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The treatment of urinary infections
THE TREATMENT OF URINARY INFECTIONS H. A. BUCHTEL, M.D. ROCHESTER, MINNESOTA
T
HE foundation for the modern treatment of urinary infection was laid twenty years ago by the pubhcation of two articIes, one by SchohI and Janney l1 on “The Growth of Bacillus-cob in Urine at Varying Hydrogen Ion Concentrations” and the other by Gross” on the “Use of Neo-arsphenamine in Coccus PyeIonephritis.” Treatment by means of acidification did not foIIow this articIe for many years, perhaps because of technica diffrcuIties in determining the hydrogen ion concentration. It was not unti1 1932 that CIark2 and HeImhoIz,6 working independently, demonstrated that acidification and ketosis produced a bactericida1 urine. Since then deIiberate controIIed acidification has been a vaIuabIe adjunct in the treatment of baciIIary infections. Neo-arsphenamine has been used sporadically by many physicians in coccus infections and by some with good success. Diagnosis. It is evident that before either of these methods of treatment can be employed, a diagnosis of the type of infection must be made. Many physicians have the idea that in order to do this specia1 training in bacterioIogy is required. This is certainIy not the case, as a stain of the urine sediment is a11 that is necessary to make the diagnosis in a high percentage of cases. TabIe I shows the comparison between stain and cuhure in making the diagnosis of urinary infection. It is seen that the stain is far superior to the cuIture (on blood agar) in making the diagnosis of cocca1 infections and practically as good as the cuIture (on Endos media) in making the diagnosis of baciIIary infections. Seidman’z discusses reasons for these differences, and points out how carefuIIy certain organisms must be handled in order to have the cuIture succeed in identifying the bacteria. One can rareIy make a diagnosis of urinary 29
infection when the bacteria cannot be found in the centrifuged specimen. The urine in the femaIe must be coIIected by catheterization; a satisfactory specimen for examination in the maIe is obtained by examination of the second portion of the voided urine. Examination should be made promptly after the urine is obtained. The gross appearance is noted and the pH checked. A centrifuged specimen is then examined for the amount of pus ceIIs and red bIood ceIIs. CrystaIs shouId be noted. A gram stain on the sediment is next done and the number and variety of bacteria noted. The overwheIming majority of bacteria found in urinary tract infection are either grampositive cocci shown in Figure I or gramnegative baciIIi shown in Figure 2. Another Iaboratory examination, necessary antecedent to the proper treatment of patients with urinary tract infection, is the determination of the hydrogen ion concentration or the pH. Many physicians beIieve this to be a diffrcuIt procedure, but modern calorimetric methods have made it very simpIe. Either a few drops of dye may be added to the urine and the coIor compared with a standard chart or dye impregnated paper is saturated with urine and the coIor again compared with a standard. Coccus Infections Treatment. The reIative incidence of coccus and baciIIary infections is shown in TabIe II. It is seen that though the bacihi cause the great majority of urinary tract infections, enough infections due to cocci occur to make their treatment worth considering. The etioIogy of urinary tract infections wiI1 not be discussed here but certainIy foci of infection pIay some part, and especiaIIy is this true in the cocca1 group. We have seen many patients in whom treatment has faiIed unti1 foci were treated. The prostate and cervix must be remembered as such foci.
30
Americun Journal of Surgery
Buchtel,
Treatment
In our hands neoarsphenamine has been the most successful drug for eradicating coccaI infections. Its mode of action is stiI1
FIG. I. Urinary tract infection with gram positive Cocci.
in dispute, but Pace9 beIieves that sufficient arsenic is eIiminated in the urine to produce a bactericida1 effect. CIinicaIIy this is supported by the fact that acidification seems to increase the efficiency of the drug, but it is refuted by evidence that infections THERELATIVE URINE IN
TABLE EFFICIENCYOFTHE
SEDIMENT MAKING
A
AND
THE
DIAGNOSIS
I GRAM'S STAINOF
CULTURE OF
OF
URINARY
THE
THE
URINE
INFECTION
Num. Per Num- Per ber Cent ber Cent ________ Stains and cukures agree. Negative stain and positive cukure. Positive stain and negative culture..
5 rg
79
102
15.6
TotaI.
653
32
158
5.4, 100 I
56.4
30
10.4
92
33.2
! I 280
100
Iimited to the bIadder do not respond as we11 as do those in which the kidneys are aIso involved. The most efficient and best toIerated dosage scheme is to give .2 gm. foIIowed in five to seven days by .3 gm. If no improvement resuIts after these two injections, it is rare for a third dose to
Urinary
Infections
OcXXMl,,937
produce good resuIts. If, however, there is no contraindication or arsenic reaction and if the patient has no demonstrabIe foci a
FIG. Z. Urinary
tract infection with gram negative BaciIIi.
