sulphamethoxazole/trimethoprim: the two years · futurerole in antibacterial chemotherapy....

J. clin. Path., 1971, 24, 430-437

Sulphamethoxazole/trimethoprim: the first two years

D. S. REEVES

From the Department of Bacteriology, St Mary's Hospital Medical School, London'

The combination of sulphamethoxazole and tri-methoprim (Bactrim, Septrin) has been available as achemotherapeutic agent in general use for about twoyears. It would therefore seem useful at this stage toreview published and personal experience with thecombination in an attempt to define its probablefuture role in antibacterial chemotherapy.

Mode of Action

Sulphonamides are thought to produce their anti-bacterial effect by competing with the natural pre-cursor p-aminobenzoic acid in the formation offolic acid (Fig. 1). In man, the folate pathwayrequires exogenous folate as its initial substrate sothe step blocked by sulphonamides is absent, thusforming the basis for their selective toxicity forbacteria. The next step in the folate pathway is theconversion of folic acid to folinic acid by the en-'Present address: Department of Bacteriology, Southmead Hospital,Westbury-on-Trym, Bristol, BS10 5NB

PABA

SULPHONAMIDE>--- -

FOLIC ACID

TRMETHOPRIM>---R-E-CURSORS

FOUNICACID

PURINES

DNA

Fig. 1 Summary ofmode of action ofsulphonamideand trimethoprim.

zyme dihydrofolate reductase. Trimethoprim bindsstrongly to this enzyme in bacteria and blocks thisreduction, but binds only weakly to the mammalianenzyme. The presence of blocks at two sequentialstages in the folate pathway leads, among otherthings, to a cessation of DNA synthesis and thedeath of the bacterium. The sequential nature of theblockage has also been taken to explain the synergisticantibacterial action between sulphonamides andtrimethoprim.The drugs are effective in vivo, where folates and

folinates abound, because almost all pathogenicbacterial species are unable to absorb and utilizethese compounds from an exogenous source (Bushbyand Hitchings, 1968).

Activity in Vitro

The activity of the individual drugs will be con-sidered first, and then their activity in combination.

TRIMETHOPRIMThe activity of trimethoprim against a number ofcommon pathogens is summarized in Table I fromthe data of Bushby and Hitchings (1968); Darrell,Garrod, and Waterworth (1968); and Phillips, Ridley,Rimmer, Lynn, and Warren (1970). Trimethoprimhas a wide spectrum of antibacterial action and there

Minimal Inhibitory Concentration (iug/ml)<025 0-5-20 >20

Staph. aureus Str. pyogenes Cl. welchiiStr. faecalis Str. pneumoniae N. gonorrhoeae

N. meningitidisH. influenzae Proteus spp. Bacteroides spp.Esch. coli Klebsiella spp. Ps. aeruginosaSalmonella spp. B. pertussisShigella spp.

Table I Antibacterial activity of trimethoprim in vitro

are examples of both Gram-negative and Gram-positive species in all three of the arbitrary ranges ofsensitivity shown. The information given is for typicalstrains but both small and large variations occur,usually in the direction of resistance. On the whole,

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however, resistant strains from those species that areusually sensitive are not common, probably becausetrimethoprim had not been in widespread use whenthe data were originally collected.

SULPHONAMIDESTo construct a similar table for sensitivity tosulphonamides would be of little value since acquiredresistance to sulphonamides is common among mostbacterial species, and in particular in those strainscoming from hospital sources. Figure 2 shows datataken from a paper by Brumfitt and Percival (1967)and illustrates this point well. Although the minimalinhibitory concentrations (MIC) shown were esti-mated using sulphadimidine, it is generally agreedthat the sensitivities of bacteria to different sul-phonamides are usually in fair agreement. The resultsin Fig. 2 could therefore be taken as being applicableto a variety of sulphonamides, including sulpha-methoxazole.

1i.5.' . :1 'I IM

Fig. 2 Minimum inhibitory concentrations ofsulphadimidine for organisms from acute urinary infectionsin general practice patients and urinary infections inhospital patients.

The sensitivity of various bacterial pathogens tosulphonamides varies widely but sensitive strainshave MICs of < 50 ,ug/ml. Infections with organismshaving an MIC above this figure are less likely to beeradicated by sulphonamide therapy (Williams andLeigh, 1966), and treatment is particularly likely tofail if the MIC is > 200 ,ug/ml.

