Co-trimoxazole
A mixture of 5 parts of sulphamethoxazole and I part of tri-
methoprim.
Diluted infusion solutions of co-trimoxazole have a limited
stability and eventually form a precipitate: this happens more
rapidly at higher concentrations. The manufacturers recom-
mend a dilution of 480 mg in 130 mL, which is usually stable
for up to 6 hours, but more concentrated solutions should be
used within shorter periods of time and a dilution of 480 mg
in 80 mL should be used within 2 hours. The usual diluent is
5% glucose, although other solutions, including 0.9% sodium
chloride, have been stated to be compatible for adequate peri-
ods.
Co-trimoxazole is reported to be incompatible with verapamil
hydrochloride.
Adverse Effects and Treatment
The adverse effects of co-trimoxazole are those of
its components (see Sulphamethoxazole and
Trimethoprim). Gastro-intestinal disturbanc-
es (mainly nausea and vomiting) and skin reactions
are the most common adverse effects.-There have
been occasional deaths, especially in elderly pa-
tients, mainly due to blood dyscrasias or severe skin
reactions.
A high incidence of adverse effects has been report-
ed in AIDS patients; desensitization may sometimes
be considered (see under Immunocompromised Pa-
tients. in Precautions, below).
There has been concern over the safety of co-trimoxazole. In
1985. reporting on 85 deaths associated with the use of co-
trimoxazole and predominantly due to blood dyscrasias (50
reports) and skin reactions ( 14 reports), the Committee on
Safety of Medicines (CSM) in the UK found that fatalities
showed a marked increase with age: below 40 years, there
were 0.25 reported deaths per million prescriptions, but for
patients over 65 years of age the number of reported deaths
per million prescriptions was more than 15-fold greater. How-
ever. at that time the CSM felt that it would be unwise to as-
sume that trimethoprim was substantially less liable than co-
trimoxazole to cause fatal adverse reactions. It was suggest-
ed by Lacey and colleagues that most of the deaths associat-
ed with the use of co-trimoxazole were typical of
sulphonamide toxicity and that the indications for the use of
co-trimoxazole should be reduced: this included the sugges-
tion that it should be contra-indicated in the elderly. The CSM
stated that their main message was that the risks of treatment
of co-trimoxazole were more apparent in the elderly, but that
there was no significant difference between the numbers of
reports received for serious adverse reactions to trimethoprim
and co-trimoxazole when corrected for prescription vol-
umes In practice, despite further occasional reports of fatal-
ities in elderly patients. there did not appear to have been a
marked reduction in the prescribing of this drug in the UK.5
A similar warning of increased risk from co-trimoxazole in
elderly patients was issued by the Adverse Drug Reactions
Advisory Committee in Australia.
More recently, a large population-based follow-up study in
the UK7 indicated that the risks of serious liver, blood, skin.
and kidney disorders with either co-trimoxazole, trimetho-
prim, or cephalexin were small and were similar to those with
many other antibacterials. Although in 1995 the CSM did re-
strict the use of co-trimoxazole on the grounds that its place
in therapy had changed (see under Uses and Administration.
below), they also noted that co-trimoxazole continued to
show a similar pattern of serious suspected adverse reactions
to that reported 10 years earlier and that adverse drug reac-
tions with trimethoprim were similar: blood dyscrasias and
generalised skin disorders were the most serious reactions in
each case and remained predominantly in elderly patients.
Precautions
As for Sulphamethoxazole and Trimetho-
prim.
Co-trimoxazole should not be given to patients with
a history of hypersensitivity to it or to the sulphona-
mides or trimethoprim. It is contra-indicated in pa-
tients with severe hepatic failure and should be used
with caution in patients with lesser degrees of hepat-
ic impairment. Like its components, co-trimoxazole
should be used with caution in impaired renal func-
tion, and dosage adjustment may be necessary: it
should not be used in severe renal impairment with-
out monitoring of plasma drug concentrations. An
adequate fluid intake should be maintained to reduce
the risk of crystalluria. but alkalinization of the
urine, although it increases urinary excretion of the
sulphamethoxazole component, decreases urinary
trimethoprim excretion. Regular blood counts and
urinalyses and renal function tests should be carried
out in patients receiving prolonged treatment with
co-trimoxazole. Elderly patients may be more sus-
ceptible to adverse effects (see above). Folate sup-
plementation may be necessary in patients
predisposed to folate deficiency, such as elderly pa-
tients and when high doses of co-trimoxazole are
given for a prolonged period.
