Recurrent Urinary Tract Infections in Men Characteristics and Response to Therapy JAMES W. SMITH, M.D.; STEPHEN R. JONES, M.D.; WILLIAM P. REED, M.D.; ALAN D. TICE, M.D.; ROBERT H. DEUPREE, Ph.D.; and BERTIL KAIJSER, M.D.; Dallas, Texas; Portland, Oregon; Albuquerque, New Mexico; Providence, Rhode Island; West Haven, Connecticut; and Goteborg, Sweden All men with recurrent urinary tract infections entered into a study had a positive antibody-coated bacteria test, and 5 2 % had evidence for prostate infection. Escherichia coli infection was present in 7 4 % and urinary tract symptoms in 5 7 % of those randomized. Thirty-eight patients were randomized in a double-blind clinical trial to receive either 10 d of treatment with trimethoprim/sulfamethoxazole or a 12-week course of the drug. The cure rate in patients receiving 12 weeks of therapy (nine of 15) was higher than that in patients receiving a single 10-d course (three of 15); difference was marginally significant (P = 0.06). Recurrences were usually with the same organism, and most ( 7 8 % ) occurred within 4 weeks of discontinuing therapy. This study indicates that a standard 10-d course of therapy usually fails to cure men with recurrent urinary tract infections with a positive antibody-coated bacteria test.
tests? [2] what is the frequency of prostatic infection? [3] if any patients have infection with no antibody-coated bacteria, can they be treated as successfully with a short course of therapy (3 d) as with the standard 10-d course? and [4] if any patients have an infection with antibodycoated bacteria, can they be treated more successfully with long-term (12 weeks) therapy than with the standard 10-d course? In this study, men from three participating Veterans Administration Medical Centers were enrolled if they met eligibility criteria. Urinary and prostatic localization studies were then done, and patients were randomly assigned to receive varying lengths of therapy with trimethoprim-sulfamethoxazole. This agent was selected because it has been effective against urinary tract and prostatic infection (8, 9).
R E C U R R E N T URINARY TRACT INFECTIONS in men have
not previously been denned as to location of infection (whether upper or lower urinary tract), frequency of prostatic infection, or the relation of these factors to response to therapy. A previous cooperative study by the United States Public Health Service evaluated the effectiveness of chronic suppressive therapy, but the patients were not characterized as to site of infection (1). Although the natural history and therapy of recurrent urinary tract infection have been well studied in women, these observations may not apply to men (2). Localization of infection to the upper or lower urinary tract with the antibody-coated bacteria test has been shown to correlate with a direct localization test, the bladder washout procedure, in patients with urinary tract infection (3, 4). By the use of this noninvasive test, some studies have differentiated patients with upper from those with lower tract infection and have thus determined if it is appropriate to tailor the course of therapy to the site of infection (5). Recent studies, predominantly in women, indicate that treatment of infections involving the bladder can be accomplished with short courses of therapy, whereas patients with upper urinary tract infection may not be cured by the usual 10-d course of antimicrobial therapy (6, 7). A Veterans Administration cooperative study was established to answer a series of questions about recurrent urinary tract infection and its treatment in men: [1] What is the frequency of positive antibody-coated bacteria • From the Veterans Administration Medical Centers, Dallas, Texas, Portland, Oregon, Albuquerque, New Mexico, and Providence, Rhode Island; the Cooperative Studies Program Coordinating Center, West Haven, Connecticut; and the Institute of Medical Microbiology, University of Goteborg, Goteborg, Sweden.
544
Methods PATIENT SCREENING
Men without urethral catheters who were receiving inpatient or outpatient care at the three participating centers were eligible for the study if they had bacteriuria and two previously documented episodes of infection treated with conventional therapy. Bacteriuria was documented by the presence of at least 100 000 colonies per millilitre of an Enterobacteriaceae in two successive urine cultures within a 7-d period. Patients were excluded from the study if they had evidence of liver disease (serum glutamic-oxalacetic transaminase or alkaline phosphatase twice normal), hematopoietic disease (hematocrit < 30%, platelet count < 100 000/mm3, or leukocyte count < 5000/mm3), systemic lupus erythematosus, or any disease with a life expectancy of less than 6 months (comorbidity). They were excluded if they had renal function impairment (serum creatinine greater than 2.1 mg/dL) or evidence of large calculi or obstruction requiring urologic instrumentation or surgery during the study period (paramorbidity). They were also excluded if they were allergic to either sulfonamides or trimethoprim or had a urinary isolate resistant to trimethoprim/sulfamethoxazole (comedication) or if they were either unwilling or unable to be followed for 6 months (compliance). Patients were entered into the study if they were capable of being followed for a 6-month period and were willing to sign an informed consent form. STUDY DESIGN
The patients were initially treated with macrocrystalline nitrofurantoin, 100 mg four times daily for 3 d, after which they underwent a prostatic localization study (10). On the third day of therapy, the first few millilitres of voided urine (VB1) and a clean voided midstream urine (VB2) were obtained. Then a prostatic massage was done to express prostatic secretions. A final voided urine (VB3), which also may contain prostatic bacteria, was then collected. The prostatic localization test was considered interpretable if fewer than 103 organisms per millilitre were present in VB2. Prostate infection was considered present if either express prostatic secretions or VB3 contained at least a tenfold greater bacterial concentration than did VB1.
Annals of Internal Medicine 1979;91:544-548.