third injection of .4 gm. may be given. We do not beIieve in further injections but turn to other methods of treatment. Acidification and urotropin, the azo dyes and hexyIresorcina1 are sometimes of value. Vaccine therapy, the vaccines being prepared from urine, throat, and prostatic or cervica1 cuItures may succeed when other methods fai1. The use of mandeIic acid and suIfaniIamide wiI1 be discussed Iater. The above pIan of treatment does not hoId for infections with the Streptococcus fecalis as this organism responds poorly to neoarsphenamine. As is seen from Table II, this is a rather common organism (12 per cent). Usually it can be differentiated from the other cocci by microscopic examination, and Figure 3 shows a typica smear of a urinary infection with Streptococcus fecalis. This organism is very resistant to suIfaniIamide treatment but responds we11 to acidification and ketosis or to mandeIic acid. Bacillury Infections. Urinary tract infections due to gram-negative baciIIi respond we11 to acidification and mandelic acid and somewhat better to aIkaIization and suIfaniIamide. Since we beIieve that in the present state of our knowIedge the former is a Iess objectionabIe method of treatment, it
New
SEHIES
VOL. XXXVIII,
No.
1 BuchteI,
Treatment
should as a ruIe be used. WhiIe the ketogenie diet was originalIy conceived as a method of acidification of the urine, it was URINE
CLLTURE
number.
Infections
Anlerican Jourrlnl vr Sul-gcry
3 I
is avaiIabIe in tabIets and capsuIes. Sodium mandeIate seems to cause Iess gastric disturbances than do the ammonium saIts
TABLE II FINDINGS. (FROM CABOT, MODERN UROLOGY, VOL. 11)
Escherichia coli. ...................... Aerobacter aerogenes .................. Proteus ammoniae. ................... Proteus (species?). .................... Pseudomonas aeruginosa ............... Pseudomonas (species?). ............... SaImoneIIa (species?). ................. Alcaligenes (species?). ................. Eberthella typhosa .................... ShigeIIa (species?). .................... Gram-negative baciIIus (unidentified). Streptococcus fecaIis ................... Streptococcus (green producing). ....... Streptococcus (sIight hemoIysis)........ Staphylococcus aureus ................. Micrococcus (species?). ................ Diphtheroids. ........................ Neisseria gonorrhoeae. ................ Total
Urinary
Jurn. ber
Per Sent
490 91 48 9 32 II 12 IO
55.9 10.4 5.5 1.0 3.6 I.2 I.4 I.1 0.2 0.7 2.6 12.0 I.1
:
..
23 105 IO 33 IO
3.8 I.1 15.0
132 4 I
0.4 0. I
877 -
I
soon evident that its effect was more potent than couId be attributed to acidification aIone. FuIIer4 soon found the expIanation for this in the discovery that one of the ketone bodies, betahydroxybutyric acid, had bactericida1 properties. This Ied Rosenheim’O to an intensive investigation of the organicacids in the hope that one of them couId be given by mouth and excreted unchanged in the urine. Mandelic acid was found to meet the requirements most fuIIy and in addition was non-toxic enough so that adequate dosage couId be given to produce a bactericida1 urine. ExperimentaIIy, Osterberg and HeImhoIz7 determined these IeveIs and their resuIts are shown in TabIe III. It wiI1 be noted that Pseudomonas and Aerobacter aerogenes are more resistant to the action of mandeIic acid. In practice we given 12 gm. of ammonium mandeIate daily in divided doses. This can be given in Iiquid form, or for those who object to the taste, the drug
FIG. 3. Urinary tract infection with Streptococcus fecalis. Typically this organism occurs as ova1 cocci joined together by the end with a refractile streak down the center. The former feature is shown in the photomicrograph. The refractile streak is not shown. Sometimes cocci which do not show these characteristics wiI1 prove on culture to be Streptococcus fecalis. If these characteristics are not shown, the organism cannot be differentiated by the stain.
but when this is used, additiona acidification by means of ammonium nitrate or chIoride is usuaIIy necessary. As is seen from TabIe III, the most important factor in the production of bactericidal urine is adequate controI of the acidity. This shouId be checked frequentIy during the course of treatment and be kept, if possible, beIow 5.2. Usually such an acidity can be obtained by the use of the ammonium saIt, but shouId this not occur additiona1 acidification by means of ammonium nitrate, or chloride, diIute hydrochIoric acid or an acid-ash diet is necessary. It is of the utmost importance that the patient take no aIkaIies, of which soda and saline Iaxatives are the most common. Patients in whom acidification is obtained with difflculty should abstain from toothpaste. Even with a11 these precautions, patients wiI1 be encountered in whom proper acidification is impossible. In addition to proper acidification, adequate concentration of the drug is aIso necessary. Since there is no simpIe test for
32
American Journalof
Buchtel,
Surgery
Treatment
the concentration of mandeIic acid in the urine, the test being that for organic acids, the majority of our patients are treated TABLE THEBACTERICIDAL BACTERICIDAL
III*
RANGEOFMANDELIC RANGE
OF MANDELIC
ACID ACID
l.0
Concentration &y$&s3
of mandelic
iFgh&}like
acid
Escherichia
Coli
*From H. F. HeImhoIz and A. E. Osterberg, Rate of excretion and bactericidal power of sulfanitamide in the urine. Proc. Staff Meetings of tbe Mayo Clinic, 12: 377-381 (June 16) 1937.