COMBINED ACTIVITYThe difficulty in reviewing the action of the sul-phamethoxazole/trimethoprim combination is thatnot only has the activity of the individual com-ponents to be described but that additive orsynergistic effects, ie, potentiation, between the twodrugs must also be considered.

SynergismThat synergism between these two drugs occurs has

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been shown by Bushby and Hitchings (1968) andDarrell et al (1968), some of the information beingsummarized in Table II. Although the degree ofpotentiation may vary for different strains of aparticular species, the table shows the results fortypical strains and gives the order of potentiation tobe expected. An important point is that the degree of

x2-x8 Potentiation xl6-x64 Potentiation

Staph. aureus N. gonorrhoeaeStr. pyogenes Pr. mirabilisStr. pneumoniaeH. influenzaeEsch. coliKlebsiella spp.Salmonella spp.Shigella spp.

Table ni Potein iationsulphonamide in vitro'

of activity of trimethoprim by

'Sulphonamide: trimethoprim ratio 9 :1 (except for N. gonorrhoeae)Data from Darrell et al (1968).

potentiation which occurs depends on the ratio ofthe concentrations of sulphamethoxazole and tri-methoprim used, and tends to be maximal when thedrug ratio of the concentrations is similar to that oftheir respective MICs (Bushby and Hitchings, 1968).Thus, for a range of organisms sensitive to bothdrugs the ratio would be about 20 parts of sulpha-methoxazole (MICs 5-50 ,ug/ml) to one part oftrimethoprim (MICs 0 25-2 ,g/ml), although it mayvary widely with individual species. Neisseriagonorrhoeae is an exception in which the ratios of theMICs of sulphamethoxazole and trimethoprim arecompletely reversed, the organism sometimes beingmore sensitive to sulphonamides than to tri-methoprim.

Evidence of synergistic activity has also beenfound in vivo in experimental infections in mice(Bushby and Hitchings, 1968; Bohni, 1969) and inthe treatment of gonorrhoeae (Table III). Typical

Drug and Daily Dose (mg) Cases Treated Failuresand Followed

Trimethoprim Sulphatriad

400 - 10 10- 4,000 13 9400 4,000 37 4200 4,000 9 0100 4,000 5 0

Table III Potenttiation of activity in vivo of trimethoprimby sulphonamide in the treatment ofgonorrhoeal'Data from Csonka and Knight (1967)

strains of N. gonorrhoeae are resistant to trimetho-prim (the MICs being almost always > 2 ,tg/ml) andtreatment with this drug alone results in uniformfailure. Treatment with a sulphonamide alone

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produces a cure rate of only about 30% because ofthe prevalence of acquired sulphonamide resistance.Combined therapy gives a high cure rate similar tothat produced by penicillin G. This effect seems tobe greater than that produced by simple addition ofactivities and must surely represent true synergy.

AdditionApart from the occurrence of synergy anotherreason for the administration of a sulphonamidewith trimethoprim is that the additive action of thetwo drugs makes the administration of a lower doseof both drugs possible, thus reducing the incidenceof side effects.Two further reasons for combined administration

are the prevention of acquisition of resistance totrimethoprim, and the conversion of the bacterio-static activity of both drugs to a bactericidal action.

Prevention of resistanceBacteria can be 'trained' to trimethoprim resistanceby serial subculture on trimethoprim-containingmedium (Darrell et al, 1968). The development ofthis resistance is reduced by the addition of sul-phonamide to the medium, the effect being lessnoticeable when the organism used is resistant tosulphonamides.

Bactericidal activityThe sulphonamides are well known to be bacterio-static, and trimethoprim is similar in this respect.When both drugs are used in combination, however,they may be bactericidal (Bushby, 1969a). How oftenthis effect occurs with individual species or strains isnot known, but it probably occurs often enough tomake it yet another indication for combiningtrimethoprim with sulphonamide rather than usingit alone.Antagonism between sulphonamides and tri-

methoprim has not been demonstrated (Bushby,1969b), nor between trimethoprim and otherantibiotics.

