14. B u c h t

Recent Trends in the Therapy of Urinary Tract Infections Summary: The frequency of chronic renal failure leading to uraemia has steadily decreased in Sweden during the last decade. The two main groups - those cases due to phenacetin abuse and those of bacterial origin - have both decreased to the same extent. The number of cases of uraemia due to glomerulonephritis and interstitial nephritis are at present equal. Earlier, cases related to pyelonephritis dominated. It was to be expected that the frequency of uraemia due to phenacetin would decrease after the sale of drugs containing phenacetin was restricted in 1962. The decrease of cases due to bacterial infection is more complex. It is obvious that practitioners have prescribed antibiotics more actively during the last 10-15 years than previously. Now there seems to be a tendency to dispense with therapy. The main reason for this is the intensive propaganda in the mass media on cases of severe druginduced accidents. In Sweden there is no tendency towards increased resistance of urinary pathogens. Therefore, the actual need of new drugs is limited. The frequency of side-effects of drugs for the treatment of UTI is discussed. There seems however, to be a need for a new trimethoprim/sulphonamide combination with a pharmacokinetically better and if possible less toxic sulphonamide. A new treatment policy with short-term treatment periods and more frequent controls is also desirable.

Zusammenfassung: Neue Entwicklungen in der Behandlung yon Harnwegsinfektionen. Chronisches Nierenversagen mit LVbergang in die Ur~imie ist in den letzten zehn Jahren in Schweden kontinuierlich seltener geworden. Beide Hanptgruppen, die durch chronischen Phenacetinabusus verursachten und auf bakterieller Basis entstandenen F~ille, haben sigh gleich stark vermindert. Zur Zeit kommen Ur'~nie-F~ille nach Glomerulonephritis gleich h~iufig vor wie auf der Basis der interstitiellen Nephritis. Friiher iiberwogen die durch Pyelonephritis bedingten F~ille. Es war zu erwarten, dab die durch Phenacetinabusus verursachten Ur~imieformen nach der Einschr~inkung des Phenacetinangebotes im Jahr 1962 abnehmen wiirden. Die Verminderung der dutch bakterielle Infektionen bedingten F~ille ist komplexer. Nachdem in den letzten zehn bis fiinfzehn Jahren von den praktizierenden .~,rzten mehr Antibiotika verordnet wurden als je zuvor, zeichnet sich jetzt ein Trend nach einem therapeutischen Nihilismus ab. Hauptursache hierfiir ist die intensive Verbreitung yon F~illen schwerer, arzneimittelbedingter Zwischenf~ille durch die Massenmedien. In Schweden zeichnet sich keine Tendenz zur vermehrten Resistenzentwicklung bei Erregern aus dem Harntrakt ab. Der Bedarf an neuen Medikamenten ist daher zur Zeit begrenzt. Die H~iufigkeit yon Nebenwirkungen yon Medikamenten zur Behandlung von Harnwegsinfektionen wird diskutiert. Es scheint ein Bedarf fiir neue Trimethoprim-/Sulphonamid-Kombinationen mit einem pharmakokinetisch giinstigeren und m6glichst weniger toxischen Sulphonamid zu bestehen. Auch sind neue Behandlungsschemata mit kurzen Therapiephasen und h~iufigeren KontroUen wiinschenswert.

T h e f r e q u e n c y of significant b a c t e r i u r i a h a s b e e n t h o r oughly i n v e s t i g a t e d b y Kass a n d others, t a k i n g into a c c o u n t age, sex, p r e g n a n c y , s o c i o - e c o n o m i c status a n d o t h e r factors. It h a s b e e n s h o w n t h a t t h e figures f r o m d i f f e r e n t p a r t s of t h e world are n o t generally applicable. O u r o w n studies of b a c t e r i u r i a d u r i n g p r e g n a n c y (1) show a f r e q u e n c y of 3.7 per cent which is l o w e r t h a n t h a t f o u n d b y o t h e r investiga-

tors. W e think, h o w e v e r , t h a t o u r figures for u r e m i a d u e to u r i n a r y t r a c t i n f e c t i o n ( U T I ) in S w e d e n reflect a t r u e t e n d e n c y in this c o u n t r y a n d m a y b e valid for o t h e r c o u n tries (Figures 1 a n d 2, T a b l e s 1 to 4). I n S w e d e n t h e r e is a statistically significant d e c r e a s e in t h e n u m b e r of cases of U T I l e a d i n g t o u r e m i a w h i c h c a n n o t b e a t t r i b u t e d to t h e r e s t r i c t i o n of t h e sale a n d c o n s u m p t i o n of p h e n a c e t i n a f t e r 1962. A f t e r t h a t y e a r p h e n a c e t i n - c o n t a i n ing drugs w e r e o n l y available o n prescription. T h e r e h a s b e e n a n e q u a l d e c r e a s e of u r e m i a d u e to interstitial n e p h r i tis, irrespective of w h e t h e r t h e a b u s e of p h e n a c e t i n was k n o w n or not. I n this c o n n e c t i o n I wish t o w a r n against u s i n g E D T A * statistics as a m e a s u r e of t h e f r e q u e n c y of d i f f e r e n t diseases leading to u r e m i a , as is o f t e n d o n e w h e n selecting p a t i e n t s f o r dialysis a n d t r a n s p l a n t .