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After this localization study, patients were followed biweekly for up to 3 months. Those patients who had a recurrence of bacteriuria after the prostatic localization study were stratified according to presence or absence of prostatic infection. Patients in both groups were randomized to receive either 10 d or 12 weeks of two tablets twice a day (each tablet containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole). This study was conducted under carefully controlled double-blind procedures with all patients receiving therapy for 10 d followed by either active drug or identically appearing placebo tablets to complete 12 weeks of total therapy. Patients were seen at 3, 10, and 14 d after the start of therapy and then biweekly through completion of treatment. At these follow-up visits, clinical observations were made and duplicate urine cultures and laboratory studies obtained. Pills were counted on each visit to ascertain if the medication had been properly taken. Sulfamethoxazole levels were measured at 8 and 10 weeks in those patients receiving the active drug. If bacteriuria recurred (two positive cultures exceeding 100 000 colonies per millilitre), then the double-blind code was broken. If the patient was receiving the study drug, therapy was stopped and the patient was classified as a drug treatment failure. If, however, the patient was receiving placebo, he was retreated with repetitive 10-d courses of drug during the 12-week treatment period so that cure rates could be ascertained for initial and repetitive treatment courses. Patients were seen at 4 d and at 2, 4, 8, and 12 weeks during the 12-week follow-up period. Recurrent infection was considered to be present if duplicate urine cultures showed significant bacteriuria. Statistical analysis was done by Fisher's exact method for 2 x 2 tables. A two-tailed test was used. LABORATORY STUDIES
Laboratory tests (hematocrit, leukocyte count, platelet count, creatinine, alkaline phosphatase, and bilirubin) were evaluated at intervals throughout the study and were repeated if abnormal. If the repeat laboratory value was abnormal, the study drug was withdrawn. Urine was placed on eosin methylene blue and blood agar plates with quantitative cultures done by the pour plate dilution method. Bacteria were classified according to the Analytab Profile Index 20E biotype code (Analytab Products, Plainview, New York) for Enterobacteriaceae (11). Antimicrobial susceptibility testing to trimethoprim/sulfamethoxazole was done by the standardized single-disc diffusion method (12), using Mueller-Hinton agar that contained < 0.3 /xg/mL of thymidine (Baltimore Biological Laboratory; Cockeysville, Maryland). Isolates were considered sensitive if the zone size was greater than 16 mm. Bacteria isolated during therapy that were found to be resistant to the drug were further analyzed by the agar plate dilution method. All Escherichia coli were serotyped using antisera to more than 69 O-antigens, as well as with antisera to the 17 most common K antigens (13, 14). Antibody-coated bacteria tests were done on urine containing a significant count by washing the sediment from 0.5 mL of
Figure 1 . Flow chart for patients admitted to study. All patients randomized to study were antibody coated bacteria (ACB) positive and stratified as to presence of prostate infection. Patients infected were those who either developed infection with a resistant organism or became infected during the follow-up period.
Table 1 . Frequency of Various Organisms by Treatment Group
10 Days
12 Weeks
Total
13 2 1 1 1 1
28 3 2 2 2 1
< Escherichia coli* Citrobacter sp. Klebsiella sp. Enterobacter sp. Proteus mirabilis Proteus rettgeri
15 1 1 1 1 1
* E. coli 018 = six; 06 = five; 04 = four; 075 and 025 = two; 02 and 08 = one; spontaneously agglutinating = three; Non-agglutinating = four.
urine with phosphate-buffered saline and reacting the sediment with fluorescein-conjugated antihuman globulin of horse origin (Roboz Laboratories, Washington, D.C.) for 30 min. at 37 °C (3). The sediment was air-dried on microscope slides and examined with an oil emersion objective using an incident-light fluorescent microscope. Samples were considered to be positive if more than two fluorescent organisms were seen of at least 1000 bacteria observed (up to 200 fields were examined in 5 min.). Aliquots of merthiolate-preserved urine were mailed from the participating laboratories to a central reference laboratory for verification of the test. Results
A total of 306 patients were screened, but 51 (17%) were excluded for comorbidity reasons, 87 (28%) for paramorbidity reasons, 19 (6%) for comedication reasons, 74 (24%) for lack of compliance, and 29 (9%) for miscellaneous reasons. Forty-six (15%) patients were considered eligible for the trial. The median age of the patients entered was 69 years (range, 41 to 88 years). Coexisting medical disorders were present in 29, including 11 with diabetes mellitus, nine with hypertension, and 14 with miscellaneous coexisting disorders including cardiac or pulmonary disease. Thirteen of the patients had complicating urinary tract conditions, including small renal calculi in five, prostatic malignancy in four, mild prostatic obstruction in three, and neurogenic bladder in one. The postvoiding cystogram showed significant residual in 14, bladder mucosal defects in three, and bladder neck obstruction in two. All patients entered into the study had a positive antibody-coated bacteria test, and in 95% of the patients, greater than 25% of the organisms fluoresced (3). There was 100% agreement between the three participating laboratories and the central reference laboratory on specimens submitted within 10 d to the reference laboratory. One patient had fewer than 1% organisms positive on repeated testing, and bladder washout studies revealed evidence of upper tract infection. Prostatic localization was successful in 42 of the patients (Figure 1). It was unsuccessful in three patients who had an organism resistant to nitrofurantoin and in one patient who failed to take the drug. Prostatic secretions were positive for bacteria in 22 of 42 patients tested. Four patients were not randomized after the prostatic localization test: One developed another illness, one had no recurrence, one had an infection with multiple organisms, and one failed to return for follow-up. Of the remaining 38 patients randomized to the clinical trial, E. coli infection was present in 28 (Table 1). Twenty-one of Smith eta/. • Recurrent Urinary Tract Infections
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545
Table 2. Patient Course During Therapeutic Trial and Follow-Up Period
10 Days
12 Weeks
Total
Randomized Dropped from study Inadequate trial Entered in error Drug toxicity
20 3 2 1 2
18 2 1 1 1
38 5 3 2 3
Total for analysis Infection with resistant organism Treatment failure* Curef
15
15
30
2 10 3
1 5 9
3 15 12
* Defined as recurrent infection during follow-up period, t Defined as free of infection during follow-up period.
