26

beneficial in angina pectoris. We now know that prolongedadministration of beta-blockers induces "adaptational"responses-that is to say, secondary effects emerge which arenot apparent on acute administration, and which persist longafter all traces of drug have been eliminated from the body.The most prominent of these is a large and uniform prolonga-tion of the cardiac action potential duration (APD), measuredwith microelectrodes in animals, and detectable as a

lengthening of the electrocardiographic Q-T interval inman.6 The anti-anginal drug amiodarone likewise prolongsAPD in animals and Q-T in man. When animals were treatedwith oxyfedrine for 6 weeks the APD became substantiallylonger, in contrast to the acute beta-receptor agonist actionwhich shortens APD. This suggests that oxyfedrine, despiteits acute agonist effects, leads ultimately to a reduction ofbackground sympathetic drive, and that this in turn causessome intracellular adaptational response, signalled (amongother ways) as a retardation of the course of repolarisation. Itis of considerable interest, therefore, that in a more recentcontrolled trial in which oxyfedrine was compared with pro-pranolol, both drugs proved equally effective after six weeks’administration. The explanation for the anti-anginal effectsof two drugs which on acute administration have oppositeactions ((3-agonist and 0-antagonist) may reside, at least inpart, in the fact that long-term administration induces similarresponses in the cardiac cell. One possibility that deserves in-vestigation is that long-term oxyfedrine acts at sites in the cen-tral nervous system, or presynaptically, to reduce the meansympathetic transmitter output. Whatever the explanationfor its action, oxyfedrine seems worth a trial in cases of anginawhere beta-blockers and other established drugs are ineffec-tive or contraindicated.

SINGLE-DOSE TREATMENT OF URINARY TRACTINFECTIONS

THE usual duration of antimicrobial therapy prescribed forurinary-tract infection is 5-21 days. Are such long coursesreally necessary? In uncomplicated infections, a single dosecan sometimes be as effective as a conventional course.

Gruneberg and Brumfitt9 reported a study in which 25women with symptomatic bacteriuria received a single doseof 2 g oral sulfadoxine: 22 were cured. Both amoxycillin andtrimethoprim-sulfamethoxazole (co-trimoxazole) have beenused as single-dose treatment for urinary tract infections. Asingle dose of 3 g amoxycillinl° was compared with 5-7 daysof amoxycillin, 250 mg four times daily, in two similar

groups of 31 patients: 23 were cured in each group. (The ex-isting commercial double-pack of amoxycillin gives the pa-tient a total of 6 g.) 40 womenll with urinary tract infectionsdiagnosed from culture of a specimen obtained by suprapubicaspiration were randomly divided into two groups receiving

5. Vaughan Williams EM. Adaptation of the heart and sympathetic system to prolongedadrenoceptor blockade. Proc Roy Soc Med 1977, 70: suppl 11, 49-62.

6. Vaughan Williams EM, Hassan MO, Floras JS, Sleight P, Jones JV. Adaptation ofhypertensives to treatment with cardioselective and non-selective beta-blockers. BrHeart J 1980; 44: 473-87.

7. Polster P, Vaughan Williams EM. The effect of prolonged treatment with oxyfedrineon intracellular potentials and on other features of cardiac function in rabbits andguinea-pigs. Br J Pharmacol 1973; 47: 187-95.

8. Whittington J, Raftery EB. Oxyfedrine and propranolol - a controlled trial in anginapectoris. Br J Clin Pharmacol 1980, 10: 439-42.

9. Gruneberg RN, Brumfitt W. Single dose treatment of acute U T.I.s Br Med J 1967;iii: 649-51.

10. Bailey RR, Abbott GD. Treatment of urinary tract infections with a single dose ofamoxycillin. Nephrology 1977; 18: 316.

