History of Sulfa Drugs

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• PRONTOSIL (azo dye) -- 1930 -- I. G. Farbenindustrie This company also made 
• ZyklonB for Hitler’s extermination camps 
• Domagk = research manager 
• tested antimicrobial potential in vitro & in vivo 
• determined that a sulfonamide (sulfonilamide) was the active portion of molecule. 
• awarded a Nobel Prize in Medicine in 1938 
• Foerster – 1933 - first clinical study – 10 month old infant with staph septicemia 
• The 1st effective chemotherapeutic agent

Overview of Sulfa Drugs

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• Single sulfonamides:
• *Trimethoprim-sulfamethoxazole (TMP-SMX)

Overview of Sulfa

Drugs Single sulfonamides:

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• Once the mainstay of chemotherapy but *now less used in US because resistance is increasing. 
• *Still commonly used in under-developed countries because they are cheap & readily available. 
• *Effective against 
• many bacteria, 
• several parasites and 
• one fungus 
• but ineffective against viruses.

Overview of Sulfa Drugs

*Trimethoprim-sulfamethoxazole (TMP-SMX)

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• combo 
• Bactrim, 
• Septra #26th
• Synergistic Very frequently used

Structure of Sulfonamides Picture

Structure of Sulfonamides

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• All sulfa drugs are chemical congeners of PABA. 
• *All Sulfas have S-C bond and p-NH2 
• *5000 synthesized, 150 marketed! 
• *Pathogens are only susceptible if they require PABA to synthesize folic acid.

Structure of Sulfonamides

*5000 synthesized, 150 marketed!

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• An example of molecular roulette
• This pioneering work also lead to development of 
• sulfonylurea hypoglycemic agents, 
• inhibitors of carbonic anhydrase, 
• & phenazopyridine

MOA of the Sulfonamides

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• *Most are competitive inhibitors of DHPS… 
• But some inhibit indirectly by serving as an *alternative substrate & exhausting the pteridine cofactor. 
• Single sulfas are generally regarded as *bacteriostatic as they prevent new DNA synthesis. 
• *Sulfas are selective for bugs because people use dietary folate

Development of Resistance to Sulfonamides

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• Can reduce drug uptake or speed its efflux (small multidrug resistance family [SMR]) 
• Can alter drug binding site on DHPS; this can occur even during therapy 
• Can cause overproduction of PABA which is competitive with drug at the active site 
• Can cause development of an alternative path for folate synthesis

• *They were widely used in the past for UTIs because:
• *Most drug is excreted in active form & concentrated 10-20x in urine which might be bactericidal for some bugs even if not normally recommended at other sites. 
• *But single sulfa drugs are now rarely used for UTIs because: 
• Increased resistance among enteric gram (-) bacilli which most frequently cause UTIs. 
• Better agents are now available (TMP-SMX, a fluoroquinolone, fosfomycin, ampicillin

Therapeutic Uses Of Single Sulfa Drugs In General Single Species

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• *In terms of species, single sulfas are backup drugs for 
• Mycobacterium fortuitum, 
• Chlamydia trachomatis, 
• Neisseria meningitides, 
• & Nocardia† 
• († but TMP-SMX is now the drug of choice).

• The individual sulfonamides are rarely drugs of first choice with the exceptions cited below. 

SULFISOXAZOLE (GANTRISIN):

ORAL Uses:

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• *Used for Rx of uncomplicated UTIs 
• *Alternate for: 
• Chlamydia, 
• Mycobacterium fortuitum, 
• Nocardia, 
• Neisseria meningitidis 
• *Ineffective for CNS infections because of its low lipid solubility

SULFAMETHOXAZOLE (GANTANOL): ORAL

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• *Similar to sulfisoxazole but: 
• It is more slowly absorbed and excreted 
• *It has a longer t½ (11 hr) 
• *It is more likely to cause crystalluria 
• *Reminder: It is usually marketed with trimethoprim in TMP-SMX

SULFADIAZINE (ORAL)

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• *Achieves highest concentration in CSF (30-80% of [plasma]) 
• Relatively rapidly absorbed & excreted 
• *Its use is limited by crystalluria!!! 
• *Urine flow must be brisk (>1.2 L/day in adults) 
• *Bicarbonate reduces renal tubular reabsorption and thereby accelerates renal clearance.