the strains were typable for an O antigen, three agglutinated spontaneously, and four had no identifiable O antigen. Twelve had a K antigen identified. Certain combinations of O and K antigens were prevalent: 0 1 8 K l in four and 0 6 K2 and 0 4 K12 in three each. Urinary tract symptoms were present in 57% of those randomized for trial. The most frequent symptoms were dysuria and urinary urgency, whereas flank pain, fever, or chills were infrequently noted (less than 10%). All but two had pyuria on microscopic examination of urine. Five of the randomized patients were dropped from the study, three from the 10-d group and two from the 12week group: Two had intercurrent diseases that prevented continued participation, one failed to return, and two were entered improperly (platelet counts below 100 0 0 0 / mm 3 before entry) (Table 2). Four of the 17 patients treated for 10 d did not complete the 12-week treatment period: Two had drug toxicity (abnormal liver function and gastrointestinal disturbance), and two had infection with an organism resistant to trimethoprim/sulfamethoxazole. Two of the 16 treated for 12 weeks did not complete the 12-week period: One had drug toxicity (slight drop in the leukocyte count), and another had infection with a resistant organism. The three patients who developed infection with a resistant organism had n o n - £ coli infections, and the new organism was a different biotype than the original infecting organism in two of these three. Eight patients randomized to the 10-d trial had recurrence of infection and thus received repeat 10-d courses of trimethoprim/sulfamethoxazole during the first 3 months of study. Four of these patients were retreated one time and four twice. Pill counts showed that patients had taken their pills regularly; all patients receiving the active drug had measurable levels of sulfamethoxazole at 8 and 10 weeks of therapy. Effectiveness of therapy was analyzed for the 27 patients who were seen in the follow-up period and the three patients who developed infection with resistant organisms. Three of 15 were free of infection after a single course of therapy in the 10-d group compared with nine of 15 in the 12-week group (Table 2, Figure 1). This large observed difference in cure rate was marginally significant (P = 0.06). Only one additional patient who received a repeat 10-d course was free of infection during 5 4 6
October 1979
the follow-up period. Analysis of treatment success for all those taking the drug (including patients retreated, those dropped due to drug toxicity, and those who developed infections with organisms resistant to trimethoprim/sulfamethoxazole) showed that five of 17 randomized to the 10-d course were successfully treated (one patient who developed drug toxicity was free of infection at the end of 24 weeks) and nine of 16 randomized to the 12-week course were free of infection. Other ways of categorizing the patients and observed differences in response rates are shown in Table 3. N o significant differences were noted, although the presence of residual excretion on postvoiding cystogram approached significance. All but two of the patients with residual excretion were randomized to the 10-d trial group. Most infections recurred within 1 month of discontinuing the active drug: four of five recurrences in the 12week treatment group and 17 of 22 recurrences after 10-d courses of therapy were within 4 weeks (including 12 retreatment periods). Thus, 78% of all recurrences were within 4 weeks. Recurrences of E. coli infection were always with the same biotype and the same serotype if the strain was typeable. Non-ii. coli infections were with the same biotype in three of four recurrences. The organism changed in one instance from Citrobacter to Klebsiella. Recurrences more than 4 weeks after discontinuation of therapy were with the same organism in five of six instances. Recurrences were asymptomatic 80% of the time. Discussion
This study was initiated to define the characteristics of recurrent bacteriuria in men and to evaluate the effectiveness of treatment with trimethoprim/sulfamethoxazole. That 306 men with chronic recurrent bacteriuria were screened in 21 months in three participating Veterans Administration Medical Centers indicates this condition is not uncommon. However, the patients frequently had Table 3. Effectiveness of Therapy by Various Categories*
Free of Infection
Infec- Success tion
%
no. Duration of therapy 10 d 12 weeks Prostate status Infected Not infected Infecting organism Won-Escherichia coli E. coli Post voiding residual Increased Normal
Significance!
3 9
12 6
20 60
P = 0.06
(NS)
4 8
10 8
29 50
P = 0.28
(NS)
2 10
7 11
22 48
P = 0.25
(NS)
1 11
7 11
12 50
P = 0.10
(NS)
* Includes those infected during follow-up period and those infected with resistant organism. t Statistical test of significance was Fisher's exact test for 2 X 2 tables, twotailed. NS = not significant.
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other significant health problems—diseases of the urinary tract or diseases not related to the urinary tract—that would have hampered clinical and laboratory assessment of response to therapy. Thus, the population accepted for study represented those men with documented recurrent bacteriuria who were sufficiently stable to warrant a 6month trial. They were generally older men with chronic disorders such as diabetes mellitus and hypertension. Slightly more than one half were asymptomatic at presentation. All but two had pyuria. Recurrent bacteriuria in men was exclusively associated with a positive antibody-coated bacteria test, shown to be a sensitive and specific test with a high predictive value for upper tract infection in adults (15). In this study, the high degree of accuracy of reading the test at each hospital was established, since positive tests were confirmed by the central reference laboratory. We cannot be certain that the presence of antibody-coated bacteria represents upper tract infection in all of the men studied, since infected prostatic fluid could have released coated bacteria into the urine (16). The number of organisms in prostatic secretions, however, was too few to be seen microscopically in many patients, suggesting that the many fluorescing organisms usually seen in the urine represented organisms from the upper urinary tract. In this study, we did not do another localization test (such as a bladder washout test) except in the single patient with fewer than 1 % organisms and with evidence for upper tract infection by this test. In an earlier study, six of seven men with recurrent urinary tract infection and with positive antibody-coated bacteria tests had upper tract infections (as determined by bladder washout test) even in the presence of prostate infections (JONES SR. Unpublished.). A positive antibody-coated bacteria test in men likely indicates infection either of the kidney or the prostate and probably represents antibody formed locally in response to infection (17). About one half of men with recurrent bacteriuria had an identifiable prostate infection. Our study showed that segmented urine collection and prostatic massage after 3 d of therapy was practical for ascertaining the presence of bacteria in the prostatic fluid. Initial infections with E. coli were predominantly with serotypes (02, 04, 06, 18, 25, 75) that have been commonly found in other studies of urinary tract infection (18). Fewer than one half of the strains had K antigens and less than 20% were K l positive, which has been postulated to be a significant determinant of upper tract infection (19). The common association of certain O-K combinations, as noted in this study for 0 1 8 K l , 0 4 K12, and 0 6 K2, has been previously reported (19). It remains unclear why certain E. coli strains are more likely to be associated with upper tract infection. There was no propensity for men with asymptomatic bacteriuria to have a high frequency of spontaneously agglutinating strains, as had been found in children (20). This study provides evidence that a single 10-d course of therapy achieves few cures (20%), and the higher observed success rate (60%) with continuous 12-week therapy was marginally significant ( P = 0 . 0 6 ) . Even repetitive