Pharmacology

ADMINISTRATIONThe drugs are presented in tablets (Septrin') ordrapsules (Bactrim') containing 400 mg of sulpha-methoxazole and 80 mg of trimethoprim, ie, asulphonamide/trimethoprim ratio of 5:1. This ratioof administration is used because it was found byexperience that it produced a ratio in the blood of20: 1 (see Fig. 3, for example) and, as mentionedabove, this is most likely to give maximal potentia-tion for a wide variety of organism.,UK only

ABSORPTIONThe uptake of both sulphamethoxazole and tri-methoprim from the intestinal tract following oraladministration is rapid and good blood levels areobtained. The results of giving Septrin to four fastingvolunteers (Fig. 3) illustrates this and also showsthat there is remarkably little deviation from themean values produced. More important, uptake ofboth drugs in patients under treatment is alsosatisfactory (Fig. 4). Some accumulates after theinitial dose, the mean levels being higher withrepeated administration. Both drugs are excreted bythe kidneys, trimethoprim largely in an unchangedform, producing high urinary levels (see Brumfitt,Faiers, Pursell, Reeves, and Turnbull, 1969). Aswould be expected, blood levels of both drugs arehigher in patients with renal failure.

4 - 8Os

M2 40

1 Stphaietoxaole26 240

1 2 4 6 24Hoturs after oral dose

Fig. 3 Blood levels ofsulphamethoxazole andtrimethoprim after giving three tablets of Septrin to fourfasting volunteers.

S

a.,EE-

Q.

After several days treatment, blood urea <40mg/lOOmlAfter several days treatment, blood urea >40mg/100mi

--- - After initial dose

10

0~*S~~~~~ ~~ ' 6t'S

Hours after dose

Fig. 4 Blood levels ofsulphamethoxazole andtrimethoprim in individual patients treatedfor urinaryinfection with Septrin. (Dose sulphamethoxazole 800 mg,trimethoprim 160 mg, twice daily.)

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DISTRIBUTIONThe standard preparation provides a fixed ratio ofthe two drugs. There are, however, a number ofreasons why having a fixed combination is far fromideal. Of the sulphonamides available, sulpha-methoxazole was chosen for combination withtrimethoprim because of its high activity and similarblood half-life. Although the ratio of drugs in theblood may be suitable for treating many infections,the organisms are more usually in other tissues orbody fluids. A study of the pharmacology of sulpha-methoxazole and trimethoprim indicates that, bothdirectly and inferentially, the ratio of the two drugsfound in the blood will almost certainly not bemaintained in the tissues. Data for concentrationsin body fluids, some unpublished, collected from avariety of sources bear out this point (Table IV).Trimethoprim base is lipid soluble and seems todiffuse throughout the tissues of the body. Data foranimal tissues (Table V) show that, in general,trimethoprim is concentrated in tissue, whereas tissuelevels of sulphamethoxazole are lower than thosefound in the serum. Thus, in the treatment ofindividual tissue infections, it may be necessary tosupplement the sulphonamide dosage ifa satisfactoryratio between the two drugs is to be maintained.Although typical ratios of urinary concentrations

of the drugs are not ideal, the overall antibacterialactivity is usually more than adequate to deal withurinary pathogens. The ratio between the drugs maybe still further disturbed, however, when renalfunction is impaired, since the renal handling of

sulphamethoxazole and trimethoprim differs (Sharp-stone, 1969). This may also affect the relative serumlevels. Apart from the differences that exist in thetissues the optimum serum ratio of 20: 1 is obviouslynot ideal for all organisms although minor deviationsfrom it are probably of little consequence. In thecase of some bacteria the optimum ratio may bevery different or even reversed, eg, N. gonorrhoeae,and in such cases it would seem logical to supplementtherapy with whichever of the two drugs isappropriate.Even where the ratio of concentrations between a

sulphonamide and trimethoprim are satisfactory,there are instances where, for pharmacologicalreasons, sulphamethoxazole may not be the idealsulphonamide. Trimethoprim is concentrated in theprostatic fluid of dogs, whereas sulphamethoxazoleis found in a concentration far less than that found inthe serum (Reeves and Ghilchik, 1970). Of the othersulphonamides available, sulphadimidine is excretedbest in prostatic fluid (Winningham and Stamey,1970), and a combination of this drug with tri-methoprim may therefore be better for treatingprostatic infection, although MICs to sulphadi-midine are in general higher than to sulpha-methoxazole.

