Relevant BNF section: 5.1.8
Co-trimoxazole, the fixed-dose preparation of trimethoprim (80mg) plus sulphamethoxazole (400mg), has been available in the UK since 1969. At its launch the Drug and Therapeutics Bulletin accepted the logic of using the combination1 but advised prescribers to be alert to the possibility of unwanted effects. In 1980 we advised that, in some infections, a single antibiotic might be at least as effective as co-trimoxazole, with a lower risk of unwanted effects.2 Later that year, when trimethoprim became available alone, we recommended it should be used in the place of co-trimoxazole for uncomplicated infections of the urinary tract,3 advice we repeated in 1986.4 In July of this year, the licensed indications for co-trimoxazole were narrowed5 and now reflect many of our earlier recommendations. In this article we review the history of co-trimoxazole, discuss the recent licensing changes and ask when the drug should be used in clinical practice.
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Relevant BNF section: 5.1.8
Trimethoprim was combined with sulphamethoxazole to provide a wide spectrum of bactericidal activity and to delay the emergence of resistance to trimethoprim.
Trimethoprim was known to inhibit bacterial dihydrofolate reductase,6 one of the enzymes responsible for bacterial folate synthesis; it was thought that by combining trimethoprim with a sulphonamide, which blocks an earlier step of folate synthesis, synergy might result. Synergy was demonstrated in vitro at low concentrations of both drugs7 and, whilst individually trimethoprim and sulphamethoxazole were bacteriostatic, used in combination their effects were bactericidal.8
How valuable was the synergy?
During the 1970s the clinical value of the synergy between sulphamethoxazole and trimethoprim was questioned as clinical trials found that, for acute urinary tract infections, trimethoprim by itself was as effective as the combination.9–11 In experimental models of such infections, using therapeutic concentrations of trimethoprim, sulphamethoxazole or co-trimoxazole, the effect of trimethoprim by itself was found to be so dominant that sulphamethoxazole contributed little to the antibacterial effect12 and any weak bactericidal effects demonstrated were probably due to trimethoprim whether present alone or in combination.13
Later, it was shown that trimethoprim was as effective as co-trimoxazole in treating common acute respiratory tract infections.14
Delayed drug resistance?
By the early 1980s it was possible to address the question of bacterial resistance. In practice, resistance to trimethoprim developed at a similar rate whether it was used by itself or in combination with sulphamethoxazole.15
The serious unwanted effects of co-trimoxazole are characteristic of those associated with sulphonamides, notably Stevens-Johnson Syndrome and blood dyscrasias. The predominant unwanted effects with trimethoprim are rash and gastrointestinal disturbance, however, it too can cause blood dyscrasias. By mid-1995, the Committee on the Safety of Medicines (CSM) had received reports of 127 deaths (71% in patients over 60 years old) associated with co-trimoxazole and 15 deaths (87% in patients over 60 years old) associated with trimethoprim. It is not possible to compare the exact incidence of trimethoprim toxicity relative to that of co-trimoxazole since the reporting of unwanted effects is not exhaustive, usage of each drug varies and co-trimoxazole has been available for 26 years compared to 15 years for trimethoprim.
A recent, large, retrospective study looked at the incidence of severe unwanted effects in 695,738 patients who were prescribed co-trimoxazole (n=232,390), trimethoprim (n=266,951) or cephalexin (n=196,397) by general practitioners. The study used data from a General Practice Research Database; the data were collected over 5 years (1988-1993) from 420 practices in the UK. The patients identified had received at least one prescription for any of the three drugs and had been referred to a specialist or hospitalised with a liver, blood, skin or kidney disorder within 45 days of receiving the prescription. Using these criteria, the study found that few serious unwanted effects occurred with any of the drugs. The risk of acute liver disorders was 5.2/100,000 users of co-trimoxazole (95%CI 3.0, 9.0) and 3.8/100,000 users of trimethoprim (95%CI 2.0, 6.9). The risk of developing erythema multiforme, Stevens-Johnson Syndrome and toxic epidermal necrolysis was 1.7/100,000 users of co-trimoxazole (95% CI 0.7, 4.4) and 0.8/100,000 users of trimethoprim (95% CI 0.2, 2.7).16
The study did not examine the incidence of unwanted effects which lead to neither hospital admission nor specialist referral.
Prescribing in older people
In July 1985 the CSM warned that co-trimoxazole was particularly likely to cause adverse effects and deaths in patients over 65 years old.17 No change was made to the licensed indications, although there were calls for restrictions.18 However, by March 1986 the British National Formulary advised that co-trimoxazole be prescribed in older patients only if there was no acceptable alternative.
Revised licence indications
In July 1995 the licensing authority announced that the licence for co-trimoxazole would be restricted. The drug is now indicated for the treatment of urinary tract infections and acute exacerbations of chronic bronchitis but 'only where there is bacterial evidence of sensitivity to co-trimoxazole and good reason to prefer the combination to a single antibiotic'. Circumstances where there might be a 'good reason' to prefer the combination were not defined but should be rare.
Similarly, the combination is now licensed for the treatment of acute otitis media in children, 'where there is good reason to prefer co-trimoxazole to a single antibiotic'. Again, there was no definition of a 'good reason' but there should be few occasions to prefer co-trimoxazole.
The combination is also licensed for the treatment of nocardiasis, the treatment and prevention of toxoplasmosis and the treatment and prophylaxis (primary and secondary) of Pneumocystis carinii pneumonitis in adults and children. Only in the treatment and prevention of Pneumocystis carinii is co-trimoxazole established as first-line treatment.19 In the treatment of nocardiasis a sulphonamide may be as effective as co-trimoxazole.20,21 In immunosuppressed patients, particularly those infected with human immunodeficiency virus (HIV), co-trimoxazole is used to prevent toxoplasmosis. For treatment, however, regimens using a sulphonamide (generally sulphadiazine) in combination with pyrimethamine are preferred to co-trimoxazole. The licence changes make no mention of the use of co-trimoxazole in older patients.
Explaining the changes
The licensing authority acted on the advice of the CSM when it limited the licence for co-trimoxazole. In explaining the changes the CSM said that 'there is no new safety data, but in the light of changing clinical practice, the indications for co-trimoxazole should be limited to specific illnesses'. The data on which the decision was made to limit the indications for co-trimoxazole this year, rather than earlier, are not cited and cannot be independently assessed.
The change in the licensed indications for co-trimoxazole means that, in practice, there will be few occasions, apart from pneumocystis pneumonia, in which co-trimoxazole should be prescribed in preference to a single antibiotic. It would have helped if the licensing authority had explained in more detail how and why the decision to change the licence was made. Arrangements should be put in place to ensure that in future explanations are more complete.
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