use of the 10-d courses of trimethoprim/sulfamethoxazole therapy for urinary tract infection led to a low success rate in men (27%) with recurrent urinary tract infections. A much higher recurrence rate has been reported in women with upper tract infection than in those with lower tract infection (7). Hence, in both men and women, a positive antibody-coated bacteria test appears to select those persons who are likely to have a recurrence after a 10-d course of therapy. Therapy of those patients with significant residual on a postvoiding cystogram also appears to be relatively ineffective (12% success), especially if the 10-d course is given. Recurrences were more frequent in those patients with prostatic infection (29% success) than in those without prostatic involvement (50% success), but the difference was not statistically significant. One might expect that the differences would be greater if we had used a drug less effective for the prostate infections. Recurrences were usually with the same organism, either the same serotype if E. coli or the same biotype if another organism. This confirms that recurrences of urinary tract infection in men with a positive antibody-coated bacteria test are with the initially infecting organism and generally occur within 4 weeks of discontinuing therapy, as was noted in women with upper tract infection (5). These recurrences were rarely symptomatic, even in those with symptoms during the initial infection. Our study provides information that can be used in developing a rational approach for treatment of men with chronic bacteriuria: [1] Men are likely to have infection with antibody-coated bacteria with or without a prostatic focus; [2] it is important to ascertain if the patient has significant residual urine before therapy, since it is unlikely that a short course of therapy will be successful in those with significant retention of urine. It may also be useful to ascertain if prostatic infection is present; [3] the commonly used 10-d course of therapy has a low probability of eradicating the infection. Microbiologic followup at 1 month after completion of therapy is essential, whether the patient is symptomatic or not, if determination of bacteriuria eradication is desired; and [4] administration of trimethoprim/sulfamethoxazole for 12 weeks appears to be a reasonably safe and relatively effective course of therapy in men with urinary tract infection. Thus, further evaluation of long-term administration of effective agents is needed in men with chronic recurrent urinary tract infections because recurrences are frequent. At present, long-term administration of any agent requires informed consent and close follow-up. Alternatively, prophylaxis or long-term suppression with lowdose trimethoprim/sulfamethoxazole or other agents after eradication of infection with usual courses of therapy may have merit in men as well as in women with recurrent infection (21). The long-term benefits of treating asymptomatic, chronic recurrent bacteriuria in men have not been adequately studied. Kass (22) has suggested that such studies may not be feasible due to the large number of patients that may need to be entered to determine significance. Our study, however, indicates that it is possible to eradicate such infections in some men. Smith eta/. • Recurrent Urinary Tract Infections
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547
A C K N O W L E D G M E N T S : This work was funded by the Veterans Administration Cooperative Studies Program of Medical Research Service. The Veterans Administration Cooperative Study includes the following—James W. Smith, M.D. (Chairman), Waudelle E. Strickley (Secretary), Ralph M. Martin (Technician), Dallas, Texas; Participants (stations, participating investigators, secretaries, nurses, and laboratory technicians) in Albuquerque, NM: William Reed, M.D., Matty Weatherby, Windy Pierce, Eileen Sierra; Portland, OR: Stephen R. Jones, M.D., Velda Bevel, Meredith Amon, Kate Patrick; Providence, RI: Alan Tice, M.D., Joan Spraque, Virginia Diaz, Alton Barney; Executive Committee: William Reed, M.D., Albuquerque, NM; James W. Smith, M.D., Dallas, TX; Stephen R. Jones, M.D., Portland, OR; Alan Tice, M.D., Providence, RI; Robert H. Deupree, Ph.D., West Haven, CT; Biostatistics and Research Data Processing (West Haven Cooperative Studies Program Coordinating Center), Study Biostatistician: Robert H. Deupree, Ph.D.; Programmer: Nic Kormanik, M.S.; Statistical Assistants: Jo-Anne Falcigno, B.S., Raymond Kilstrom, M.BA.; Keypunch Operators: Stella Marcinauskis, Velma Williams; Operations Committee: C.E. Cox, II, M.D. (Chairman), Memphis, TN; Kenneth L. Vosti, M.D., Palo Alto, CA; Polly Feigl, Ph.D., Seattle, WA; Human Rights Committee: Mrs. Priscilla Fehm, R.N. (Chairman), West Haven, CT; Jack Evans, Esq., New Haven, CT; Rev. David A. Buehler, West Haven, CT; Sister Barbara A. Kathe, West Hartford, CT; Mr. Edward Grant, New Haven, CT; and Central Administration Cooperative Studies Program: James A. Hagans, M.D., Ph.D., Chief; Ping C. Huang, Ph.D., Staff Assistant; Mrs. Helen G. Bickley, Administrative Aide for Travel and Budget; Mrs. Freda Cherry, Administrative Aide for Budget Control; Mr. Dennis Gilliland, Administrative Aide for Planning and Evaluation; Ywick-Kwong Chan, Ph.D., Chief, Cooperative Studies Program Coordinating Center; Michael Sather, Chief, CSPRP. The investigators thank Hoffmann-LaRoche Inc., Nutley, New Jersey, and Burroughs Wellcome Co., Research Triangle Park, North Carolina, for their kind support. • Requests for reprints should be addressed to James W. Smith, M.D.; Infectious Disease Section ( H I D ) , Veterans Administration Medical Center, 4500 South Lancaster Road; Dallas, TX 75216. Received 11 May 1979; revision accepted 31 May 1979.
References 1. F R E E M A N RB, S M I T H WM, R I C H A R D S O N JA, et al. Long-term therapy
for chronic bacteriuria in men: U.S. Public Health Service cooperative study. Ann Intern Med. 1975;83:133-47. 2. STAMEY TA, G O V A N DE, P A L M E R JM: The localization and treatment
of urinary tract infections: the role of bactericidal urine levels as opposed to serum levels. Medicine (Baltimore). 1965;44:1-36. 3. T H O M A S V, SHELOKOV A, F O R L A N D M: Antibody-coated bacteria in
the urine and the site of urinary-tract infection. TV Engl J Med. 1974;290:588-90.
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4. J O N E S SR, S M I T H JW, SANFORD JP. Localization of urinary-tract infec-
tions by detection of antibody-coated bacteria in urine sediment. N Engl J Med. 1974;290:591-3. 5. T U R C K M, R O N A L D AR, P E T E R S D O R F RG. Relapse and reinfection in
chronic bacteriuria: II. The correlation between site of infection and pattern of recurrence in chronic bacteriuria. N Engl J Med. 1968;278:422-7. 6. R O N A L D AR, BOUTROS P, M O U R T A D A H. Bacteriuria localization and
response to single-dose therapy in women. JAMA 1976;235:1854-6. 7. F A N G LST, TOLKOFF-RUBIN R H . Efficacy of single-dose and conventional amoxicillin therapy in urinary-tract infection localized by the antibody-coated bacteria technic. N EnglJ Med. 1978;298:413-6. 8. G L E C K M A N RA. A cooperative controlled study of the use of trimethoprim/sulfamethoxazole in chronic urinary tract infections. / Infect Dis. 1973;128(suppl):S647-51. 9. D R A C H GW. Trimethoprim/sulfamethoxazole therapy of chronic bacterial prostatitis. J Urol. 1974;111:637-9. 10. STAMEY TA. Diagnosis of bacteriuria. In: Urinary Infections. Baltimore: The Williams and Wilkins Company; 1973;24-25. 11. S M I T H PB, T O M F O H R D E K M , R H O D E N DL, et al. API system: a multi-
tude micromethod for identification of Enterobacteriaceae. Appl biol. 1972;24:449-52.