Table 1: Mortality of uremia (deaths + actively treated patients) in an urban and rural area respectively (Patients/million inhabitants/year).

Age (years)

Gothenburg (1966-1971)

County (1974-1975)

16--65 128

15-64 112

Table 2: Mortality (deaths + actively treated patients) of pyelonephritis and glomerulonephritis (Patients/miUion inhabitants/year).

Age (years) Pyelonephritis Glomerulonephritis Nephropathy NUD

Gothenburg (1966-1971)

County (1974-1975)

16-65 53 28 -

15-64 19 30 7

NUD = not defined renal disease

T o t a k e a n e x a m p l e : g l o m e r u l o n e p h r i t i s leads to u r e m i a a t a n earlier age t h a n pyelonephritis. This m e a n s t h a t m a n y p a t i e n t s with c h r o n i c p y e l o n e p h r i t i s c a n n o t b e a c c e p t e d for active t r e a t m e n t of u r e m i a . T h e g l o m e r u l o n e p h r i t i s g r o u p thus d o m i n a t e s t h e p y e l o n e p h r i t i s g r o u p statistically ( T a b l e

5). * European Dialysis and Transplant Association Prof. H. Bucht, Department of Medicine, Sahlgrenska skjukhuset, Gothenburg, Sweden.

Infection 7 (1979) Suppl. 4

S 309

H. Bucht: Therapy of Urinary Tract Infections Table 3: Incidence of azotemia (serum creatinine >440 gmol/l) in an urban and rural area (Patients/million inhabitants/year).

Gothenburg (1966-197i)

County (1974-1975)

16-65 143

15-454 157

Age (years)

Table 4: Incidence of azotemia due to pyelonephritis and glomerulonephritis (Patients/million inhabitants/year).

Gothenburg (1966-1971)

County (1974-1975)

16-65 53 33 -

15-64 26 35 12

Age (years) Pyelonephritis Glomerulonephritis Nephropathy NUD

Table 7: Reported severe side-effects (deaths in brackets).

Sulphonamides TrimethoprimSulphonamides Nitrofurantoin Nalidixic acid











83(1) 174(2) 27(0)

72(1) 145(3) 24(0)

112(0) 73(2) 227(2) 207(2) 34(0) 33(0)

340(4) 753(9) 118(0)

Table 8: The sale of the drugs on the Swedish market in million daily doses per year.

Sulphonamides Nitrofurantoin Nalidixic acid TrimethoprimSulphonamides





9.1 8.6 0.50

8.2 8.1 0.60

7.0 7.8 0.63

6,0 6.4 (0.70)





NUD = not defined renal disease

Treatment o| Urinary Tract Intection Table 5: Regular dialysis treatment and transplantation in Europe

divided into diagnostic groups (according to EDTA), Regular dialyses


64% 21% 6% 1% 1% 7%

61% 19 % 7% 2.2% 0.8% 10 %

Chronic glomerulonephritis Pyelonephritis Polycystic kidneys Primary malignant hypertension Congenital nephritis Other

Table 6: Index of reported side-effects taking into consideration the sale of the respective drug.

Nitrofurantoin Sulphonamide Trimethoprim-Sulphonamide Naldixic acid





257 66 119 143

421 85 359 260

284 107 343 205

456 153 366 193

What is the reason for this decrease in frequency of uremia due to chronic UTI and does it reflect a decrease in the number of U T I cases as a whole? The answer to the first question is not simple and is probably subjective. I think earlier detection and better antibiotic treatment of patients at risk is an important factor. The second question is more difficult to answer. We know that in Sweden during the last ten years a constant number of about 10 per cent of outpatients in general medicine and/or gynaecology report because of urinary tract symptoms. This figure does not seem to have changed during the last decade.

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Infection 7 (1979) Suppl. 4

Only a few years ago there was no disagreement on treatment policy. All patients with symptoms of UTI and bacteriuria, and even those without symptoms, were treated. In my own experience the number of Cases with acute, severe, relapsing pyelonephritis has diminished. This may be because they are treated as' outpatients, and thus never come to my knowledge, or there may be a real decrease in number. Today, opinion on treatment policy is divided. This is especially true concerning patients with asymptomatic bacteriuria, defined as screening bacteriuria. Even the definition may be controversial as some of these patients may turn out to be symptomatic if they are treated and their often unspecific symptoms disappear. Children with asymptomatic bacteriuria are often not treated, and the same may apply in the aged. This is a controversial policy. Pregnant women on the other hand are always treated. The hitherto unsolved problem of diagnosing asymptomatic cases could perhaps be solved if we had a simple and safe diagnostic technique, which we do not have for the present. Unfortunately there is a tendency in Sweden today not even to treat symptomatic patients, a policy which I do not agree with. One of the reasons for this decision is the claim that infection often does not damage the kidney parenchyma. Renal scarring is said to be confined to children only, and even this is sometimes denied (2). Although UTI only exceptionally leads to severely impaired renal function, it may give rise to long lasting symptoms or interstitial fibrosis only. This is clearly demonstrated in our kidney donors who can only poorly compensate their donation with increased functional hypertrophy if they have previously had symptomatic UTI, in comparison to those who have never been aware of having had UTI previously (Figure 3).