Glucose 6-phosphate dehydrogenase deficiency.
Some have expressed the opinion that co-trimoxazole should
be avoided by people with glucose fa-phosphate dehydroge-
nase deficiency.
Immunocompromised patients. An extraordinarily high
frequency of adverse reactions to co-trimoxazole-has been re-
ported in patients with AIDS being treated for Pneumocystis
carinii pneumonia. Masur' commented that. when therapeu-
tic doses of co-trimoxazole are used. hypersensitivity rashes
and leucopenia each develop in 30% of patients compared
with less than 5% for each complication in patients without
AIDS but other studies have reported an even higher inci-
dence of toxicity, and the overall incidence of adverse effects,
including fever, malaise, and hepatitis, may be 80% or
more.- Adverse reactions also appear to be unusually fre-
quent when prophylactic doses are used.
The occurrence of high serum concentrations of trimethoprim
and sulphamethoxazole in patients has been proposed as a
contributing factor to the high incidence of adverse effects,
and Saltier and colleagues reported that adverse effects, and
in particular myelosuppression. were kept to tolerable levels
in a group of patients in whom the dose of co-trimoxazole was
adjusted to maintain serum trimethoprim concentrations at 5
to 8 ng per mL. However, McLean and others demonstrated
no difference in the frequency of side-effects when the sul-
phamethoxazole dose was modified. A lower frequency of cu-
taneous reactions has been reported among African, Haitian.
and American black AIDS patients compared with white
AIDS patients suggesting a genetic susceptibility for such re-
actions.
Some workers have used diphenhydramine alone or with
adrenaline to manage hypersensitivity reactions associated
with co-trimoxazole therapy thus allowing continuation of
treatment and other workers have tried desensitization to
co-trimoxazole in patients with AIDS. For mention of de-
sensitization to sulphonamides in patients with AIDS. see un-
der Sulphamethoxazole. Van der Ven and others' have
suggested that it is the reactive hydroxylamine metabolites of
sulphamethoxazole which produce the adverse effects in
HIV-infected individuals and that acetylcysteine. which
would address the glutathione deficiency in these patients and
thus perhaps enable increased scavenging of such metabo-
lites. might be of benefit.
An increased incidence of myelosuppression, although not.
apparently, of other adverse effects, has been reported in pa-
tients with leukaemia receiving maintenance chemotherapy.
Interference with diagnostic tests. Cohen and others'
have reported that co-trimoxazole causes a small reduction in
serum thyroxine and tri-iodothyronine concentrations, proba-
bly due to the sulphonamide component' and suggest that al-
though co-trimoxazole cannot be concluded to be a cause of
hypothyroidism (as all concentrations remained within the
normal range), tests of thyroid function should be interpreted
with care in patients on such treatment.
Porphyria. See under Sulphamethoxazole, and Tri-
methoprim.
Interactions
Any of the drug interactions reported with sulpham-
ethoxazole or trimethoprim may
occur with co-trimoxazole.
Antimicrobial Action
The actions and spectrum of activity of co-trimoxa-
zole are essentially those of its components, sul-
phamethoxazole and trimethoprim .
Because they act at different points of the folate met-
abolic pathway a potent synergy exists between its
components in vitro with an increase of up to about
IO-fold in antibacterial activity, and a frequently
bactericidal action where the components individu-
ally are generally bacteriostatic. The optimum effect
against most organisms is seen at a ratio of I part
trimethoprim to 20 of sulphamethoxazole: although
co-trimoxazole is formulated as a I to 5 ratio, differ-
ences in the pharmacokinetics of the two drugs
mean that the ratio of the peak concentrations is ap-
proximately 1:20. However, it is not clear that the
optimum ratio is achieved at all sites, and given that
both drugs are present in therapeutic concentrations
the contribution of synergy to the effects of co-tri-
moxazole in vivo is uncertain.