Micro-
12. B A U E R AW, K I R B Y W M M , SHERRIS JC, et al. Antibiotic susceptibility
testing by a standardized single disk method. Am J Clin 1966;45:493-6.
Pathol.
13. L I D I N - J A N S O N G, F A L S E N E, J O D A L U, K A I J S E R B, L I N C O L N K. Char-
acteristics of antibiotic-resistant Escherichia coli in the rectum of healthy school children. J Med Microbiol. 1977;10:299-308. 14. KAIJSER B. A simple method for typing of acidic polysaccharide K antigens of Escherichia coli. FEBS Microbiol Lett. 1977;1:285-8. 15. JONES SR. The current status of urinary tract infection localization by the detection of antibody-coated bacteria in the urine sediment. In: G I L BERT D, ed. Infectious Diseases. Current Topics, vol. 1. New York: Grune and Stratton; 1979. 16. JONES SR. Prostatitis as cause of antibody-coated bacteria in urine. TV EnglJ Med. 1974;291:365. Letter. 17. S M I T H JW, J O N E S SR, K A I J S E R B. Significance of antibody-coated bac-
teria in urinary sediment in experimental pyelonephritis. J Infect Dis. 1977;135:577-81. 18. HOLMGREN J, SMITH JW. Immunological aspects of urinary tract infections. Prog Allergy. 1975;18:289-352. 19. KAIJSER B. Immunology of Escherichia coli: K antigen and its relation to urinary-tract infection. J Infect Dis. 1973;127:670-7. 20.
H A N S O N LA, A H L S T E D T S, J O D A L U, et al. The host-parasite relation-
ship in urinary tract infections. Kidney Int [supplj. 1975;8:S28-34. 21. STAMEY TA, C O N D Y M, M I H A R A G. Prophylactic efficacy of nitrofu-
rantoin macrocrystals and trimethoprim-sulfamethoxazole in urinary infections. TV Engl J Med. 1977;296:780-3. 22. K A S S EH. Should bacteriuria be treated? Med J Aust. 1973;1:538-43.
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tests? [2] what is the frequency of prostatic infection? [3] if any patients have infection with no antibody-coated bacteria, can they be treated as successfully with a short course of therapy (3 d) as with the standard 10-d course? and [4] if any patients have an infection with antibodycoated bacteria, can they be treated more successfully with long-term (12 weeks) therapy than with the standard 10-d course? In this study, men from three participating Veterans Administration Medical Centers were enrolled if they met eligibility criteria. Urinary and prostatic localization studies were then done, and patients were randomly assigned to receive varying lengths of therapy with trimethoprim-sulfamethoxazole. This agent was selected because it has been effective against urinary tract and prostatic infection (8, 9).
R E C U R R E N T URINARY TRACT INFECTIONS in men have
not previously been denned as to location of infection (whether upper or lower urinary tract), frequency of prostatic infection, or the relation of these factors to response to therapy. A previous cooperative study by the United States Public Health Service evaluated the effectiveness of chronic suppressive therapy, but the patients were not characterized as to site of infection (1). Although the natural history and therapy of recurrent urinary tract infection have been well studied in women, these observations may not apply to men (2). Localization of infection to the upper or lower urinary tract with the antibody-coated bacteria test has been shown to correlate with a direct localization test, the bladder washout procedure, in patients with urinary tract infection (3, 4). By the use of this noninvasive test, some studies have differentiated patients with upper from those with lower tract infection and have thus determined if it is appropriate to tailor the course of therapy to the site of infection (5). Recent studies, predominantly in women, indicate that treatment of infections involving the bladder can be accomplished with short courses of therapy, whereas patients with upper urinary tract infection may not be cured by the usual 10-d course of antimicrobial therapy (6, 7). A Veterans Administration cooperative study was established to answer a series of questions about recurrent urinary tract infection and its treatment in men: [1] What is the frequency of positive antibody-coated bacteria • From the Veterans Administration Medical Centers, Dallas, Texas, Portland, Oregon, Albuquerque, New Mexico, and Providence, Rhode Island; the Cooperative Studies Program Coordinating Center, West Haven, Connecticut; and the Institute of Medical Microbiology, University of Goteborg, Goteborg, Sweden.
544
Methods PATIENT SCREENING
Men without urethral catheters who were receiving inpatient or outpatient care at the three participating centers were eligible for the study if they had bacteriuria and two previously documented episodes of infection treated with conventional therapy. Bacteriuria was documented by the presence of at least 100 000 colonies per millilitre of an Enterobacteriaceae in two successive urine cultures within a 7-d period. Patients were excluded from the study if they had evidence of liver disease (serum glutamic-oxalacetic transaminase or alkaline phosphatase twice normal), hematopoietic disease (hematocrit < 30%, platelet count < 100 000/mm3, or leukocyte count < 5000/mm3), systemic lupus erythematosus, or any disease with a life expectancy of less than 6 months (comorbidity). They were excluded if they had renal function impairment (serum creatinine greater than 2.1 mg/dL) or evidence of large calculi or obstruction requiring urologic instrumentation or surgery during the study period (paramorbidity). They were also excluded if they were allergic to either sulfonamides or trimethoprim or had a urinary isolate resistant to trimethoprim/sulfamethoxazole (comedication) or if they were either unwilling or unable to be followed for 6 months (compliance). Patients were entered into the study if they were capable of being followed for a 6-month period and were willing to sign an informed consent form. STUDY DESIGN
The patients were initially treated with macrocrystalline nitrofurantoin, 100 mg four times daily for 3 d, after which they underwent a prostatic localization study (10). On the third day of therapy, the first few millilitres of voided urine (VB1) and a clean voided midstream urine (VB2) were obtained. Then a prostatic massage was done to express prostatic secretions. A final voided urine (VB3), which also may contain prostatic bacteria, was then collected. The prostatic localization test was considered interpretable if fewer than 103 organisms per millilitre were present in VB2. Prostate infection was considered present if either express prostatic secretions or VB3 contained at least a tenfold greater bacterial concentration than did VB1.