11. Bailey RR, Abbott GD Treatment of urinary tract infections with a single dose oftrimethoprim sulfamethoxazole. Can Med Assoc J 1978; 118: 551-52

12. Bailey RR, Blake E. Treatment of uncomplicated urinary tract infections with a singledose of co-trimoxazole NZ Med J 1980, 92: 285-86

either a single large dose of co-trimoxazole (2’ 88 g) or 5 daysof 0 - 96 g co-trimoxazole twice daily. In both groups 17 of the20 patients were cured. A new organism was cultured fromthe urine of the three failures in the first group, the originalorganism having been Escherichia coli; in two of the failures inthe second group the organism was not eradicated, and theother patient later became infected with Streptococcusfaecalis.This work has been taken further. Bailey and B1ake12 latelyreported a trial in which the conventional 5-day course of co-trimoxazole was compared with single doses of 0 - 96 g,1’ 92 g, and 2 - 88 g. Success rates in all four groups weremuch the same, but these workers suggest that a single doseshould be at least 1 92 g.Success with a single dose of amoxycillin has also been

reported by Fang et al.13 61 patients with amoxycillin-sensitive organisms had their urine examined by the

antibody-coated bacteria assay’—a specialised test un-suitable for routine practice. 43 patients with negative assayswere randomised to receive either a single 3 g oral dose ofamoxycillin or 10 days of amoxycillin 250 g four times daily.All were cured. After conventional therapy 9 of the 18 pa-tients with antibody-coated bacteria relapsed within a week.A single dose of only 1 g amoxycillin can be effective. 16

There were three treatment failures in 11 patients on thistreatment compared with two failures in 11 patients on a con-ventional 7-day course. In the single-dose group there was farless alteration or reduction of faecal flora, so one might expecta lower incidence of diarrhoea and less chance of selecting outresistant bacterial populations. Sulphafurazole, a short-

acting sulphonamide, has likewise been tried as a single-doseagent: 17 29 patients with sensitive organisms were treatedwith a single dose, of whom 27 were cured. Recurrence rateswere no higher than those after conventional 10-daytreatment.

One way to prolong the useful clinical life of antibiotics is toselect regimens which discourage development of bacterialresistance: minimum effective dose and minimum duration oftreatment are important elements of such a policy.Apart from this, single-dose therapy has the advantages of

reduced cost and better patient acceptability. Some patientsstop treatment when symptoms disappear; in those wheresymptoms are confined to the lower urinary tract this is oftenafter the first dose. We need some way of identifying the pa-tients likely to respond to single-dose therapy. The absence ofantibody-coated bacteria in the urine seems to correlate wellwith responsiveness to single-dose therapy, and in these pa-tients the infection is thought to be confined to the lower uri-nary tract. Though the method occasionally gives false re-sults, at present it seems the most reliable way of predictingresponse. In general practice the simple infections can beidentified with some confidence on symptoms alone. In ad-dition, failure to eradicate a urinary tract infection after singledose therapy may indicate ’8 which patients require furtherinvestigation.

13 Fang LST, Tolkoff-Rubin NE, Rubin RH Efficacy of single dose and conventionalamoxycillin therapy m urinary tract infections localised by the antibody-coatedbacteria technique, N Engl J Med 1978; 298: 413-16

14. Fang LST, Tolkoff-Rubin NE, Rubin RH Localisation and antibiotic management ofurinary tract infection Annu Rev Med 1979; 30: 225-39.

15. Thomas V, Shelokov A, Forland M. Antibody-coated bacteria in the urine and the siteof urinary tract infection. N Engl J Med 1974, 290: 588-90.

16. Anderson JD, Aird MY, Johnson AM. Ree R, Goresky D, Brammell CA, Percival-Smith RXL The use of 1 g dose of amoxyrillin for the treatment of urinary tract in-fections. J Antimicrob Chemother 1979, 5: 481-3.

17. Kallenius G, Winberg J. Urinary tract infections treated with a single dose of short-acting sulphonamide. Br Med J 1979; i: 1 175.

18 Bailey RR Single dose antibacterial therapy for uncomplicated U T I.s. Drugs 1979;17: 219-21