In spite of these criticisms of the fixed ratio, themarketing of a number of preparations with differentratios would produce complexities beyond the com-prehension of many prescribers and could lead toserious therapeutic errors. All that can be said atpresent is that for serious and difficult infections in

Trimethoprim Animal Sulphamethoxazole AnimalConcentration Concentration

Urine x 100 (approx.) Man x 5 (approx.) ManCerebrospinal fluid (uninflamed meningitis) x 05 Man x 0 3 ManSputum x2-5 Man x0 1 ManMilk x I Man ?Bile x 2 Man ?

x 15 Dog ?Prostatic fluid x 3 Dog x 0-25 Dog

Table IV Trimethoprim/sulphamethoxazole concentrations in body fluids relative to serum level

Trimethoprim Animal Sulphamethoxazole AnimalTissue/Serum Ratio Tissue/Serum Ratio

Liver 6-2 Rat 0-3 Rat3-2 Mouse 0 25 Rabbit

Lungs 2-0 Rat 0-4 Rat17-5 Mouse 0 5 Rabbit

Heart 1-2 Rat 0 35 Rat6-5 Mouse 0-6 Rabbit

Kidneys 7-3 Rat 0-6 Rat7-6 Mouse 2-4 Rabbit

Brain 0-08 Rat 0 05 Rat0-25 Rabbit

Table V Trimethoprim/sulphanmethoxazole concentrations in animal tissue relative to serum levels"tData from Bushby and Hitchings (1968) and other sources.

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particular tissues the fixed ratio may not provideideal therapy and supplementation of treatment byone or other drug may be advisable.

PARENTERAL ADMINISTRATIONBecause of its high degree of activity against a widerange of pathogens, the combination would seemsuitable for treating serious infections if it could beadministered parenterally. Unfortunately, no prep-aration is generally available although trimethoprimlactate alone can be obtained for treating specialcases, and parenteral sulphonamide preparations aregenerally available. Should intravenous therapy beused trimethoprim should not be mixed with sul-phonamide in the infusion fluid since they may bepharmaceutically incompatible.

Therapeutic Uses

Numerous reports on the use of sulphamethoxazole/trimethoprim in the treatment of infective diseasesand some non-infective diseases have appeared.Some references are listed in Table VI. There is nospace here for detailed analysis of published findingsbut, in summary, the reports are generally favourable.There are, however, some specific points of interestarising from the treatment of certain infections,notably urinary infections, respiratory infections, andgonorrhoea.

Urinary infections arising in both domiciliary andhospital patients have been successfuly treated. Wehave found a particularly high cure rate in the treat-ment of bacteriuria in pregnancy (Williams, Brumfitt,Condie, and Reeves, 1969), even in those patientsin whom treatment with another agent had alreadyfailed. In view of the fact that pregnancy pyelone-phritis is as common in women in whom treatmentfor bacteriuria has failed as in untreated women(Williams, Brumfitt, Condie, and Reeves, 1969),confirmation of our findings would seem to representan advance in therapy. Unfortunately, because ofteratogenicity in animals given high doses of trime-thoprim (Udall, 1969), its use in pregnancy is notrecommended and such confirmation is unlikely tobe forthcoming in the near future. In the relativelysmall number of women we treated, all after the 12thweek of pregnancy, no congenital malformationsattributable to the drug were found in a carefulfollow-up study.As mentioned previously, sulphonamide resistance

is common among urinary pathogens isolated fromhospital patients (Fig. 2) and, hardly surprisingly, thecure rate with sulphonamide therapy allocated on arandom basis as treatment for urinary infection islow (Table VII, Reeves, Faiers, Pursell, and Brumfitt,1969). Sulphamethoxazole/trimethoprim gave a

Treatments Disorder ReferenceDescribed

Many

rUrinary infection Allison et al (1969)Cox and MontgomeryGruneberg and Kolbe (1969)

- snnKeeves et at (19YO)O'Grady et al (1969)Williams et al (1969)

Respiratory infection Drew et al (1967a and b)Hughes (1969)Hughes et al (1969)Lal and Bhalla (1969)Pines et al (1969)

Venereal disease Csonka and Knight (1967)Csonka (1969)Caroll and Nicol (1970)Wright and Grimble (1970)

rColiform meningitis Morzaria et al (1969)