Annals of Internal Medicine 1979;91:544-548.
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After this localization study, patients were followed biweekly for up to 3 months. Those patients who had a recurrence of bacteriuria after the prostatic localization study were stratified according to presence or absence of prostatic infection. Patients in both groups were randomized to receive either 10 d or 12 weeks of two tablets twice a day (each tablet containing 80 mg of trimethoprim and 400 mg of sulfamethoxazole). This study was conducted under carefully controlled double-blind procedures with all patients receiving therapy for 10 d followed by either active drug or identically appearing placebo tablets to complete 12 weeks of total therapy. Patients were seen at 3, 10, and 14 d after the start of therapy and then biweekly through completion of treatment. At these follow-up visits, clinical observations were made and duplicate urine cultures and laboratory studies obtained. Pills were counted on each visit to ascertain if the medication had been properly taken. Sulfamethoxazole levels were measured at 8 and 10 weeks in those patients receiving the active drug. If bacteriuria recurred (two positive cultures exceeding 100 000 colonies per millilitre), then the double-blind code was broken. If the patient was receiving the study drug, therapy was stopped and the patient was classified as a drug treatment failure. If, however, the patient was receiving placebo, he was retreated with repetitive 10-d courses of drug during the 12-week treatment period so that cure rates could be ascertained for initial and repetitive treatment courses. Patients were seen at 4 d and at 2, 4, 8, and 12 weeks during the 12-week follow-up period. Recurrent infection was considered to be present if duplicate urine cultures showed significant bacteriuria. Statistical analysis was done by Fisher's exact method for 2 x 2 tables. A two-tailed test was used. LABORATORY STUDIES
Laboratory tests (hematocrit, leukocyte count, platelet count, creatinine, alkaline phosphatase, and bilirubin) were evaluated at intervals throughout the study and were repeated if abnormal. If the repeat laboratory value was abnormal, the study drug was withdrawn. Urine was placed on eosin methylene blue and blood agar plates with quantitative cultures done by the pour plate dilution method. Bacteria were classified according to the Analytab Profile Index 20E biotype code (Analytab Products, Plainview, New York) for Enterobacteriaceae (11). Antimicrobial susceptibility testing to trimethoprim/sulfamethoxazole was done by the standardized single-disc diffusion method (12), using Mueller-Hinton agar that contained < 0.3 /xg/mL of thymidine (Baltimore Biological Laboratory; Cockeysville, Maryland). Isolates were considered sensitive if the zone size was greater than 16 mm. Bacteria isolated during therapy that were found to be resistant to the drug were further analyzed by the agar plate dilution method. All Escherichia coli were serotyped using antisera to more than 69 O-antigens, as well as with antisera to the 17 most common K antigens (13, 14). Antibody-coated bacteria tests were done on urine containing a significant count by washing the sediment from 0.5 mL of
Figure 1 . Flow chart for patients admitted to study. All patients randomized to study were antibody coated bacteria (ACB) positive and stratified as to presence of prostate infection. Patients infected were those who either developed infection with a resistant organism or became infected during the follow-up period.
Table 1 . Frequency of Various Organisms by Treatment Group
10 Days
12 Weeks
Total
13 2 1 1 1 1
28 3 2 2 2 1
< Escherichia coli* Citrobacter sp. Klebsiella sp. Enterobacter sp. Proteus mirabilis Proteus rettgeri
15 1 1 1 1 1
* E. coli 018 = six; 06 = five; 04 = four; 075 and 025 = two; 02 and 08 = one; spontaneously agglutinating = three; Non-agglutinating = four.
urine with phosphate-buffered saline and reacting the sediment with fluorescein-conjugated antihuman globulin of horse origin (Roboz Laboratories, Washington, D.C.) for 30 min. at 37 °C (3). The sediment was air-dried on microscope slides and examined with an oil emersion objective using an incident-light fluorescent microscope. Samples were considered to be positive if more than two fluorescent organisms were seen of at least 1000 bacteria observed (up to 200 fields were examined in 5 min.). Aliquots of merthiolate-preserved urine were mailed from the participating laboratories to a central reference laboratory for verification of the test. Results
A total of 306 patients were screened, but 51 (17%) were excluded for comorbidity reasons, 87 (28%) for paramorbidity reasons, 19 (6%) for comedication reasons, 74 (24%) for lack of compliance, and 29 (9%) for miscellaneous reasons. Forty-six (15%) patients were considered eligible for the trial. The median age of the patients entered was 69 years (range, 41 to 88 years). Coexisting medical disorders were present in 29, including 11 with diabetes mellitus, nine with hypertension, and 14 with miscellaneous coexisting disorders including cardiac or pulmonary disease. Thirteen of the patients had complicating urinary tract conditions, including small renal calculi in five, prostatic malignancy in four, mild prostatic obstruction in three, and neurogenic bladder in one. The postvoiding cystogram showed significant residual in 14, bladder mucosal defects in three, and bladder neck obstruction in two. All patients entered into the study had a positive antibody-coated bacteria test, and in 95% of the patients, greater than 25% of the organisms fluoresced (3). There was 100% agreement between the three participating laboratories and the central reference laboratory on specimens submitted within 10 d to the reference laboratory. One patient had fewer than 1% organisms positive on repeated testing, and bladder washout studies revealed evidence of upper tract infection. Prostatic localization was successful in 42 of the patients (Figure 1). It was unsuccessful in three patients who had an organism resistant to nitrofurantoin and in one patient who failed to take the drug. Prostatic secretions were positive for bacteria in 22 of 42 patients tested. Four patients were not randomized after the prostatic localization test: One developed another illness, one had no recurrence, one had an infection with multiple organisms, and one failed to return for follow-up. Of the remaining 38 patients randomized to the clinical trial, E. coli infection was present in 28 (Table 1). Twenty-one of Smith eta/. • Recurrent Urinary Tract Infections
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Table 2. Patient Course During Therapeutic Trial and Follow-Up Period
10 Days
12 Weeks
Total
Randomized Dropped from study Inadequate trial Entered in error Drug toxicity
20 3 2 1 2
18 2 1 1 1
38 5 3 2 3
Total for analysis Infection with resistant organism Treatment failure* Curef
15
15
30
2 10 3
1 5 9
3 15 12
* Defined as recurrent infection during follow-up period, t Defined as free of infection during follow-up period.