with this as an unknown factor. If the fluids are limited so that the urinary output is around I ooo C.C. daiIy, adequate concentration wiII develop except when there is poor renaI function. * Excretory urography, since it tests the function of each kidney separateIy, provides a most satisfactory method of determining renaI function when using excretory antiseptics. If the kidney visuaIizes we11 in five minutes after injection of the drug, it has adequate function. It must aIways be remembered that in uniIatera1 kidney disease the bIadder urine may be bactericida1 whiIe urine from the diseased kidney is not. We do not believe that mandeIic acid therapy shouId be continued for more than two weeks. At the end of that time, if improvement has not occurred, the drug is discontinued for a week or ten days. A * Mandelic acid is of great value in the treatment of acute urinary infections. When so used, the fluids must not be Iimited, especiaIIy if there is fever.
Urinary
Infections
OcroeEn.,937
second course may prove more beneficial than the first. MandeIic acid used as has been described wiI1 prove successful in more than go per cent of uncompIicated baciIIary infections, and is about 50 per cent efficacious in baciIIary infections complicated by prostatitis, miId urinary obstruction, or chronic pyeIonephritis without great renaI damage. In our experience the Aerobacter aerogenes responds practicaIIy as we11 as the other baciIIi. FaiIure wiI1 be the rule in the presence of Iithiasis, foreign body, severe urinary obstruction or chronic pyelonephritis with marked renaI destruction.3 CoccaI infections, with the exception of Streptococcus fecaIis, respond but poorIy. Good resuIts, however, are often obtained when the infection is confined to the Iower urinary tract. In resumC then, the cocca1 infections of hematogenous origin seem to respond to neoarsphenamine, whiIe those of ascending origin respond to mandeIic acid. Since the cocca1 infections of chiIdhood are aImost invariabIy of the Iatter type, drugs other than mandelic acid have IittIe pIace. MandeIic acid has IittIe if any effect on norma kidney function. In fact, experimenta1 animaIs show more Iiver than kidney damage. There is no doubt, however, that the drug is a renaI irritant, as it is common to find red bIood ceIIs or casts in the urine of patients under treatment. Gross hematuria is rare. Patients with reduced renal function must be treated with the greatest care, as treatment by acidification runs considerabIe risk of producing acidosis. Such patients must be carefuIIy watched and their bIood chemistry frequentIy checked. Acidification by means of ammonium nitrate is safer for this group than with ammonium chIoride. Gastro-intestina1 upsets are infrequent, as are genera1 toxic disturbances such as tinnitus, vertigo, paIpitation, and dermatitis. Such reactions caI1 for reduction of dosage or discontinuance of the drug. Very
NOW %RIE~VOLXXXVIII. NO.I Buchtel,
Treatment
rareIy these reactions may prove very severe. The most recent drug Suljanilamide. used in urinary tract infections has a Ionger history than either of the previous methods of treatment, as the origina prototype of s.ulfaniIamide was prepared as an azo dye in 1909. Its use in urinary infections, however, has developed within the past year, when many physicians, encouraged by the good results obtained in sepsis elsewhere in the body were led to try it in urinary tract infections. StrangeIy enough it has proved of greater value in bacillary than in coccaI infections. Experience with this drug suggests that it is a more potent antiseptic than mandehc acid. This drug is aIso active in an aIkaIine urine and wil1 deveIop a bactericida1 urine in the presence of marked renaI insuffIciency. It is eIiminated in good concentration in the urine but in poor concentration in. the prostatic secretion.’ In spite of this, a very saIutory effect or prostatitis is noted. Urinary tract infection associated with prostatitis is eradicated as easiIy by suIfaniIamide as other methods of treatment cIear up uncompIicated urinary tract infection. The drug wiI1 not sterilize the urine immediateIy foIIowing prostatic resection, but has been the most successfu1 drug we have to cIear the urine before prostatic surgery. The proteus baciIIus responds as we11 as the other baciIIi. FaiIure usuaIIy resuIts in the presence of Iithiasis or chronic pyeIonephritis with renaI destruction. BaciIIary infections respond better than coccal infections, and especiaIIy does this hoId for Streptococcus fecalis where good results wil1 practicaIIy never be obtained. This has been a most successfu1 method of treatment of gonorrhea of both men and women. From the discussion above, suIfaniIamide wouId seem to be the drug of choice in the treatment of a11 baciIIary infections, and were it not for the frequent reactions which foIIow its use such wouId be the case. While it is unnecessary to produce even the sIightest reaction to obtain a favorabIe
