Sulfonamides & Trimethoprim Overview

This study material, presented by Dr. Salma Naqvi, focuses on sulfonamides and trimethoprim, which are antimicrobial agents significant in the treatment of bacterial infections.

Sulfonamides

Introduction

Sulfonamides were the first antimicrobial agents (AMAs) discovered and are structural analogs of para-aminobenzoic acid (PABA). They are primarily bacteriostatic, meaning they inhibit bacterial growth rather than kill bacteria directly; however, bactericidal concentrations can be achieved in urine. It is important to note that anaerobic bacteria are not susceptible to sulfonamides.

Classification of Sulfonamides

Short-acting: Sulfadiazine
Intermediate-acting: Sulfamethoxazole
Long-acting: Sulfadoxine
Special purpose: This category includes:
- Sulfacetamide: used as ocular drops
- Silver sulfadiazine: used for burn dressing
- Sulfasalazine: used in rheumatoid arthritis and ulcerative colitis
Orally non-absorbable agents: Include Sulfasalazine, Olsalazine, and Balsalazine

Despite their historical significance, sulfonamides have largely been superseded by other antibiotics and the combination of trimethoprim-sulfamethoxazole.

Mechanism of Action

Sulfonamides inhibit the enzyme dihydrofolic acid (DHF) synthase, which is responsible for converting PABA to DHF. This process is crucial for the synthesis of tetrahydrofolic acid (THF), purines, and ultimately DNA. Due to their structural similarity to PABA, sulfonamides effectively compete with it for binding to DHF synthase, thus impairing the bacterial DNA formation. Unlike bacteria, humans do not require this pathway as they derive DHF from dietary folate, thereby protecting human cells from the toxic effects of sulfonamides.

Pharmacokinetics

Sulfonamides are predominantly administered orally and are rapidly absorbed into body tissues and fluids, including the central nervous system (CNS), cerebrospinal fluid (CSF), and the placenta. They are approximately 70% bound to plasma proteins and are metabolized through acetylation, creating inactive and less soluble metabolites. Sulfonamides are excreted in urine, both in their unchanged form and as metabolites; some sulfonamides are particularly insoluble in acidic urine.

Adverse Effects

Side effects commonly associated with sulfonamides include malaise and diarrhea, which may not prompt discontinuation of therapy. Rarely, crystalluria occurs, along with potential allergic reactions manifesting as rashes, fever, hepatitis, and agranulocytosis, among others. Serious skin reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis may occur in rare cases. Additionally, hemolysis may present in patients with glucose-6-phosphate dehydrogenase deficiency, and individuals with AIDS are prone to heightened allergic reactions when treated with co-trimoxazole for Pneumocystis carinii pneumonia.

Combination Therapy: Sulfonamides + Trimethoprim

The emergence of resistance to sulfonamides has necessitated their use primarily in combination with trimethoprim. Trimethoprim is a broad-spectrum antimicrobial agent effective against many Gram-positive and Gram-negative microorganisms, although it is not effective against enterococci and Pseudomonas aeruginosa. Trimethoprim is utilized effectively for urinary and respiratory tract infections and can serve as a low-dose prophylactic treatment for urinary tract infections.

Trimethoprim (TMP)

Mechanism of Action

Trimethoprim is a bacteriostatic antibiotic that acts as a dihydrofolate reductase inhibitor, reducing the availability of THF cofactors necessary for purine, pyrimidine, and amino acid synthesis. Trimethoprim is usually administered orally and is predominantly employed for prophylaxis and treatment of urinary tract infections. Cotrimoxazole, a fixed-dose combination of sulfamethoxazole and trimethoprim, was introduced in the 1970s and has become a popular therapeutic agent.

Pharmacokinetics

Trimethoprim is likewise well-absorbed from the gastrointestinal tract, distributes widely in body fluids including the CSF, and possesses a greater lipid solubility than sulfamethoxazole. Approximately 40% of trimethoprim binds to plasma proteins and is noted to concentrate within the prostatic fluid.