Relativelyfew orsingletreatments

Coliformendocarditis

Coliform tissueinfe-tion

Typhoid cases andcarriers

Cholera carriers

Acute brucellosis

Staphylococcalosteomyelitis

Gram-negativebacteraemia

Fowle and Zorab (1970)

Akinkugbe et al (1968)Brodie et al (1970)Kamat (1970)Farid et al (1970)

Gharagozloo et al (1970)

Lal et al (1970)

Pugsley et al (1969)Craven et al (1970)

Noall et al (1962)Cooper and Wald (1964)Darrell et al (1968)

Nocardiosis Marcovitch & Harvey (1970)Murray and Mahgout (1970)

Ulcerative colitis

Prophylaxis inleucopenia

Savidge (1969)

Gruneberg et al (1970)

Table VI Some reported therapeutic uses of sul-phonamide/trimethoprim

higher cure rate than ampicillin, although thedifference was not statistically significant. Most ofthe infecting organisms were sensitive to trimetho-prim and this may have been the reason for the goodresults.

Because patients with urinary infections can bedivided into more or less homogeneous groups, amore precise analysis of the results of treatment canbe meaningful. Only in such patients has anyattempt been made to define the degree of poten-tiation in vitro in determining the outcome oftherapy. The results of Gruneberg and Kolbe (1969)

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Treatment No. of One Week after No. oJ Patients Four to Five weeksPatients Treated End of Treatment Treated and Cured After End of

Treatment

Sulphamethoxazole-trimethoprim 5 :1 41 35 (85%)1 27 18 (67%)Ampicillin 30 21 (70%)' 27 14 (52%)Sulphadimidine 35 14 (40%) 26 4 (15%)

Table VII Results of treating hospital-acquired urinary infectionlP = 0-102 for the difference between the results at one week for sulphamethoxazole-trimethoprim and ampicillin.

suggested that the chances of successful treatmentof a urinary infection with the combination increasedwith increasing in vitro potentiation of sulphameth-oxazole by trimethoprim, although a statisticalsignificance was not reached.

Successful results have also been claimed inrespiratory infections, including the prevention andtreatment of the exacerbations of chronic bronchitisand the treatment of pneumonia. A disturbing aspectof respiratory infections has been the description ofthe isolation of Haemophilus influenzae highlyresistant to trimethoprim from patients on long-term treatment with the combination (Waterworth,1969). In view of the possible importance of sul-phonamide in preventing the emergence of resistanceto trimethoprim, the relatively low sputum levels ofsulphamethoxazole (Table IV) may be relevant.Furthermore, May (1969) has described the earlyrelapse of infection in patients treated for chronicbronchitis and suggested that the therapy appears tobe bacteriostatic in nature. The levels of sulpha-methoxazole in sputum may again be relevant. Infairness it must be mentioned, however, that otherworkers have clearly demonstrated eradication ofpathogens from thesputum (Hughes, 1969) andacom-paratively low early recurrence rate (Pines, 1970).The use of sulphamethoxazole/trimethoprim for

the treatment of gonorrhoea has definite attractions.In addition to producing a high cure rate, the combi-nation has no activity against the spirochaetescausing syphilis and there is therefore no chance ofmasking a concomitant syphilitic infection. A dis-advantage is that at least four days' treatment mustbe taken if conventional doses are employed.Two other particular reports are of interest. One

is the use of the combination in ulcerative colitis,where the effect produced might be associated withthe recently described immunosuppressive activity oftrimethoprim (Ghilchik, Morris, and Reeves, 1970).The other is a report of successful use in the pre-vention of infection in leucopenic patients (Grine-berg, Emmerson, Prankerd, and Souhamie, 1970).Although some bacteria commonly causingopportunistic infections are 'resistant' to sulpha-methoxazole/trimethoprim, it should be rememberedthat the combination is only required to preventestablishment of infection from a small, initiating

inoculum whereas sensitivity or resistance is usuallyjudged on the basis of what is needed for treatingthe large number oforganisms in established infection.

