Co-trimoxazole, Sulfa, and Urinary antiseptics

Co-trimoxazole is a classic example of drug synergism.

(Synergism is the term used when the various components when used in a combination help each other and produce profoundly more effect than the addition of individual effects)

A purely synthetic combination of a sulfonamide and trimethoprim; Co-trimoxazole, exhibits bactericidal effect on a large variety of organisms.

Cotrimoxazole was invented in 1970s; it came to market around 1974.

Do not feel the name Co-trimoxazole is difficult.

“Co” stands for combination. “Trim” stands for “Trimethoprim”. and “Oxazole” stands for “Sulfa-methoxazole.”

Co-Trim-Oxazole = Co-trimoxazole

Importance of Co-trimoxazole has reappeared due to its effectiveness in prevention and treatment of Pneumocystis jiroveci (Pneumocystis carinii) – an opportunistic fungal infection, associated with HIV disease.

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SAQ/LAQ/Viva

Mention the mechanism of action of Co-trimoxazole.

Mechanism of action:

Co-trimoxazole is a combination of Sulfamethoxazole and Trimethoprim in the ratio of 5:1 (5 parts of Sulfamethoxazole and 1 part of Trimethoprim).

These two agents inhibit two  consecutive steps in the biosynthesis of nucleic acid in the microorganisms.

When used individually they are bacteristatic (they reduce the growth of the microorganisms),

but when they are combined,  –

the combination – Co-trimoxazole exhibits bactericidal effect.

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First step: Inhibited by Sulfamethoxazole

PABA ——-//——PABA reductase —–//——-> Folic acid (Dihydrofolate) (DHF)

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Second step: Inhibited by Trimethoprim

Folic Acid (DHF) -//–Folate reductase -//–> Folinic acid (Tetrahydrofolate) (THF)

(Remember – In alphabets, S comes first, then T – first step inhibited by S=Sulfamethoxaole, Second step by T=Trimethoprim)

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If only one of the two steps is inhibited, the drug exhibits bacteristatic effect – so sulfamethoxazole and trimethoprim, when used individually are bacteristatic. But when they are combined, two consecutive steps are inhibited, which produces sequential blockade, and bactericidal effect.

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SAQ/LAQ/Viva

Explain: Why trimethoprim is combined with Sulfamethoxazole?/ Explain the rationale behind combining trimethoprim with sulfamethoxazole.

Mention advantages of trimethoprim-sulfamethoxazole combination.

Please note the word – “rationale” means logic. “Rationale” does not mean “ratio” !!!!

(So the above question has 2 parts – why they are combined/rationale behind the combination both means same. It is like explaining how co-trimoxazole works as a combination – so the answer is explaining the two steps in the nucleic acid synthesis and which drug inhibits which one, and how using them in combination produces sequential blockade and produces bactericidal effect, instead of individual bacteristatic effects), so the answer shall be –

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Sulfamethoxaole inhibits the first step in the nucleic acid synthesis – as shown below.

First step: Inhibited by Sulfamethoxazole

PABA ——-//——PABA reductase —–//——-> Folic acid (Dihydrofolate) (DHF)

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Trimethoprim inhibits the second step in the same pathway – as shown below.

Second step: Inhibited by Trimethoprim

Folic Acid (DHF) -//–Folate reductase -//–> Folinic acid (Tetrahydrofolate) (THF)

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These two drugs when used individually, they inhibit only one step individually, and hence produce bacteristatic effect. But when used in combination, they inhibit the two consecutive steps, and produce sequential blockade, hence the combination – Co-trimoxazole – produces bactericidal effect.

This is why sulfamethoxazole is combined with trimethoprim.

Now – mention the advantages of the combination –

This combination produces many advantages as listed below:

1. The two drugs in combination inhibit two consecutive steps in the nucleic acid synthesis in the microorganisms to produce sequential blockade.
2. Individual drugs are bacteristatic, but the combination is bactericidal; thus this combination produces drug synergism.
3. Doses of individual drugs required are reduced.
4. Dose-related adverse effects are minimized.
5. Duration of action is increased.
6. Decreased frequency of administration; Co-trimoxazole is administered every 12 hours (only 2 times a day)
7. Widended spectrum of activity
8. Better penetration in genital fluids
9. Bacterial resistance less frequent to the combination than to individual agents in the combination.
10. Relatively safe, well tolerated
11. It is less expensive.