Urinary
Infections
American
Journal
of Surgery:
33
resuIt, it is aImost invariabIe that some malaise, dizziness, and headache develop. If these are reIieved by rest, it is not necessary to reduce the dose. The occurrence of any other reaction caIIs for reduction in dosage or discontinuance of the drug. The number and variety of reactions that can be produced by SuIfaniIamide is Iegion. We consider cyanosis, hemogIobinuria, anemia or Ieukopenia, fever, dermatitis, and jaundice to be serious and call for cessation of treatment. Dermatitis and anemia or Ieukopenia are probabIy good reasons for permanentIy discontinuing the drug. The mode of action of this drug is as yet not we11 understood. ExperimentaIIy, a urine to which SuIfaniIamide has been added wiI1 not have the bactericida1 power of a urine produced in the body containing the same suIfaniIamide concentration.8 ExperimentaIIy the drug seems to work better in a urine of pH of about 7.5, and even though this cannot be supported cIinicaIIy, there is certainIy no objection to giving aIkaIies during treatment. Magnesium sulfate shouId not be given. There is as yet no accepted dosage scheme for this drug. We start with a daiIy dose of 60 to 80 grains in four doses. After one to two days the dose is reduced and after another two days the patient is pIaced on a maintenance dose which is usuaIIy 40 grains daiIy. This is continued for not Ionger than ten days. Patients with gonorrhea, once cIinica1 cure is obtained, are pIaced on a 20 grain daiIy dose for two weeks. Using this dosage scheme we have not seen the frequent recurrence in Neisserian infections that others have reported. In spite of frequent re-examinations after discontinuing the drug, a11 our patients have remained weI1. Our results using this dosage scheme have been so superior to those obtained by smaI1 doses that we pIan to continue its use. Fifteen per cent of patients cannot toIerate this dosage. About 5 per cent wiII either respond to smaI1 doses or can graduaIIy work up to a Iarger
j_$
American
Journal
OC Surgery
dose. The remainder method of treatment.
Buchtel,
arc intoIerant
Treatment to this
Urinary
Infections
prostate must not routine focal check.
be
forgotten
in the
I
SUMMARY
Proper treatment of urinary tract infections depends upon a rough identification of the bacteria in the urine by means of a gram-stain of the centrifuged sediment. Neoarsphenamine is the most efficient drug in the treatment of coccal infections, especiaIIy if these be of the hematogenous origin. Acidification and mandelic acid is a most successful treatment for ordinary baciIIary infections and coccaI infections of the ascending type, especiaIIy Streptococcus fecaIis. SuIfaniIamide shouId be used when mandelic acid faiIs and especiaIIy when acidification of the urine is impossibIe, such as occurs in Proteus infections, or when there is renaI insufficiency. It is aIso the treatment of choice where urinary infection is complicated by marked prostatitis, and in Neisserian infections. Any method of treatment is attended by a high percentage of faiIure in the presence of Iithiasis, chronic pyeIonephritis with marked renaI destruction, or immediateIy foIlowing prostatic surgery. Attention to foci of infection is important not onIy in treatment but aIso in the prevention of recurrences. The cervix and
Oc,naF.H. lo,-
A. and COOK, E. N. The use of sulfanilamide in treatment of urinary infections. Proc. Stu$ Meet. Mqu CLinic, 12: 444-447 (July
I. BUCHTEL,
11.
14) 1937. 2. CLARK, A.
L. Escherichia coli baciIIuria under ketonenic treatment. Proc. Staff .., Meet. IVUVO Clinic, 6: 605608 (Oct. 14) 1931. 3. COOK, E. N. and BUCHTEI.. H. A. Mandelic acid in the treatment of infections of the urinary tract. J. A. M. A., 107: I7gg-1800. 4. FULLER, A. T. The ketogenic diet. Nature of bactericidal agent. Lancer, I : 855-856 (April 22) ‘933.
5. GROSS, S. Zur behandlung der zystopyelitis. Wien. Klin. Wocb., 30: 1381-1384, 1917. 6. HELMHOLZ, H. F. The ketogenic diet in the treatment of pyuria of chiIdren with anomalies of the urinary tract. Proc. Staj’ Meet. Mayo Clinic, 6: 609-613 (Oct. 14) Ig3I. 7. HELMHOLZ, H. F. and OSTERBERG, A. E. Rate of excretion and bactericida1 power of mandelic acid in the urine. J. A. M. A., 107: 1794-1796 (Nov. 28) 1936. 8. HELMHOU, H. F. and OST~RBERG, A. E. Rate of excretion and bactericida1 power of sutfanilamide in the urine. Proc. Staff Meet. Mayo Clinic, 12: 377-381 (June 16) 19x7. g. PACE, J. M. In press. IO. ROSENHEIM, M. L. MandeIic acid in the treatment of Urinary infections. Lancet, I : 1032-1037 (May 4) 1935.
II.
A. T. and JANNEY, J. H. The growth of bacillus coli in urine at varying hydrogen ion concentrations. J. Uroi., I: 21 I-229 (April)
SHOHI.,
1917.
12. SEIDMAN, L. R.,
ELLIS, M. G. and HILL, J. R. A comparative study of direct smear and cultures in three thousand urine specimens. J. Ural., 22: 717-724
(December)
Igzg.