SULFASALAZINE (AZULFIDINE):

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• POORLY ABSORBED ORAL DRUG 
• *One of top 300 drugs 
• *Mostly held in GI tract/bowel & excreted in feces 
• *Used for inflammatory bowel disease (IBD), ulcerative colitis, regional enteritis bec. of antiinflammatory properties. 
• It is a *prodrug Sulfasalazine ▬► Sulfapyridine + 5-aminosalicylate (5AS) 
• *5AS (mesalamine) is an active antiinflammatory compound that inhibits cyclooxygenase 
• *A comparable concentration of mesalamine in the colon cannot otherwise be obtained. 
• *Sulfapyridine can cause systemic toxic effects

SILVER SULFADIAZINE (SILVADENE):

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• TOPICAL 
• *Agent of choice for prevention of infections in 2nd & 3rd degree burns 
• *Silver released is a broad-spectrum agent x bacteria and fungi. 
• *It reduces colonization, prevents sepsis, & encourages healing but is *not useful against established deep infections. 
• *It is used topically on burns with little toxicity. 
• *Systemic absorption is possible when applied to a large area.

SULFACETAMIDE (SULAMYD)

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• A topical opthalmic 
• *It is used for Rx of many sulfonamide- sensitive ophthalmic infections.
• *It is an impt. alternate for Chlamydia trachomatis. 
• *High concentrations (30%) aren’t irritating or allergenic & are of neutral pH 
• *It readily penetrates ocular fluids and tissues.

Pharmacokinetics Of Sulfonamides

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• *Most are well absorbed orally (70-95%) 
• *Most are widely distributed including into the CSF, fetus (but sulfadiazine best for CSF) 
• *Acetylation occuring in liver inactivates & decreases solubility which increases crystallization. 
• *Elimination is by glomerular filtration so renal function is required.

Sulfas: Renal Damage

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• *Crystals of sulfonamide & acetylated sulfonamide can cause renal damage [Least common with sulfisoxazole.] 
• *Most common with sulfadoxine used for prophylaxis of malaria with pyrimethamine (Remember fluids, bicarbonate!) 
• *Must use reduced dosage (or cease use) if kidney function is impaired.

Sulfas: Hypersensitivity Reactions

Frequent

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• *Drug Fever (3% w sulfisoxazole) 
• *Skin Rashes (2%) during 1st wk 
• *Photosensitivity

Sulfas: Hypersensitivity Reactions

Occasional but Serious:

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• *Erythema multiforme (Stevens-Johnson syndrome): the most serious sulfa rash 
• It can cause exfoliation 
• It occurs very infrequently 
• It can occur with any sulfa drug but occurs most often with long-acting sulfas

Sulfas: Other Toxicities & Drug Interactions

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• *Hematopoietic anemia or abnormalities: occasional serious blood dyscrasias including agranulocytosis (0.1%) 
• Vasculitis (opccasional) 
• Hepatotoxicity (occasional; 0.1%) 
• *Kernicterus (occasional) 
• Displaces bilirubin from albumin 
• Shouldn’t be given to near-term women 
• Also, keep in mind that sulfas are secreted in milk of nursing moms 
• Pregnancy: FDA Recommendation “C” but contraindicated near term

Structure of Trimethoprim Pyrimethamine Mechanism of TMP-SMX

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• *TMP/PMA [trimethoprim or pyrimethamine] competitively inhibits DHFR by binding to the active site for dihydrofolic acid. 
• *The simultaneous presence of SMX in TMP/SMX *potentiates action of TMP/PMA by ↓ the concentration of dihydrofolic acid.

Mechanism of TMP-SMX

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• *TMP/PMA [trimethoprim or pyrimethamine] competitively inhibits DHFR by binding to the active site for dihydrofolic acid. 
• *The simultaneous presence of SMX in TMP/SMX *potentiates action of TMP/PMA by ↓ the concentration of dihydrofolic acid

Antifolate: (3) Trimethoprim Alone

(Proloprim)

Trimethoprim Alone

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• Only marketed for oral Rx of uncomplicated UTIs caused by gm(-) bacilli. 
• Can result in resistance to this drug and to trimethoprim-sulfamethoxazole. 
• Resistance to TMP alone occurs by: 
• Alteration of dihydrofolate reductase 
• Reduced permeability 
• Conversion to thymidine dependence

Major Rx Uses of TMP-SMX General

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• *Med Lett drug of choice for 11 organisms including: 
• Gram-negative bacilli (5) 
• Actinomycetes (2) 
• Parasites (3) 
• One fungus (*Pneumocystis jiroveci; formerly called P. carinii ) 
• *An important backup drug for 17 other organisms.