Toxicity

The toxicity of sulphamethoxazole/trimethoprimcan be that of the individual components of thecombination and perhaps also the result of both drugsacting to produce a single effect. Although much ofthe recent literature concentrates on the mechanismof the toxic potential of trimethoprim (e.g. Kahn,Fein, and Brodsky, 1968), it must be rememberedthat large amounts of sulphamethoxazole are beingadministered in the combination, and sulphonamideside effects will also occur. Minor side effects (skinrash, nausea, vomiting, glossitis) occur occasionallyafter giving the combination (Reeves et al, 1969;Williams et al, 1969). On the evidence available,serious haematological side effects have onlyoccurred very rarely during the administration ofwhat is conservatively estimated to be 40,000,000tablets of the combination so far. Thrombocytopeniaseems to be the most common serious blood defect(Handley, 1969), but as both this and neutropeniaare found in ill patients, particularly those with virusinfections, the significance of their presence afterdrug administration is hard to assess. There seemsto be a particular association between thrombo-cytopenia and heart failure (Palva, Salokannel, andTakkunen, 1970). The administration of the combi-nation to patients with heart failure might be betteravoided, especially if a thiazide drug is also beinggiven. It has also been suggested that neutropenia isparticularly likely to occur when the combination isgiven to patients within 60 days of receiving ahomotransplanted kidney (Hulme and Reeves, un-published data).

Laboratory Control

DISC SENSITIVITY TESTINGThe practical aspects of this topic have already beendiscussed by Waterworth (1969). The importanceof the correct choice of medium and control ofinoculum size should be emphasized. It would appearthat Oxoid DST agar containing lysed horse blood

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is a generally suitable medium. Very heavy inoculashould be avoided since they selectively reduceinhibition zones to sulphonamides.A more controversial problem is the choice of

suitable discs since bacteria can be tested eitheragainst each drug separately or both together in acombined disc. The former method gives the mostinformation about the activity of the individualdrugs against the bacteria but significant and usefuldegrees of synergy may well be missed. Althoughsynergy cannot be conclusively demonstrated by theuse of a combined disc alone, its effect (and hence itstherapeutic potential), if present at the ratio of thetwo drugs employed, is more likely to be detected.There is no doubt that ideally both methods shouldbe employed and this can be recommended forserious or difficult infections. It is, however, timeconsuming and extravagant in materials and, forsimple infections (for example a lower urinary tractinfection) a combined disc test determining overallsensitivity to the combination is probably sufficient.

Further argument on this point is fruitless atpresent since more work is needed, for example, inassessing the importance of initial resistance tosulphonamide in determining the development ofresistance to trimethoprim during therapy, or theoccurrence of potentiation when the organism ispartially or fully resistant to one or both drugs.Until points like these are resolved by carefullyconducted clinico-microbiological studies the formu-lation of sensitivity testing procedures cannotusefully be finalized.DETERMINATION OF MINIMAL INHIBITORYCONCENTRATIONFor both sulphonamide and trimethoprim an agardilution technique with multiple loop inoculation(Darrell et al, 1968) can be used. Careful control ofthe inoculum size is essential for reproducible resultsandwe use an inoculum concentration ofonly 10%-104organisms/ml to ensure meaningful sulphonamideminimum inhibitory concentrations.SERUM LEVELS OF DRUGSThe estimation ofsulphonamide in body fluids can berapidly and simply done by a chemical method(Bratton and Marshall, 1939, as described andmodified by Varley, 1967). Trimethoprim can beestimated by a rather complex microbiologicalmethod fully described by Reeves and Ghilchik(1970). Although a simpler method, more suitablefor clinical use, has been described (Pechere, 1970)it still requires a full evaluation by comparison withstandard methods. A spectrofluorimetric methodhas also been described (Schwartz, Koechlin, andWeinfeld, 1969) a micromodification of whichapparently gives results in good agreement with the

D. S. Reeves

microbiological assay (A. S. E. Fowle, personalcommunication). But it is a time-consuming pro-cedure, needing specialized apparatus and requiringcareful attention to detail for reproducible results.

Prospect

The resuts of laboratory and clinical studies to datehave shown sulphamethoxazole/trimethoprim incombination to be a chemotherapeutic agent of wideapplication. Its place in the chemotherapeutic arma-mentarium of the future will depend on three mainfactors considered in relationship to other drugsavailable: (1) the ease of development of resistantstrains in domiciliary and hospital acquiredinfections; (2) the frequency and seriousness ofside effects; and (3) teratogenicity.

