamyd
- widely used for superficial infections of the eye
(conjunctivitis, corneal
ulcer)
- may cause blurred vision, sensitivity to bright
light, headache, brow
ache, and local irritation
- hypersensitivity is rare
- available in solution and ointment formulations

ii. Silver Sulfadiazine and Mafenide – employed to prevent

bacterial colonization
in patients with second- and third-degree burns
- mafenide is frequently painful
- can suppress renal excretion of acid,
causing acidosis
- patients should be monitored for acid-base
status
- marketed under the trade name
Sulfamylon
- silver sulfadiazine is usually pain free
- trade names include Silvadene,
Thermazens, and SSD
Cream
II. TRIMETHOPRIM
- trade names Proloprim, Trimpex
- active against a broad spectrum of microbes, gram-positive bacilli and
some gram-negative bacilli
- suppresses bacterial synthesis of DNA, RNA, and proteins

1. Therapeutic Uses – approved only for initial therapy of acute,

uncomplicated urinary tract infections

2. Pharmacokinetics – absorbed rapidly and completely from the GI tract

- wide distribution to body fluids and tissues
- readily crosses the placenta

3. Adverse Effects – generally well tolerated

- most frequent adverse effects are itching and rash
- gastrointestinal reactions occur occasionally
- hematologic effects = megaloblastic anemia, thrombocytopenia,
neutropenia
- occur only in individuals with pre-existing folic acid deficiency
- if early signs (sore throat, fever, pallor) of bone marrow
suppression occur, complete
blood counts should be performed
- large doses have caused fetal malformations (in animals)
- readily crosses the placenta, prudence dictates avoiding
routine use during pregnancy
- excreted in breast milk and may interfere with folic acid
utilization by nursing infant

III. TRIMETHOPRIM-SULFAMETHOXAZOLE
- marketed together in a fixed-dose combination product
- trade names are Bactrim, Cotrim, and Septra
- active against a wide range of gram-positive and gram-negative bacteria
- administered orally or IV infusion

1. Therapeutic Uses – preferred or alternative medication for a variety of

infectious diseases
- especially valuable for urinary tract infections, otitis media,
bronchitis, shigellosis, and
pneumonia (caused by P. Carinii)
- urinary tract infection = indicated for chemotherapy of
uncomplicated urinary tract infection
- particularly useful for chronic and recurrent infections
- pneumocystis carinii infections = treatment of choice for
pneumonia and other infections
caused by P. Carinii, an opportunistic organism that thrives in
immunocompromised
hosts (cancer patients, organ transplant recipients, individuals
with AIDS)
- gastrointestinal infections caused by several gram-negative bacilli
 - used for otitis media and acute exacerbations of chronic bronchitis
- used against urethritis and pharyngeal infection
- can treat whooping cough, nocardiosis, brucellosis, melioidosis and
chancroid
2. Pharmacokinetics – may be administered orally or by IV infusion
- well distributed throughout the body
- readily crosses the placenta and enters breast milk
- excreted primarily by the kidneys

3. Adverse Effects – generally well tolerated, toxicity from routine use if

rare
- common adverse effects are nausea, vomiting, and rash
- combination can cause hypersensitivity reactions (including
Stevens-Johnson syndrome),
blood dyscrasias (hemolytic anemia, agranulocytosis,
leucopenia, thrombocytopenia,
aplastic anemia), kernicterus, and renal damage
- may cause adverse CNS effects (headache, depression,
hallucinations)
- those suffering from AIDS have a 55% incidence of adverse effects

4. Drug Interactions – combination can intensify the effects of warfarin,

phenytoin, and sulfonylurea-type
oral hypoglycemics