Combining TMP with Sulfamethoxazole

When trimethoprim (TMP) is combined with sulfamethoxazole (SMX), the combination is referred to as cotrimoxazole. This ratio is generally 1:5 (TMP:SMX) and is effective because TMP and SMX sequentially inhibit the enzymes necessary for folic acid synthesis in bacteria.

Clinical Applications

Urinary Tract Infections (UTIs)

Identification of complicated vs. uncomplicated UTIs is crucial, as complicated infections typically require longer antimicrobial therapy. Uncomplicated UTIs, often caused by Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis, and Klebsiella species, exhibit symptoms like increased urinary frequency and dysuria. Treatment regimens for uncomplicated infections often include a three-day course of antibiotics, while one-day regimens with trimethoprim-sulfamethoxazole are less effective and not typically recommended.

Other Clinical Uses

Ophthalmology: Sulfacetamide solution/ointment for ocular infections.
Autoimmune diseases: Sulfasalazine for ulcerative colitis and rheumatoid arthritis.
Burn treatment: Silver sulfadiazine for infected burns.
Malaria: Sulfadoxine combined with pyrimethamine for chloroquine-resistant malaria.
Infections in burns: Mafenide is a topical agent effective against Gram-positive and negative bacteria, including Pseudomonas.

Other Therapeutic Uses of Cotrimoxazole

Cystitis, chronic and recurrent prostatitis
Respiratory tract infections including chronic bronchitis and otitis media
Bacterial diarrhea and dysentery due to pathogens like campylobacter and E. coli
Preventing Pneumocystis jiroveci pneumonia in AIDS patients.

Advantages of Cotrimoxazole

The trimethoprim-sulfamethoxazole combination provides higher cure rates for uncomplicated UTIs compared to beta-lactam antibiotics and reduces the risk of subsequent UTIs due to its ability to eliminate gastrointestinal colonization of uropathogens.

Emerging Resistance

Increasing drug resistance among uropathogens poses a challenge in treating uncomplicated UTIs. Significant clinical factors contributing to trimethoprim-sulfamethoxazole resistance include recent antibiotic use, hospitalization history, diabetes mellitus, and multiple prior UTIs. Although fluoroquinolones demonstrate efficacy in patients with drug resistance risk factors, resistance to these agents is also on the rise.

Adverse Effects

Adverse effects may include hypersensitivity reactions, presenting as rashes or urticaria in 2-5% of patients. Severe consequences such as hepatitis, bone marrow depression, crystalluria, and kernicterus in newborns may also arise due to sulfonamide treatment, especially in high-risk groups. Other common side effects include nausea, vomiting, and epigastric pain.

Kernicterus

Kernicterus results from the displacement of bilirubin from plasma binding sites, causing free bilirubin to enter the central nervous system and leading to potentially severe neurological outcomes in newborns.

Contraindications for Use

Pregnancy
Nursing mothers
Infants under 6 weeks
Patients with renal or hepatic failure
Individuals with blood disorders

Quiz Questions

1. What is the primary target of sulfonamides in bacterial cells?
a. DNA gyrase
b. Dihydropteroate synthase
c. Dihydrofolate reductase
d. RNA polymerase

2. Trimethoprim acts by inhibiting which bacterial enzyme?
a. Beta-lactamase
b. Dihydropteroate synthase
c. Dihydrofolate reductase
d. Transpeptidase

3. The combination of trimethoprim and sulfamethoxazole is considered:
a. Additive
b. Synergistic
c. Antagonistic
d. Ineffective

4. A major adverse effect of cotrimoxazole, especially in HIV-positive patients, is:
a. Nephrotoxicity
b. Stevens-Johnson syndrome
c. Hypokalemia
d. Hepatic failure

Thank you for reviewing this comprehensive examination of sulfonamides and trimethoprim.

Comprehensive Overview of Sulfonamides and Trimethoprim

Comprehensive Overview of Sulfonamides and Trimethoprim