These problems will only be resolved by the con-tinuing use of the combination under carefulobservation and control. The evidence available sofar does not suggest that it is any more toxic thanmany other commonly used antibacterial agents.From the point of view of practical chemo-

therapeutics other problems remain to be solved, inparticular the importance of initial sulphonamideresistance in infecting bacteria treated with thecombination, and the part played by synergicactivity in controlling and eradicating infections.Until these problems are resolved by clinicomicro-biological studies the correct laboratory control oftherapy with the combination will remain partlyconjectural.

Finally, it would seem that the administration ofa fixed ratio of the two drugs is not ideal for treatingall infections. For treating infections in certain sites,or infections caused by certain organisms, separatetablets of trimethoprim or sulphamethoxazolewould be of value so that the ratio with sulphona-mide could be altered or a different sulphonamidebe employed.

I wish to thank Professor R. E. 0. Williams for hishelpful criticism in compiling this review.

ReferencesAkinkugbe, 0. O., Lewis, E. A., Montefiore, D., and Okubadejo,

0. A. (1968). Trimethoprim and sulphamethoxazole in typhoid.Brit. med. J., 3, 721-722.

Allison, M. E. M., Kennedy, A. C., McGeachie, J., and McDonald,G. A. (1969). Sulphamethoxazole-trimethoprim therapy inurinary tract infection with reference to its haematologicaleffects. Scott. med. J., 14, 355-360.

Bohni, E. (1969). Chemotherapeutic activity of the combination oftrimethoprim and sulphamethoxazole in infections of mice.Postgrad. med. J., 45, Suppl., 18-21.

Bratton, A. C., and Marshall, E. K., Jr. (1939). A new coupling com-ponent for sulfanilamide determination. J. Biol. Chem., 128,537-550.

Brodie, J., Macqueen, I. A., and Livingstone, D. (1970). Effect oftrimethoprim-sulphamethoxazole on typhoid and salmonellacarriers. Brit. med. J., 3, 318-319.

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Turnbull, A. R. (1969). Bacteriological, pharmacological andclinical studies with trimethoprim-sulphonamide combinations.Postgrad. med. J., 45, Suppl. (Nov.), 56-61.

Brumfitt, W., and Percival, A. (1967). Laboratory control of anti-biotic therapy in urinary tract infection. Ann. N. Y. Acad. Sci.,145, 329-343.

Bushby, S. R. M. (1969a). Combined antibacterial action in vitro oftrimethoprim and sulphonamides. Postgrad. med. J., 45, Suppl.(Nov.), 10-18.

Bushby, S. R. M. (1969b). Discussion to Waterworth. Postgrad. med.J., 45, Suppl. (Nov.), 28.

Bushby, S. R. M., and Hitchings, G. H. (1968). Trimethoprim, asulphonamide potentiator. Brit. J. Pharmacol., 33, 72-90.

Carroll, B. R. T., and Nicol, C. S. (1970). Trimethoprim/sulpha-methoxazole in the treatment of non-gonococcal urethritis andgonorrhoea. Brit. J. vener. Dis., 46, 31-33.

Condie, A. P., Williams, J. D., Reeves, D. S., and Brumfitt, W. (1968).Complications of bacteriuria in pregnancy. In Urinary TractInfection, ed. F. 0 Grady, and W. Brumfitt, p. 148. London,Oxford University Press.

Cooper, R. G., and Wald, M. (1964). Successful treatment of proteussepticaemia with a new drug, trimethoprim. Med. J. Aust., 2,93-96.

Cox, C. E., and Montgomery, W. G. (1969). Combined trimethoprim-sulfisoxazole therapy of urinary infections. Clinical studies.Postgrad. med. J., 45, Suppl. (Nov.), 65-71.

Craven, J. L., Pugsley, D. J., and Blowers, R. (1970). Trimethoprim-sulphamethoxazole in acute osteomyelitis due to penicillin-resistant staphylococci in Uganda. Brit. med. J., 1, 201-203.

Csonka, G. W. (1969). Therapeutic trial of some genital infectionswith trimethoprim-sulphamethoxazole. Postgrad. med. J., 45,Suppl. (Nov. ), 77-80.

Csonka, G. W., and Knight, G. J. (1967). Therapeutic trial of tri-methoprim as a potentiator of sulphonamides in gonorrhoea.Brit. J. vener. Dis., 43, 161-165.

Darrell, J. H., Garrod, L. P., and Waterworth, P. M. (1968). Tri-methoprim: laboratory and clinical studies. J. clin. Path., 21,202-209.

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