T
HE foundation for the modern treatment of urinary infection was laid twenty years ago by the pubhcation of two articIes, one by SchohI and Janney l1 on “The Growth of Bacillus-cob in Urine at Varying Hydrogen Ion Concentrations” and the other by Gross” on the “Use of Neo-arsphenamine in Coccus PyeIonephritis.” Treatment by means of acidification did not foIIow this articIe for many years, perhaps because of technica diffrcuIties in determining the hydrogen ion concentration. It was not unti1 1932 that CIark2 and HeImhoIz,6 working independently, demonstrated that acidification and ketosis produced a bactericida1 urine. Since then deIiberate controIIed acidification has been a vaIuabIe adjunct in the treatment of baciIIary infections. Neo-arsphenamine has been used sporadically by many physicians in coccus infections and by some with good success. Diagnosis. It is evident that before either of these methods of treatment can be employed, a diagnosis of the type of infection must be made. Many physicians have the idea that in order to do this specia1 training in bacterioIogy is required. This is certainIy not the case, as a stain of the urine sediment is a11 that is necessary to make the diagnosis in a high percentage of cases. TabIe I shows the comparison between stain and cuhure in making the diagnosis of urinary infection. It is seen that the stain is far superior to the cuIture (on blood agar) in making the diagnosis of cocca1 infections and practically as good as the cuIture (on Endos media) in making the diagnosis of baciIIary infections. Seidman’z discusses reasons for these differences, and points out how carefuIIy certain organisms must be handled in order to have the cuIture succeed in identifying the bacteria. One can rareIy make a diagnosis of urinary 29
infection when the bacteria cannot be found in the centrifuged specimen. The urine in the femaIe must be coIIected by catheterization; a satisfactory specimen for examination in the maIe is obtained by examination of the second portion of the voided urine. Examination should be made promptly after the urine is obtained. The gross appearance is noted and the pH checked. A centrifuged specimen is then examined for the amount of pus ceIIs and red bIood ceIIs. CrystaIs shouId be noted. A gram stain on the sediment is next done and the number and variety of bacteria noted. The overwheIming majority of bacteria found in urinary tract infection are either grampositive cocci shown in Figure I or gramnegative baciIIi shown in Figure 2. Another Iaboratory examination, necessary antecedent to the proper treatment of patients with urinary tract infection, is the determination of the hydrogen ion concentration or the pH. Many physicians beIieve this to be a diffrcuIt procedure, but modern calorimetric methods have made it very simpIe. Either a few drops of dye may be added to the urine and the coIor compared with a standard chart or dye impregnated paper is saturated with urine and the coIor again compared with a standard. Coccus Infections Treatment. The reIative incidence of coccus and baciIIary infections is shown in TabIe II. It is seen that though the bacihi cause the great majority of urinary tract infections, enough infections due to cocci occur to make their treatment worth considering. The etioIogy of urinary tract infections wiI1 not be discussed here but certainIy foci of infection pIay some part, and especiaIIy is this true in the cocca1 group. We have seen many patients in whom treatment has faiIed unti1 foci were treated. The prostate and cervix must be remembered as such foci.
30
Americun Journal of Surgery
Buchtel,
Treatment
In our hands neoarsphenamine has been the most successful drug for eradicating coccaI infections. Its mode of action is stiI1
FIG. I. Urinary tract infection with gram positive Cocci.
in dispute, but Pace9 beIieves that sufficient arsenic is eIiminated in the urine to produce a bactericida1 effect. CIinicaIIy this is supported by the fact that acidification seems to increase the efficiency of the drug, but it is refuted by evidence that infections THERELATIVE URINE IN
TABLE EFFICIENCYOFTHE
SEDIMENT MAKING
A
AND
THE
DIAGNOSIS
I GRAM'S STAINOF
CULTURE OF
OF
URINARY
THE
THE
URINE
INFECTION
Num. Per Num- Per ber Cent ber Cent ________ Stains and cukures agree. Negative stain and positive cukure. Positive stain and negative culture..
5 rg
79
102
15.6
TotaI.
653
32
158
5.4, 100 I
56.4
30
10.4
92
33.2
! I 280
100
Iimited to the bIadder do not respond as we11 as do those in which the kidneys are aIso involved. The most efficient and best toIerated dosage scheme is to give .2 gm. foIIowed in five to seven days by .3 gm. If no improvement resuIts after these two injections, it is rare for a third dose to
Urinary
Infections
OcXXMl,,937
produce good resuIts. If, however, there is no contraindication or arsenic reaction and if the patient has no demonstrabIe foci a
FIG. Z. Urinary
tract infection with gram negative BaciIIi.