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SAQ/LAQ/Viva

Mention the antimicrobial spectrum and uses of Co-trimoxazole.

1. Opportunistic fungus: Pneumocystis jiroveci

2. Gram negative organisms: 

E. coli, Proteus, Klebsiella, Salmonella, Shigella, Bordetella pertussis, Brucella, Pasteurella (Yersinia), Legionella, Vibrio cholera, Serratia

Neisseria gonorrhea, Neisseria meningitidis

Hemophilus influenzae, Hemophilus ducreyi

3. Chlamydia: Trachomatis, lymphogranuloma venerum, inclusion conjunctivitis

4. Gram positive organisms: Staphylococcus, Streptococcus, Cornybacterium diphtheriae, Nocardia,  Clostridium welchii, Listeria

5. Nocardia, 6. Actinomycetes, 7. Toxoplasma gondi

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Uses of Co-trimoxazole

How to remember by logic / sequence (based on common uses, better penetration of cotrimoxazole in urinary and genital tracts, then chlamydia and other gram negative, then others)

Mention pneumocystis jiroveci first.

Then urinary infections and genital infections

Then chlamydial infections

Then – salmonella and shigella –  typhoid fever and bacillary dysentery

Then gram positive infections related to respiratory tract – and finally

meningitis, osteomylelitis, plague, brucellosis, nocardiosis etc.

1. Pneumocystis jiroveci (carinii)  an opportunistic fungal infection associated with HIV disease. Prevention and treatment of Pneumocystis Pneumonia (PCP pneumonia – Pneumocystis carinii pneumonia)
2. Urinary tract infection: E coli, Proteus, Prostatitis, Vaginitis
3. Gonorrhea, Chancroid, Granuloma inguinale, Lymphogranuloma venerum
4. Trachoma and inclusion conjunctivitis
5. Bacillary dysentery – (Shigellosis), Typhoid fever
6. Respiratory infections – Sinusitis, pharyngitis, bronchitis, otitis media, Whooping cough, community acquired pneumonia (CAP)
7. Mentingitis, Osteomyelitis
8. Plague, Brucellosis, Nocardiosis, Toxoplasmosis

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SAQ/LAQ/Viva

Mention adverse effects of Co-trimoxazole.

Adverse effects are due to both sulfa component as well as trimethoprim.

1. Allergic reactions – 1:  Immediate hypersensitivity – Steven Johnson Syndrome – may be serious and fatal. It is mostly due to the sulfa component. Also Lyell Syndrome – a serious, rare, and potentially fatal allergic reaction. In both conditions, there is erythema multiformis with toxic epidermal necrolysis.

2. Allergic reactions – 2: Delayed:     —–Fixed drug eruption: A typical skin lesion appears on drug intake. If the same drug is taken any time again, the same type of lesion appears at same sites.   —-Glossitis, stomatitis     —Exfoliative dermatitis, morbilliform rashes, urticaria

3. Gastrointestinal intolerance such as nausea, loss of appetite, diarrhea, vomiting, hyperacidity

4. Hemolysis and bleeding in patients with G6PD deficiency

5. Megaloblastic anemia especially in patients with pre-existing folic acid deficiency

6. Crystalluria, burning micturition, hematuria, renal damage on using in high doses

7. Teragogenic effects  (if used in 1st trimester) and kernicterus in the newborn if used during 2nd or 3rd trimester –  Hence it should not be used in pregnancy.

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SAQ/LAQ/Viva

Mention preparations and routes of administration of Co-trimoxazole.

Co-trimoxazole is the combination of Sulfamethoxazole (5 parts) and Trimethoprim (1 part).

Preparations/Formulations and routes of administration:

Oral: Tablets. Suspensions

Intravenous: Solution for injection (Intravenous injections/infusions)

Single strength: Sulfamethoxazole (400 mg) + Trimethoprim (80 mg) (adult tablet)

Double strength tablet: Sulfamethoxazole (800 mg) + Trimethoprim (160 mg) 

Pediatric strength 1: Sulfamethoxazole (200 mg) + Trimethoprim (40 mg) 

Pediatric strength 2: Sulfamethoxazole (100 mg) + Trimethoprim (20 mg) 

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