Major Rx Uses of TMP-SMX

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• *Oral Rx of UTIs & Prostatis 
• *Bacterial Respiratory Tract Infections 
• *GI Infections: 
• *MRSA

Major Rx Uses of TMP-SMX

*Oral Rx of UTIs & Prostatis

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• Especially useful for recurrent UTIs 
• Bacterial prostatis Used as a backup to FQs

Major Rx Uses of TMP-SMX

*Bacterial Respiratory Tract Infections

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• Otitis media in kids 
• Sinusitis in adults 
• Acute chronic bronchitis

Major Rx Uses of TMP-SMX *GI Infections:

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• Shigellosis (backup to FQs) 
• Traveler’s diarrhea 
• Enterohemorrhagic E. coli O157:H7 
• BUT Rx can ↑ risk of hemolytic–uremic syndrome

Major Rx Uses of TMP-SMX

*MRSA

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• Methicillin-resistant Staph aureus (MRSA) infections 
• Only used as a backup, limited experience 

Major Rx Uses of TMP-SMX

AIDs Patients Bacterial Infections

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• *Treatment of choice for 3 parasitic infections especially prevalent in AIDS patients.
• *Cyclospora cayetanensis (cyclosporiasis) 
• *Isospora belli diarrhea (IV) (isosporiasis) 
• *Toxoplasmosis (actually pyrimethamine + sulfadiazine + leucovorin (10-25 mg with each dose of pyrimethamine))

Major Rx Uses of TMP-SMX

AIDs Patients Fungal Infections

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• *Treatment of choice for one fungal infection especially common in AIDS patients 
• *Pneumocystis jiroveci pneumonia (“PCP”: IV); both treatment and prophylaxis 
• Listed as a parasite in the Med. Letter Handbook; formerly called P. carini

Toxicity of TMP-SMX

General

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• *Drug-induced glossitis (inflam. of the tongue) and/or stomatitis (inflam. of the mucous membranes in the mouth) are not uncommon! 
• BUT DRUG-INDUCED ANGIOEDEMA IS RARELY THIS BAD!

Toxicity of TMP-SMX

Overview

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• *Other hypersensitivity reactions, 
• *Skin problems 
• *CNS 
• *Crystalluria 
• *Anti-folate effects 
• Also includes toxicities listed for sulfonamides alone.

Toxicity of TMP-SMX

*Other hypersensitivity reactions,

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• include 
• fever, 
• rashes, 
• photosensitivity, 
• leukopenia, & 
• diarrhea (esp. in AIDS pts).

Toxicity of TMP-SMX

*Skin problems

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• 3x more likely than with SMX alone; 
• especially common in the elderly

Toxicity of TMP-SMX

*CNS

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• rare: 
• headache, 
• depression, 
• hallucinations

Toxicity of TMP-SMX

*Crystalluria

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• is rare but the combo is contraindicated in pts w ⬇⬇ renal function as it can cause permanent kidney damage.

Toxicity of TMP-SMX

*Anti-folate effects

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• anemia, 
• leukopenia, 
• thrombocytopenia 
• are: blocked by 
• coadministration of folinic acid without loss of antimicrobial action. 
• rare unless patient is folate deficient

Specific Therapeutic Uses Of Individual Sulfonamides

SULFISOXAZOLE (GANTRISIN): ORAL General

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• *The Oral Sulfonamide Of Choice 
• *Very soluble in water so unlikely to cause crystalluria 
  *However, has the shortest t½ (ca 5-6 hr)
• Specific Therapeutic Uses Of Individual Sulfonamides 

Drug Resistance to TMP-SMX

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• *Resistance is less common than against a single sulfonamide 
• Two genetic changes must take place. 
• It can occur via plasmid transfer.