third injection of .4 gm. may be given. We do not beIieve in further injections but turn to other methods of treatment. Acidification and urotropin, the azo dyes and hexyIresorcina1 are sometimes of value. Vaccine therapy, the vaccines being prepared from urine, throat, and prostatic or cervica1 cuItures may succeed when other methods fai1. The use of mandeIic acid and suIfaniIamide wiI1 be discussed Iater. The above pIan of treatment does not hoId for infections with the Streptococcus fecalis as this organism responds poorly to neoarsphenamine. As is seen from Table II, this is a rather common organism (12 per cent). Usually it can be differentiated from the other cocci by microscopic examination, and Figure 3 shows a typica smear of a urinary infection with Streptococcus fecalis. This organism is very resistant to suIfaniIamide treatment but responds we11 to acidification and ketosis or to mandeIic acid. Bacillury Infections. Urinary tract infections due to gram-negative baciIIi respond we11 to acidification and mandelic acid and somewhat better to aIkaIization and suIfaniIamide. Since we beIieve that in the present state of our knowIedge the former is a Iess objectionabIe method of treatment, it
New
SEHIES
VOL. XXXVIII,
No.
1 BuchteI,
Treatment
should as a ruIe be used. WhiIe the ketogenie diet was originalIy conceived as a method of acidification of the urine, it was URINE
CLLTURE
number.
Infections
Anlerican Jourrlnl vr Sul-gcry
3 I
is avaiIabIe in tabIets and capsuIes. Sodium mandeIate seems to cause Iess gastric disturbances than do the ammonium saIts
TABLE II FINDINGS. (FROM CABOT, MODERN UROLOGY, VOL. 11)
Escherichia coli. ...................... Aerobacter aerogenes .................. Proteus ammoniae. ................... Proteus (species?). .................... Pseudomonas aeruginosa ............... Pseudomonas (species?). ............... SaImoneIIa (species?). ................. Alcaligenes (species?). ................. Eberthella typhosa .................... ShigeIIa (species?). .................... Gram-negative baciIIus (unidentified). Streptococcus fecaIis ................... Streptococcus (green producing). ....... Streptococcus (sIight hemoIysis)........ Staphylococcus aureus ................. Micrococcus (species?). ................ Diphtheroids. ........................ Neisseria gonorrhoeae. ................ Total
Urinary
Jurn. ber
Per Sent
490 91 48 9 32 II 12 IO
55.9 10.4 5.5 1.0 3.6 I.2 I.4 I.1 0.2 0.7 2.6 12.0 I.1
:
..
23 105 IO 33 IO
3.8 I.1 15.0
132 4 I
0.4 0. I
877 -
I
soon evident that its effect was more potent than couId be attributed to acidification aIone. FuIIer4 soon found the expIanation for this in the discovery that one of the ketone bodies, betahydroxybutyric acid, had bactericida1 properties. This Ied Rosenheim’O to an intensive investigation of the organicacids in the hope that one of them couId be given by mouth and excreted unchanged in the urine. Mandelic acid was found to meet the requirements most fuIIy and in addition was non-toxic enough so that adequate dosage couId be given to produce a bactericida1 urine. ExperimentaIIy, Osterberg and HeImhoIz7 determined these IeveIs and their resuIts are shown in TabIe III. It wiI1 be noted that Pseudomonas and Aerobacter aerogenes are more resistant to the action of mandeIic acid. In practice we given 12 gm. of ammonium mandeIate daily in divided doses. This can be given in Iiquid form, or for those who object to the taste, the drug
FIG. 3. Urinary tract infection with Streptococcus fecalis. Typically this organism occurs as ova1 cocci joined together by the end with a refractile streak down the center. The former feature is shown in the photomicrograph. The refractile streak is not shown. Sometimes cocci which do not show these characteristics wiI1 prove on culture to be Streptococcus fecalis. If these characteristics are not shown, the organism cannot be differentiated by the stain.
but when this is used, additiona acidification by means of ammonium nitrate or chIoride is usuaIIy necessary. As is seen from TabIe III, the most important factor in the production of bactericidal urine is adequate controI of the acidity. This shouId be checked frequentIy during the course of treatment and be kept, if possible, beIow 5.2. Usually such an acidity can be obtained by the use of the ammonium saIt, but shouId this not occur additiona1 acidification by means of ammonium nitrate, or chloride, diIute hydrochIoric acid or an acid-ash diet is necessary. It is of the utmost importance that the patient take no aIkaIies, of which soda and saline Iaxatives are the most common. Patients in whom acidification is obtained with difflculty should abstain from toothpaste. Even with a11 these precautions, patients wiI1 be encountered in whom proper acidification is impossible. In addition to proper acidification, adequate concentration of the drug is aIso necessary. Since there is no simpIe test for
32
American Journalof
Buchtel,
Surgery
Treatment
the concentration of mandeIic acid in the urine, the test being that for organic acids, the majority of our patients are treated TABLE THEBACTERICIDAL BACTERICIDAL
III*
RANGEOFMANDELIC RANGE
OF MANDELIC
ACID ACID
l.0
Concentration &y$&s3
of mandelic
iFgh&}like
acid
Escherichia
Coli
*From H. F. HeImhoIz and A. E. Osterberg, Rate of excretion and bactericidal power of sulfanitamide in the urine. Proc. Staff Meetings of tbe Mayo Clinic, 12: 377-381 (June 16) 1937.