the strains were typable for an O antigen, three agglutinated spontaneously, and four had no identifiable O antigen. Twelve had a K antigen identified. Certain combinations of O and K antigens were prevalent: 0 1 8 K l in four and 0 6 K2 and 0 4 K12 in three each. Urinary tract symptoms were present in 57% of those randomized for trial. The most frequent symptoms were dysuria and urinary urgency, whereas flank pain, fever, or chills were infrequently noted (less than 10%). All but two had pyuria on microscopic examination of urine. Five of the randomized patients were dropped from the study, three from the 10-d group and two from the 12week group: Two had intercurrent diseases that prevented continued participation, one failed to return, and two were entered improperly (platelet counts below 100 0 0 0 / mm 3 before entry) (Table 2). Four of the 17 patients treated for 10 d did not complete the 12-week treatment period: Two had drug toxicity (abnormal liver function and gastrointestinal disturbance), and two had infection with an organism resistant to trimethoprim/sulfamethoxazole. Two of the 16 treated for 12 weeks did not complete the 12-week period: One had drug toxicity (slight drop in the leukocyte count), and another had infection with a resistant organism. The three patients who developed infection with a resistant organism had n o n - £ coli infections, and the new organism was a different biotype than the original infecting organism in two of these three. Eight patients randomized to the 10-d trial had recurrence of infection and thus received repeat 10-d courses of trimethoprim/sulfamethoxazole during the first 3 months of study. Four of these patients were retreated one time and four twice. Pill counts showed that patients had taken their pills regularly; all patients receiving the active drug had measurable levels of sulfamethoxazole at 8 and 10 weeks of therapy. Effectiveness of therapy was analyzed for the 27 patients who were seen in the follow-up period and the three patients who developed infection with resistant organisms. Three of 15 were free of infection after a single course of therapy in the 10-d group compared with nine of 15 in the 12-week group (Table 2, Figure 1). This large observed difference in cure rate was marginally significant (P = 0.06). Only one additional patient who received a repeat 10-d course was free of infection during 5 4 6
October 1979
the follow-up period. Analysis of treatment success for all those taking the drug (including patients retreated, those dropped due to drug toxicity, and those who developed infections with organisms resistant to trimethoprim/sulfamethoxazole) showed that five of 17 randomized to the 10-d course were successfully treated (one patient who developed drug toxicity was free of infection at the end of 24 weeks) and nine of 16 randomized to the 12-week course were free of infection. Other ways of categorizing the patients and observed differences in response rates are shown in Table 3. N o significant differences were noted, although the presence of residual excretion on postvoiding cystogram approached significance. All but two of the patients with residual excretion were randomized to the 10-d trial group. Most infections recurred within 1 month of discontinuing the active drug: four of five recurrences in the 12week treatment group and 17 of 22 recurrences after 10-d courses of therapy were within 4 weeks (including 12 retreatment periods). Thus, 78% of all recurrences were within 4 weeks. Recurrences of E. coli infection were always with the same biotype and the same serotype if the strain was typeable. Non-ii. coli infections were with the same biotype in three of four recurrences. The organism changed in one instance from Citrobacter to Klebsiella. Recurrences more than 4 weeks after discontinuation of therapy were with the same organism in five of six instances. Recurrences were asymptomatic 80% of the time. Discussion
This study was initiated to define the characteristics of recurrent bacteriuria in men and to evaluate the effectiveness of treatment with trimethoprim/sulfamethoxazole. That 306 men with chronic recurrent bacteriuria were screened in 21 months in three participating Veterans Administration Medical Centers indicates this condition is not uncommon. However, the patients frequently had Table 3. Effectiveness of Therapy by Various Categories*
Free of Infection
Infec- Success tion
%
no. Duration of therapy 10 d 12 weeks Prostate status Infected Not infected Infecting organism Won-Escherichia coli E. coli Post voiding residual Increased Normal
Significance!
3 9
12 6
20 60
P = 0.06
(NS)
4 8
10 8
29 50
P = 0.28
(NS)
2 10
7 11
22 48
P = 0.25
(NS)
1 11
7 11
12 50
P = 0.10
(NS)
* Includes those infected during follow-up period and those infected with resistant organism. t Statistical test of significance was Fisher's exact test for 2 X 2 tables, twotailed. NS = not significant.