Resistance to co-trimoxazole develops more slowly
in vitro than to either component alone. Resistance
has increased, and although initially slow, a more
rapid increase was seen in many countries during the
1980s, occurring in both Gram-positive and Gram-
negative organisms. Resistance has occurred nota-
bly among Enterobacteriaceae. Resistant strains of
Haemophilus influenzae, streptococci, and Vibrio
cholerae have been reported rarely. Although resist-
ant organisms' are usually resistant to both compo-
nents of the mixture, strains resistant to either the
sulphonamide or trimethoprim and with a reduced
sensitivity to co-trimoxazole have been reported.
Pharmacokinetics
See sulphamethoxazole and trimethoprim.
When co-trimoxazole is administered by
mouth, plasma concentrrations of trimethoprim and
sulphamethoxazole are generally around the opti-
mal ratio of 1:20. although they may vary from 1:2
to 1:30 or more. The ratio of the two drugs is usually
much lower in the tissues (often around 1:2 to 1:5)
since trimethoprim, the more lipophilic drug, pene-
trates many tissues better than sulphamethoxazole
and has a much larger volume of distribution. In
urine the ratio may vary from 1:1 to 1:5 depending
on the pH.
Uses and Administration
Co-trimoxazole is a mixture of the sulphonamide,
sulphamethoxazole. and trimethoprim, and has been
used in a wide variety of infections due to suscepti-
ble organisms, particularly those of the urinary, res-
piratory, and gastro-intestinal tracts, although the
indications for its use were restricted recently in the
UK (see below). Its main use now is in Pneurno-
cystis carinii pneumonia, toxoplasmosis, and nocar-
diosis.
Its other uses have included the treatment of: acne;
biliary-tract infections: brucellosis (generally in
combination with other drugs); cat scratch disease;
chancroid: Burkholderia (Pseudomonas) cepacia
infections in cystic fibrosis; some forms of AIDS-
associated diarrhoea such as the protozoal infection
isosporiasis; gonorrhoea; granuloma inguinale: the
prophylaxis of infections in immunocompromised
patients and selective decontamination for patients
in intensive care: listeriosis: melioidosis; myceto-
ma: otitis media: pertussis: typhoid and paratyphoid
fever: and Whipple's disease. For details of the bac-
terial infections listed above and their treatment, see
under Choice of Antibacterial, p. 1 16.
Co-trimoxazole is usually given by mouth in a dose
of 960 mg (trimethoprim 160 mg and sulphameth-
oxazole 800 mg) twice daily; in severe infections
2.88 g daily in 2 divided doses may be given. Lower
doses are given for long-term treatment and in pa-
tients with renal impairment: half the usual dosage
has been suggested in patients with a creatinine
clearance between 30 and 15 mL per minute, but co-
trimoxazole is generally not recommended when the
creatinine clearance is less than 15 mL per minute
unless facilities for haemodialysis are available.
Suggested doses of co-trimoxazole to be given twice
daily to children are: from 6 weeks to 5 months of
age, 120 mg: 6 months to 5 years, 240 mg; 6 lo 12
years, 480 mg. Co-trimoxazole should not be given
to infants below 6 weeks of age because of the risk
of kernicterus from the sulphonamide component
(see Pregnancy and Breast Feeding, under Precau-
tions of Sulphamethoxazole.
Higher doses of co-trimoxazole of up to 120 mg per
kg body-weight daily given in two to four divided
doses for 14 to 21 days are used in the treatment of
Pneumocystis carinii pneumonia; serum concentra-
tions should be monitored and consideration of
folate supplementation has been suggested (but see
Pneumocystis carinii Pneumonia, below). For
prophylaxis in patients with AIDS. the standard
dose of co-trimoxazole (960 mg twice daily) may be
given, but has been associated with a high incidence
of adverse effects (see under Precautions, above).