with this as an unknown factor. If the fluids are limited so that the urinary output is around I ooo C.C. daiIy, adequate concentration wiII develop except when there is poor renaI function. * Excretory urography, since it tests the function of each kidney separateIy, provides a most satisfactory method of determining renaI function when using excretory antiseptics. If the kidney visuaIizes we11 in five minutes after injection of the drug, it has adequate function. It must aIways be remembered that in uniIatera1 kidney disease the bIadder urine may be bactericida1 whiIe urine from the diseased kidney is not. We do not believe that mandeIic acid therapy shouId be continued for more than two weeks. At the end of that time, if improvement has not occurred, the drug is discontinued for a week or ten days. A * Mandelic acid is of great value in the treatment of acute urinary infections. When so used, the fluids must not be Iimited, especiaIIy if there is fever.
Urinary
Infections
OcroeEn.,937
second course may prove more beneficial than the first. MandeIic acid used as has been described wiI1 prove successful in more than go per cent of uncompIicated baciIIary infections, and is about 50 per cent efficacious in baciIIary infections complicated by prostatitis, miId urinary obstruction, or chronic pyeIonephritis without great renaI damage. In our experience the Aerobacter aerogenes responds practicaIIy as we11 as the other baciIIi. FaiIure wiI1 be the rule in the presence of Iithiasis, foreign body, severe urinary obstruction or chronic pyelonephritis with marked renaI destruction.3 CoccaI infections, with the exception of Streptococcus fecaIis, respond but poorIy. Good resuIts, however, are often obtained when the infection is confined to the Iower urinary tract. In resumC then, the cocca1 infections of hematogenous origin seem to respond to neoarsphenamine, whiIe those of ascending origin respond to mandeIic acid. Since the cocca1 infections of chiIdhood are aImost invariabIy of the Iatter type, drugs other than mandelic acid have IittIe pIace. MandeIic acid has IittIe if any effect on norma kidney function. In fact, experimenta1 animaIs show more Iiver than kidney damage. There is no doubt, however, that the drug is a renaI irritant, as it is common to find red bIood ceIIs or casts in the urine of patients under treatment. Gross hematuria is rare. Patients with reduced renal function must be treated with the greatest care, as treatment by acidification runs considerabIe risk of producing acidosis. Such patients must be carefuIIy watched and their bIood chemistry frequentIy checked. Acidification by means of ammonium nitrate is safer for this group than with ammonium chIoride. Gastro-intestina1 upsets are infrequent, as are genera1 toxic disturbances such as tinnitus, vertigo, paIpitation, and dermatitis. Such reactions caI1 for reduction of dosage or discontinuance of the drug. Very
NOW %RIE~VOLXXXVIII. NO.I Buchtel,
Treatment
rareIy these reactions may prove very severe. The most recent drug Suljanilamide. used in urinary tract infections has a Ionger history than either of the previous methods of treatment, as the origina prototype of s.ulfaniIamide was prepared as an azo dye in 1909. Its use in urinary infections, however, has developed within the past year, when many physicians, encouraged by the good results obtained in sepsis elsewhere in the body were led to try it in urinary tract infections. StrangeIy enough it has proved of greater value in bacillary than in coccaI infections. Experience with this drug suggests that it is a more potent antiseptic than mandehc acid. This drug is aIso active in an aIkaIine urine and wil1 deveIop a bactericida1 urine in the presence of marked renaI insuffIciency. It is eIiminated in good concentration in the urine but in poor concentration in. the prostatic secretion.’ In spite of this, a very saIutory effect or prostatitis is noted. Urinary tract infection associated with prostatitis is eradicated as easiIy by suIfaniIamide as other methods of treatment cIear up uncompIicated urinary tract infection. The drug wiI1 not sterilize the urine immediateIy foIIowing prostatic resection, but has been the most successfu1 drug we have to cIear the urine before prostatic surgery. The proteus baciIIus responds as we11 as the other baciIIi. FaiIure usuaIIy resuIts in the presence of Iithiasis or chronic pyeIonephritis with renaI destruction. BaciIIary infections respond better than coccal infections, and especiaIIy does this hoId for Streptococcus fecalis where good results wil1 practicaIIy never be obtained. This has been a most successfu1 method of treatment of gonorrhea of both men and women. From the discussion above, suIfaniIamide wouId seem to be the drug of choice in the treatment of a11 baciIIary infections, and were it not for the frequent reactions which foIIow its use such wouId be the case. While it is unnecessary to produce even the sIightest reaction to obtain a favorabIe
