Trimethoprim and Co-trimoxazole

Main problem with sulphonamides is that of resistance. Thus uses are declining. They are used in combination. Co-trimoxazole is combination of sulfamethoxazole and trimethoprim, having synergistic actions.

Trimethoprim

Chemistry:

Trimethoxybenzyl Pyrimidine

Chemically related to anti malarial drug pyrimethamine, both are folate antagonist

Trimethoprim has broad activity against micro-organisms. It is especially effective in the management of UTI when used alone. Later on it was discovered that monotherapy was not as effective as combination with sulfamethoxazole.

Trade name of co-trimoxazole is Ceptron.

Advantages of combination

When given together, have synergistic activity.

Both drugs are bacteriostatic, when combined bactericidal actions occur. They cause destruction of the cell wall and are thus more effective than bacteriostatic effect.

Pharmacokinetics:

Given orally fully absorbed from GIT.

Distribution: Widely distributed, in body fluids and tissues, including CSF concentrates in acidic media of prostatic and vaginal fluid.

PPB: 65 – 70 %

Excretion: in urine within 24 hrs.

Co-Trimoxazole

• Combination gives synergistic antibacterial action
• Pharmacodynamic synergism: because of inhibition of successive steps
• Pharmacokinetic synergism: because have equal half life

Mechanism of Action

It is 50 times more efficacious in specific bacteria than in mammalian cells. It is more specific for bacteria synthesizing own folic acid. As mammalian cells utilize preformed folic acid, they are not affected.

Resistance

Resistance is the issue with this combination. Some proposed mechanisms include:

1. Mutational changes –defective binding of combination to dihydrofolate reductase, which is plasmid coated, producing less affinity for binding.
2. Less permeability of combination within cells, decreased influx or increased efflux
3. Production of dihydrofolate reductase enzyme is increased, due to which available antimicrobial agents are not enough to inhibit.

Resistance is not a major issue with co-trimoxazole, in some strains the sensitivity has decreased.

Co-trimoxazole

Mixture of trimethoprim with sulfamethoxazole.

• Sulfamethoxazole – 400 mg.      Ratio 1:5
• Trimethoprim – 80 mg.

Trimethoprim has a large volume of distribution, so its dose is decreased. It is quickly absorbed and after absorption, the ratio is plasma becomes 1:20 (works best at this ratio). PPB of trimethoprim is also less than sulfamethoxazole.

Advantages of Using Co-Trimoxazole

1. Bactericidal. (Individual drugs are bacteriostatic)
2. Wide antibacterial spectrum.
3. Increased efficacy
4. Less dose of each drug.
5. Less incidence of toxicity.
6. Have same half life (TMP 11 hrs. SMZ 10 hrs.)
7. Both inhibit the same metabolic pathway, so synergize each others effect.
8. Decreased chances of resistance (because if bacterium is resistant to one drug, it will be sensitive to other)

Pharmacokinetics

Can be given orally or I/V. after oral administration absorption is good, peak plasma levels appear within 2 hours. Given I/V for infectious conditions.

Trimethoprim is a weak base with pH of 7 .2. It is found in bile, sputum, high concentration in CSF, also concentrates in acidic media of prostate and vagina.

PPB of trimethoprim is 40-45% while that of sulfamethoxazole is 60%.

Volume of distribution of trimethoprim is 9 times more than sulfamethoxazole.

Most products are excreted in urine; traces of drug appear within 24 hours. Dose is adjusted as required (esp. in renal insufficiency).

Anti bacterial spectrum

Combination has wider antibacterial spectrum.

1. Gram positive ,
2. Gram negative bacteria,
3. Some enterobacteriaceae like Shigella, Klebsiella
4. Salmonella Typhi and Para typhi,
5. Nocardia,
6. Pneumocystis Jiroveci,
7. Escherichia coli,
8. Serratia,
9. MRSA,
10. Staphylococcus aureus,
11. Staphylococcus epidemidis,
12. Proteus,
13. Brucella

Clinical uses

1. Respiratory infections:

Highly effective in:

• Chronic bronchitis
• Community acquired Pneumonia
• Otitis media in children
• Acute maxillary sinusitis
• Pneumocystis Jiroveci Pneumonia
• Non tuberculous mycobacterial infections –esp. AIDS

(DOSE: SMX 800mg: TMP 160mg)

DS dose 240 mg TMP 1200 mg SMX)

• Hemophilis influenzae
• Streptococcus Pneumoniae
• Moraxella Catarrhalis
• Klebsiella Pneumoniae

Have no activity against Pharyngitis

GIT Infections:

1. Although amoxicillin is good, trimethoprim is highly effective in Shigellosis
2. Typhoid Fever (SMX 800mg: TMP 160mg BD) (cephalosporin or ceftriaxone are 1^st line for typhoid fever. Use as alternative
3. Systemic Salmonella infection (Typhoid Fever) for salmonella typhae and paratyphae, effective when used for prophylaxis given for 3 months

UTI:

1. Said to be effective against uncomplicated and chronic & Recurrent UTI. Given either 800 mg x 160 mg or small dose is administered for management of chronic recurrent UTI in 200 mg SMZ 40 mg TMP BD dose.
2. As highly concentrated in acidic media effective in Prostatitis
3. Acute Gonococcal Urethritis

Other drugs used in UTI include ampicillin, fluroquinolones, and in uncomplicated refractory cases even sulfonamides can be used.

Brucellosis

Drug of choice is doxycycline, streptomycin and gentamicin.

Co-trimoxazole is used as alternative.

MRSA

Also used in sensitive MRSA.

Intravenous Uses:

1. I/V preparation is ideally used for Pneumocystis Pneumonia

2. Gram negative Bacterial sepsis
3. Shigellosis,
4. Typhoid Fever,
5. UTI

I/V preparations are used when drugs cannot be given orally or patient is uncooperative.

Adverse Effects

As the main component is sulfonamide, all effects are also seen and include:

1. Hematological

Trimethoprim – Megaloblastic Anemia, Leukopenia, thrombocytopenia, Granulocytopenia

Prevented by simultaneous administrations of folic acid 6 – 8 mg/D which does not enter bacteria for 3-6 weeks

2. Hypersensitivity reactions -Rashes, Fever, Vasculitis
3. CNS effects –headache, depression, hallucinations
4. GIT disturbance – Nausea, Vomiting, Glossitis & stomatitis.
5. HIV patients with pneumocystis pneumonia or immune compromised show fever, rashes, leukopenia, diarrhea, elevation of hepatic aminotransferases, hyperkalemia, hyponatremia.