Alternatively the following dose regimens may be
used: 960 mg daily (7 days each week): 960 mg dai-
ly on alternate days ( 3 days each week); or 960 mg
twice daily on alternate days (3 days each week).
For serious infections, if oral administration is not
possible, co-trimoxazole may be given initially by
intravenous infusion diluted immediately before use
in a suitable diluent. The contents of each ampoule
containing 480 mg of co-trimoxazole in 5 mL are
added to 125 mL of diluent and infused over 60 to
90 minutes, unless fluid restriction is required, in
which case the manufacturers permit the use of only
75 mL of diluent. Dosage is similar to that by
mouth.
The current place of co-trimoxazole in therapy was reviewed
by the UK Committee on Safety of Medicines (CSM) in 1995
(see also under Adverse Effects and Treatment, above). ' As a
result they recommended that its use should be limited to:
Pneumocystis carinii pneumonia, toxoplasmosis. and nocar-
diosis: urinary-tract infections and acute exacerbations of
chronic bronchitis, but only when there is bacteriological ev-
idence of sensitivity io co-trimoxazole and good reason to
prefer it to a single antibiotic: and acute otitis media in chil-
dren. but again only when there is good reason to prefer the
combination.
Blastocystis Infection. For a mention of the use of co-tri-
moxazole in the treatment of Blastocystis hominis infection.
Cyclosporiasis. Patients with Cyctospora infection
have responded to treatment with co-trimoxazole.
Granulomatous diseases. Although co-trimoxazole ap-
pears to be effective in reducing the incidence of bacterial
in-
fection in patients with chronic granulomatous disease, a
disorder of leucocyte function associated with recurrent life-
threatening infection and granuloma formation, its use in sys-
temic vasculitis is much more controversial. There have been
a number of reports of benefit from co-trimoxazole in patients
with Wegener's granulomatosis but even where
benefit has been reported relapse appears to be common and
Hoftman and others.J reporting the experience of the USA
National Institutes of Health in 158 patients are skeptical of
its value: only 1 of 9 patients given 960 twice daily by
mouth had any prolonged improvement.
More recently evidence has emerged that addition of co-tri-
moxazole to maintenance regimens in patients already in re-
mission reduces the incidence of relapse.
Isosporiasis. In isosporiasis WHO recommends co-
trimoxazole 960 mg four times daily for 10 days by mouth
for treatment, such a regimen followed by 960 mg twice
daily for 3 weeks has been reported to be initially
effective in patients with AIDS suffering from
isosporiasis. with resolution of diarrhoea within 2 days
of beginning treatment, but was
associated with a high rate of recurrence.' A shorter
initial regimen followed by indefinite prophylaxis may be
preferable in persons with AIDS.
Nocardiosis. Co-trimoxazole is used in the treatment of no-
cardiosis. There is no consensus on the optimum dos-
age: doses of 2.88 to 3.84 g daily in divided doses for up
to 3 months have been used.
Pneumocystis carinii pneumonia. Co-trimoxazole is
used for both the treatment and prophylaxis of Pneumocystis
cannii pneumonia . Various studies have shown in-
termittent dosing (such as 960 mg three times a week on al-
temate days) is effective for the prophylaxis of pneumonia
and is Welter tolerated than daily dosing; the addition of
folinic acid had no effect on tolerability and may be
associated with a higher rate of therapeutic failure . A single
daily dose of 480 mg may also be effective and better tolerat-
ed.
Toxoplasmosis. There is some evidence that administration
of co-trimoxazole for prophylaxis of Pneumocystis carinii
pneumonia produces an additional benefit in acting prophy-
lactically against toxoplasmic encephalitis in persons wilh
AIDS. But the evidence(as for other drugs)has been largely
anecdotal or from small retrospective studies. In the retro-
spective study by Carr et all prophylaxis with co-trimoxa-
zole 960 mg twice daily every Monday and Thursday
appeared to be effective. More recently 960 mg twice daily on
3 days per week (Monday. Wednesday, and Friday) was con-
sidered effective prophylaxis against toxoplasmosis and
Pneumocystis carinii pneumonia in patients with HIV infec-
lion.