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other significant health problems—diseases of the urinary tract or diseases not related to the urinary tract—that would have hampered clinical and laboratory assessment of response to therapy. Thus, the population accepted for study represented those men with documented recurrent bacteriuria who were sufficiently stable to warrant a 6month trial. They were generally older men with chronic disorders such as diabetes mellitus and hypertension. Slightly more than one half were asymptomatic at presentation. All but two had pyuria. Recurrent bacteriuria in men was exclusively associated with a positive antibody-coated bacteria test, shown to be a sensitive and specific test with a high predictive value for upper tract infection in adults (15). In this study, the high degree of accuracy of reading the test at each hospital was established, since positive tests were confirmed by the central reference laboratory. We cannot be certain that the presence of antibody-coated bacteria represents upper tract infection in all of the men studied, since infected prostatic fluid could have released coated bacteria into the urine (16). The number of organisms in prostatic secretions, however, was too few to be seen microscopically in many patients, suggesting that the many fluorescing organisms usually seen in the urine represented organisms from the upper urinary tract. In this study, we did not do another localization test (such as a bladder washout test) except in the single patient with fewer than 1 % organisms and with evidence for upper tract infection by this test. In an earlier study, six of seven men with recurrent urinary tract infection and with positive antibody-coated bacteria tests had upper tract infections (as determined by bladder washout test) even in the presence of prostate infections (JONES SR. Unpublished.). A positive antibody-coated bacteria test in men likely indicates infection either of the kidney or the prostate and probably represents antibody formed locally in response to infection (17). About one half of men with recurrent bacteriuria had an identifiable prostate infection. Our study showed that segmented urine collection and prostatic massage after 3 d of therapy was practical for ascertaining the presence of bacteria in the prostatic fluid. Initial infections with E. coli were predominantly with serotypes (02, 04, 06, 18, 25, 75) that have been commonly found in other studies of urinary tract infection (18). Fewer than one half of the strains had K antigens and less than 20% were K l positive, which has been postulated to be a significant determinant of upper tract infection (19). The common association of certain O-K combinations, as noted in this study for 0 1 8 K l , 0 4 K12, and 0 6 K2, has been previously reported (19). It remains unclear why certain E. coli strains are more likely to be associated with upper tract infection. There was no propensity for men with asymptomatic bacteriuria to have a high frequency of spontaneously agglutinating strains, as had been found in children (20). This study provides evidence that a single 10-d course of therapy achieves few cures (20%), and the higher observed success rate (60%) with continuous 12-week therapy was marginally significant ( P = 0 . 0 6 ) . Even repetitive
use of the 10-d courses of trimethoprim/sulfamethoxazole therapy for urinary tract infection led to a low success rate in men (27%) with recurrent urinary tract infections. A much higher recurrence rate has been reported in women with upper tract infection than in those with lower tract infection (7). Hence, in both men and women, a positive antibody-coated bacteria test appears to select those persons who are likely to have a recurrence after a 10-d course of therapy. Therapy of those patients with significant residual on a postvoiding cystogram also appears to be relatively ineffective (12% success), especially if the 10-d course is given. Recurrences were more frequent in those patients with prostatic infection (29% success) than in those without prostatic involvement (50% success), but the difference was not statistically significant. One might expect that the differences would be greater if we had used a drug less effective for the prostate infections. Recurrences were usually with the same organism, either the same serotype if E. coli or the same biotype if another organism. This confirms that recurrences of urinary tract infection in men with a positive antibody-coated bacteria test are with the initially infecting organism and generally occur within 4 weeks of discontinuing therapy, as was noted in women with upper tract infection (5). These recurrences were rarely symptomatic, even in those with symptoms during the initial infection. Our study provides information that can be used in developing a rational approach for treatment of men with chronic bacteriuria: [1] Men are likely to have infection with antibody-coated bacteria with or without a prostatic focus; [2] it is important to ascertain if the patient has significant residual urine before therapy, since it is unlikely that a short course of therapy will be successful in those with significant retention of urine. It may also be useful to ascertain if prostatic infection is present; [3] the commonly used 10-d course of therapy has a low probability of eradicating the infection. Microbiologic followup at 1 month after completion of therapy is essential, whether the patient is symptomatic or not, if determination of bacteriuria eradication is desired; and [4] administration of trimethoprim/sulfamethoxazole for 12 weeks appears to be a reasonably safe and relatively effective course of therapy in men with urinary tract infection. Thus, further evaluation of long-term administration of effective agents is needed in men with chronic recurrent urinary tract infections because recurrences are frequent. At present, long-term administration of any agent requires informed consent and close follow-up. Alternatively, prophylaxis or long-term suppression with lowdose trimethoprim/sulfamethoxazole or other agents after eradication of infection with usual courses of therapy may have merit in men as well as in women with recurrent infection (21). The long-term benefits of treating asymptomatic, chronic recurrent bacteriuria in men have not been adequately studied. Kass (22) has suggested that such studies may not be feasible due to the large number of patients that may need to be entered to determine significance. Our study, however, indicates that it is possible to eradicate such infections in some men. Smith eta/. • Recurrent Urinary Tract Infections
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A C K N O W L E D G M E N T S : This work was funded by the Veterans Administration Cooperative Studies Program of Medical Research Service. The Veterans Administration Cooperative Study includes the following—James W. Smith, M.D. (Chairman), Waudelle E. Strickley (Secretary), Ralph M. Martin (Technician), Dallas, Texas; Participants (stations, participating investigators, secretaries, nurses, and laboratory technicians) in Albuquerque, NM: William Reed, M.D., Matty Weatherby, Windy Pierce, Eileen Sierra; Portland, OR: Stephen R. Jones, M.D., Velda Bevel, Meredith Amon, Kate Patrick; Providence, RI: Alan Tice, M.D., Joan Spraque, Virginia Diaz, Alton Barney; Executive Committee: William Reed, M.D., Albuquerque, NM; James W. Smith, M.D., Dallas, TX; Stephen R. Jones, M.D., Portland, OR; Alan Tice, M.D., Providence, RI; Robert H. Deupree, Ph.D., West Haven, CT; Biostatistics and Research Data Processing (West Haven Cooperative Studies Program Coordinating Center), Study Biostatistician: Robert H. Deupree, Ph.D.; Programmer: Nic Kormanik, M.S.; Statistical Assistants: Jo-Anne Falcigno, B.S., Raymond Kilstrom, M.BA.; Keypunch Operators: Stella Marcinauskis, Velma Williams; Operations Committee: C.E. Cox, II, M.D. (Chairman), Memphis, TN; Kenneth L. Vosti, M.D., Palo Alto, CA; Polly Feigl, Ph.D., Seattle, WA; Human Rights Committee: Mrs. Priscilla Fehm, R.N. (Chairman), West Haven, CT; Jack Evans, Esq., New Haven, CT; Rev. David A. Buehler, West Haven, CT; Sister Barbara A. Kathe, West Hartford, CT; Mr. Edward Grant, New Haven, CT; and Central Administration Cooperative Studies Program: James A. Hagans, M.D., Ph.D., Chief; Ping C. Huang, Ph.D., Staff Assistant; Mrs. Helen G. Bickley, Administrative Aide for Travel and Budget; Mrs. Freda Cherry, Administrative Aide for Budget Control; Mr. Dennis Gilliland, Administrative Aide for Planning and Evaluation; Ywick-Kwong Chan, Ph.D., Chief, Cooperative Studies Program Coordinating Center; Michael Sather, Chief, CSPRP. The investigators thank Hoffmann-LaRoche Inc., Nutley, New Jersey, and Burroughs Wellcome Co., Research Triangle Park, North Carolina, for their kind support. • Requests for reprints should be addressed to James W. Smith, M.D.; Infectious Disease Section ( H I D ) , Veterans Administration Medical Center, 4500 South Lancaster Road; Dallas, TX 75216. Received 11 May 1979; revision accepted 31 May 1979.
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