H, Bucht." Therapy of Urinary Tract Infections


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Figure 1: Deaths due to uremia in Sweden (cases per million inhabitants).















Figure 2: Uremia deaths in Sweden due to pyelonephritis and glomerulonephritis (cases per million inhabitants).

Choice of Drugs

prescribed drugs sometimes leading to headlines in the press. Neglect to treat is always more difficult to prove than inadequate information and inadequate control of sideeffects. The frequencies shown in Table 6 and 7 are the official figures for UTI just for the side-effects after treatment with drugs (the figures come from a govermental board for the study of side-effects from drugs). It is impossible to give a general recommendation concerning the length of treatment. The tendency in the literature is obvious: shorten the treatment period. A n extreme example of this is our treatment of UTI in transplanted patients. When the ureteral and bladder catheters are

Is there any reason to prefer bactericidal drugs to bacteriostatic drugs? In my opinion only in acute life-threatening situations. If treatment could definitely be shortened by using a bactericidal drug this might be a reason for prefering bactericidal drugs, but as far as I know would only give rise to a marginal theoretical gain. In our country sulphonamides, ampicillin, nalidixic acid and nitrofurantoin are the drugs of first choice. In Gothenburg practically all bacterial strains from outpatients are sensitive to one or more of these drugs. Another reason for the apparent renunciation of therapy practised by younger colleagues is the fear of side-effects of





Donors without

Donors without UTI and GFR betow 2 SD

Donors with recurrent UTI



O o



8 65

O o



o o


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o O

55 n=40



Figure 3: Renal hypertrophy in living kidney donors one year after nephrectomy measured by the glomerular filtration rate (GFR) in ml/min.

Infection 7 (1979) Suppl. 4

S 311

H. Bucht: Therapy of Urinary Tract Infections



Figure 4: Urinary concentration of gentamicin 1 mg/kg body weight given the day of removal of urinary tract catheters (= start of renal function) in primary necrotransplants..

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URINARY C O N C . # g / m l

withdrawn after the start of kidney function the patient is given 2 mg/kg of gentamicin in one single i. m. dose. The unique pharmacokinetics of the drug result in active concentrations in the urine for several days. This investigation was conducted together with AhlmOn (3) (Figure 4), on 50 patients with primary cadaver grafts. The long-term results of this unconventional and, as a general principle, not to be recommended treatment is too early to evaluate. If gentamicin could be replaced by a less toxic drug with similar pharmacokinetic properties, this would be worth trying. Treatment of lower UTI for more than one week is as a rule not necessary. In acute pyelonephritis one to two weeks is generally sufficient. This of course depends on the state of the kidneys and urinary tract of the patient. Patients with obstructed urine flow, reflux and incomplete bladder emptying may require longer treatment periods. Long-term treatment for months and years is recommended in a few selected cases only. Some patients have acute symptomatic relapses after withdrawal of therapy in spite of an apparently normal urinary tract. Many of these patients can be kept free of symptoms with one bedtime dose following meticulous bladder emptying. The shortening of the treatment period has been made possible by a simplified technique of urinary bacteriological check-up, i. e. chemical self-testing. The main problem of successful treatment of UTI in our country is not increased

S 312

Infection 7 (1979) Suppl. 4

resistance towards antibiotics. The place of trimethoprimsulphonamide in daily practice is not easy to define. I do not consider it the drug of first choice. Furthermore, as shown by Bergan and Brodwall (4), if renal function is reduced the ratio of sulphonamide to trimethoprim is far from ideal in the drugs now on the market. Most sideeffects of trimethoprim-sulphonamides today seem to be due to the sulphonamide component. We hope the new trimethoprim-sulphonamide combination containing another sulphonamide which we will hear about during the following days will be better and safer than the previous drugs, with improved pharmacokinetic properties and fewer side-effects.

Literature 1. Henning, C., Bucht, H., KaUings, L. 0.: Results from the routine detection of bacteria in antenatal care in Stockholm County. Acta Pathol Microbiol Scand, Section B 79 (1971) 440--448. 2. Kincaid-Srnith, P., Fairtey, If. F.: Renal infection and renal scarring. Mercedes Publishing Services, Melbourne, 1970. 3. AhlmOn, J., Bucht, 11.: Treatment of urinary tract infections in transplanted patients with a single dose of gentamicin. To be published. 4. Bergan, T., Brodwall, E. 1

Recent trends in the therapy of urinary tract infections.

14. B u c h t Recent Trends in the Therapy of Urinary Tract Infections Summary: The frequency of chronic renal failure leading to uraemia has steadil...
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