Cotrimoxazole

COTRIMOXAZOLE

The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole. Trimethoprim is a diaminopyrimidine related to the antimalarial drug pyrimethamine which selectively inhibits bacterial dihydrofolate reductase (DHFRase). Cotrimoxazole introduced in 1969 causes sequential block of folate metabolism as depicted in Fig. 50.1. Trimethoprim is >50,000 times more active against bacterial DHFRase than against the mammalian enzyme. Thus, human folate metabolism is not interfered at antibacterial concentrations of trimethoprim. Individually, both sulfonamide and trimethoprim are bacteriostatic, but the combination becomes cidal against many organisms. Maximum synergism is seen when the organism is sensitive to both the components, but even when it is moderately resistant to one component, the action of the other may be enhanced.

Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (~ 10 hr). Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim 1, the MIC of each component may be reduced by 3–6 times. This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : 1, because trimethoprim enters many tissues, has a larger volume of distribution than sulfamethoxazole and attains lower plasma concentration. However, the concentration ratio in many tissues is less than 20 : 1. Trimethoprim adequately crosses blood-brain barrier and placenta, while sulfamethoxazole has a poorer entry. Moreover, trimethoprim is more rapidly absorbed than sulfamethoxazole—concentration ratios may vary with time. Trimethoprim is 40% plasma protein bound, while sulfamethoxazole is 65% bound. Trimethoprim is partly metabolized in liver and excreted in urine.

Spectrum Of Action

Antibacterial spectra of trimethoprim and sulfonamides overlap considerably. Additional organisms covered by the combination are—Salmonella typhi, Serratia, Klebsiella, Enterobacter, Yersinia enterocolitica, Pneumocystis jiroveci and many sulfonamide-resistant strains of Staph. aureus, Strep. pyogenes, Shigella, enteropathogenic E. coli, H.influenzae, gonococci and meningococci.

Resistance

Bacteria are capable of acquiring resistance to trimethoprim mostly through mutational or plasmid mediated acquisition of a DHFRase having lower affinity for the inhibitor. However, resistance to the combination has been slow to develop compared to either drug alone. Widespread use of the combination has resulted in reduced responsiveness of over 20% originally sensitive strains.

Adverse Effects

All adverse effects seen with sulfonamides can be produced by cotrimoxazole.

·          Nausea, vomiting, stomatitis, headache and rashes are the usual manifestations.

·      Folate deficiency (megaloblastic anaemia) is infrequent, occurs only in patients with marginal folate levels.

·          Blood dyscrasias occur rarely.

It should not be given during pregnancy: trimethoprim being an antifolate, there is theoretical teratogenic risk. Neonatal haemolysis and methaemo-globinaemia can occur if it is given near term.

·         Patients with renal disease may develop uremia. Dose should be reduced in moderately severe renal impairment.

·    A high incidence (upto 50%) of fever, rash and bone marrow hypoplasia due to cotrimoxazole has been reported among AIDS patients with Pneumocystis jiroveci infection.

·          The elderly are also at greater risk of bone marrow toxicity from cotrimoxazole.

·  Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia.

Preparations SEPTRAN, SEPMAX, BACTRIM, CIPLIN, ORIPRIM, SUPRISTOL, FORTRIM

Trimethoprim           Sulfamethoxazole

8 0 mg +                400 mg tab: 2 BD for 2 days then 1 BD.

160 mg +               800 mg tab: double strength (DS); 1 BD.

2 0 mg +                100 mg pediatric tab.

4 0 mg +             200 mg per 5 ml susp; infant 2.5 ml (not to be used in newborns), children 1–5 yr 5 ml, 6–12 year 10 ml (all BD).

160 mg +                 800 mg per 3 ml for i.m. injection 12 hourly. (CIPLIN, ORIPRIM-IM)

8 0 mg +             400 mg per 5 ml for i.v. injection (WK-TRIM, ORIPRIM-IV) 10–15 ml BD.

Cotrimazine It is a combination of trimethoprim with sulfadiazine. Its utility is similar to that of cotrimoxazole.

Trimethoprim                    Sulfadiazine

90 mg +                                410 mg: TRIGLOBE, ULTROX tab and per 10 ml susp.; 2 tab BD for 2 days, then 1 BD.

180 mg +                               820 mg: TRIGLOBE FORTE, ULTROX DS tabs.

Uses

Though cotrimoxazole is still widely used, its popularity in the treatment of systemic infections has declined. Common indications are:

1. Urinary Tract Infections

Most acute uncomplicated infections respond rapidly. Single dose therapy with 4 tablets of cotrimoxazole has been recommended for acute cystitis. Courses of 3–10 days have been advised for lower and upper urinary tract infections, according to associated features. It is specially valuable for chronic and recurrent cases and in prostatitis, because trimethoprim is concentrated in prostate.

2. Respiratory Tract Infections

Both upper and lower respiratory tract infections, including chronic bronchitis and faciomaxillary infections, otitis media caused by gram positive cocci and H. influenzae respond well.

3. Typhoid

Initially cotrimoxazole was an effective alternative to chloramphenicol. However, in many areas resistant S. typhi have appeared, and now it is seldom used. Sensitive strains of S. typhi respond to one DS tab BD for 2 weeks.

4. Bacterial Diarrhoeas And Dysentery

Cotrimoxazole may be used for severe and invasive infections by Campylobacter, E. coli, Shigella and Y. enterocolitica (see p. 661). Though response rate is lower than previously, and fluoroquinolones are more commonly used, it is effective in ampicillin resistant cases.

5. Pneumocystis jiroveci  

Pneumocystis jiroveci  causes severe pneumonia in neutropenic and AIDS patients. Cotrimoxazole has prophylactic as well as therapeutic value, but high doses are needed. One DS tablet 4–6 times/day for 2–3 weeks may be curative, but adverse effects necessitate discontinuation in upto 20% cases. One DS tab. daily has been used for prophylaxis and is better tolerated.

6. Chancroid Cotrimoxazole (800 + 160 mg) BD for 7 days is a 3rd choice inexpensive alternative to ceftriaxone, erythromycin or ciprofloxacin.

7. Cotrimoxazole is an effective alternative to penicillin for protecting agranulocytosis patients and treating respiratory and other infections in them. Intensive parenteral cotrimoxazole therapy has been used successfully in septicaemias, but other drugs are more commonly employed now.

Trimethoprim

It has been argued that in certain situations trimethoprim alone may be as effective as the combination, while majority of adverse effects are due to the sulfonamide. Thus, wherever shown effective, trimethoprim alone may be preferred.

However, comparable efficacy of trimethoprim alone has been demonstrated only in:

1. Urinary tract infections: treatment of acute cases, suppressive treatment of chronic and recurrent cases— especially in females.

2. Prostatitis: Trimethoprim is concentrated in prostate, but not sulfonamide.

Dose: 100–200 mg BD (children 6 mg/kg/day).