Urinary
Infections
American
Journal
of Surgery:
33
resuIt, it is aImost invariabIe that some malaise, dizziness, and headache develop. If these are reIieved by rest, it is not necessary to reduce the dose. The occurrence of any other reaction caIIs for reduction in dosage or discontinuance of the drug. The number and variety of reactions that can be produced by SuIfaniIamide is Iegion. We consider cyanosis, hemogIobinuria, anemia or Ieukopenia, fever, dermatitis, and jaundice to be serious and call for cessation of treatment. Dermatitis and anemia or Ieukopenia are probabIy good reasons for permanentIy discontinuing the drug. The mode of action of this drug is as yet not we11 understood. ExperimentaIIy, a urine to which SuIfaniIamide has been added wiI1 not have the bactericida1 power of a urine produced in the body containing the same suIfaniIamide concentration.8 ExperimentaIIy the drug seems to work better in a urine of pH of about 7.5, and even though this cannot be supported cIinicaIIy, there is certainIy no objection to giving aIkaIies during treatment. Magnesium sulfate shouId not be given. There is as yet no accepted dosage scheme for this drug. We start with a daiIy dose of 60 to 80 grains in four doses. After one to two days the dose is reduced and after another two days the patient is pIaced on a maintenance dose which is usuaIIy 40 grains daiIy. This is continued for not Ionger than ten days. Patients with gonorrhea, once cIinica1 cure is obtained, are pIaced on a 20 grain daiIy dose for two weeks. Using this dosage scheme we have not seen the frequent recurrence in Neisserian infections that others have reported. In spite of frequent re-examinations after discontinuing the drug, a11 our patients have remained weI1. Our results using this dosage scheme have been so superior to those obtained by smaI1 doses that we pIan to continue its use. Fifteen per cent of patients cannot toIerate this dosage. About 5 per cent wiII either respond to smaI1 doses or can graduaIIy work up to a Iarger
j_$
American
Journal
OC Surgery
dose. The remainder method of treatment.
Buchtel,
arc intoIerant
Treatment to this
Urinary
Infections
prostate must not routine focal check.
be
forgotten
in the
I
SUMMARY
Proper treatment of urinary tract infections depends upon a rough identification of the bacteria in the urine by means of a gram-stain of the centrifuged sediment. Neoarsphenamine is the most efficient drug in the treatment of coccal infections, especiaIIy if these be of the hematogenous origin. Acidification and mandelic acid is a most successful treatment for ordinary baciIIary infections and coccaI infections of the ascending type, especiaIIy Streptococcus fecaIis. SuIfaniIamide shouId be used when mandelic acid faiIs and especiaIIy when acidification of the urine is impossibIe, such as occurs in Proteus infections, or when there is renaI insufficiency. It is aIso the treatment of choice where urinary infection is complicated by marked prostatitis, and in Neisserian infections. Any method of treatment is attended by a high percentage of faiIure in the presence of Iithiasis, chronic pyeIonephritis with marked renaI destruction, or immediateIy foIlowing prostatic surgery. Attention to foci of infection is important not onIy in treatment but aIso in the prevention of recurrences. The cervix and
Oc,naF.H. lo,-
A. and COOK, E. N. The use of sulfanilamide in treatment of urinary infections. Proc. Stu$ Meet. Mqu CLinic, 12: 444-447 (July
I. BUCHTEL,
11.
14) 1937. 2. CLARK, A.
L. Escherichia coli baciIIuria under ketonenic treatment. Proc. Staff .., Meet. IVUVO Clinic, 6: 605608 (Oct. 14) 1931. 3. COOK, E. N. and BUCHTEI.. H. A. Mandelic acid in the treatment of infections of the urinary tract. J. A. M. A., 107: I7gg-1800. 4. FULLER, A. T. The ketogenic diet. Nature of bactericidal agent. Lancer, I : 855-856 (April 22) ‘933.
5. GROSS, S. Zur behandlung der zystopyelitis. Wien. Klin. Wocb., 30: 1381-1384, 1917. 6. HELMHOLZ, H. F. The ketogenic diet in the treatment of pyuria of chiIdren with anomalies of the urinary tract. Proc. Staj’ Meet. Mayo Clinic, 6: 609-613 (Oct. 14) Ig3I. 7. HELMHOLZ, H. F. and OSTERBERG, A. E. Rate of excretion and bactericida1 power of mandelic acid in the urine. J. A. M. A., 107: 1794-1796 (Nov. 28) 1936. 8. HELMHOU, H. F. and OST~RBERG, A. E. Rate of excretion and bactericida1 power of sutfanilamide in the urine. Proc. Staff Meet. Mayo Clinic, 12: 377-381 (June 16) 19x7. g. PACE, J. M. In press. IO. ROSENHEIM, M. L. MandeIic acid in the treatment of Urinary infections. Lancet, I : 1032-1037 (May 4) 1935.
II.
A. T. and JANNEY, J. H. The growth of bacillus coli in urine at varying hydrogen ion concentrations. J. Uroi., I: 21 I-229 (April)
SHOHI.,
1917.
12. SEIDMAN, L. R.,
ELLIS, M. G. and HILL, J. R. A comparative study of direct smear and cultures in three thousand urine specimens. J. Ural., 22: 717-724
(December)
Igzg.