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Single dose treatment of urinary tract infection in females
IIDN1 Volume 5, Number 6, June 1986
Editor P a u l D. H o e p r i c h , MD Division of Infectious and Immunologic Diseases University of California, Davis Medical Center
Associate Editors R u t h M. L a w r e n c e , MD
Larry K. Pickering, MD
C h a r l e s W. Stratton, MD
Division of Infectious Diseases Texas Tech University Health Sciences Center
Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston
Department of Pathology Vanderbilt University Medical Center
Single Dose Treatment of Urinary Tract Infection in Females
~?lmtent~
Single Dose Treatment of Urinary Tract Infection in Females
Allan R. Ronald, MD 41
University of Manitoba, Department of Medicine, Winnepeg, Manitoba, Canada
A l l a n R. R o n a l d
Current Status and Future Trends of Methods for Detecting Exposure to the AIDS Viruses (LAV/HTLVIII/ARV)
43
W i l l i a m M. Mitchell
CASE REPORT
45
Larry Corman
COMMENTS
ON C U R R E N T
PUBLICATIONS
Elsevier 0278-2316,86'$0.00+220
46
Early evaluations (1967-1975) of single dose therapy in the treatment of urinary tract infections (UTI) were largely noncontributory because the site of infection was not identified. However, when UTI confined to the bladder were treated by irrigation with neomycin, cure resulted. In 1976, we reported the first study in which the results of single dose therapy were correlated with site of UTI as determined by a bladder washout procedure. We localized 119 episodes of bacteriuria in 115 adult women most of whom were asymptomatic. A number had minor lower tract symptoms that did not demand immediate treatment; none was actually ill with invasive upper tract disease. Fiftyfour of the 119 episodes were confined to the bladder, and 15 of these were cured by the washout test itself. The 39 patients with continuing infection after localization were each treated with a single dose of
500 mg of kanamycin given by IM injection. Thirty-six of these 39 were cured. In the past decade, over 50 publications have appeared on single dose treatment of acute cystitis or asymptomatic bacteriuria. All but 4 of these studies have concluded that single dose treatment is equivalent in efficacy to more prolonged treatment regimens for acute cystitis in adult women. Among females with asymptomatic bacteriuria, between 50 and 80% are cured with single dose treatment. In 6 studies of adult females in whom radiographic investigation was carried out, single dose failure predicted the overwhelming majority of patients in whom radiographic abnormalities were subsequently detected. However, in a pediatric study, a number of patients cured with single dose treatment did have significant renal abnormalities. From prospective studies, between 10 and 40% of women with
ISSN0278-2316
IDINDN 5(6) 41-48, 1986
42
Infectious Diseases Newslelter 516~ .lunc
acute cystitis have asymptomatic renal involvement. Failure of cure with single dose treatment identifies many of these patients. Women cured with single dose therapy do not need radiographic investigation. In one study, two-thirds of patients with upper tract infection as determined by a positive antibody coated bacteria (ACB) test were cured with a single dose regimen. Presumably, these patients, despite ACB evidence of renal infection, had only superficial colonization of the upper tract. Another study in adult women has shown not only that single dose treatment fails to cure many women with asymptomatic renal infection but also that many of these patients will relapse after a conventional 10 day course of treatment. The diagnosis of upper tract infection, using the criteria of immediate relapse, appears to be as specific and, perhaps, as sensinve as any other readily performed test to identify women that require a more prolonged course of therapy and. perhaps, additional investigation. Additional advantages of single dose treatment have been shown in a number of prospective studies. In one study, significant adverse effects occurred in 27% of patients treated with a conventional course of trimethoprim-sulfamet hoxazole, but in only 4% of patients treated with a single dose regimen. The drug costs are substantially lower for single dose therapy and patient compliance is assured. Patients presenting with acute cystitis with low count bacteriuria, are cured with single dose regimens. Also. single dose therapy results in less emergence of resistance within the colonic flora. with less opportunity for subsequent reinfections with resistant organisms.
1986
Pregnant patients with asymptomanc infection can also be managed with single dose regimens. Renal infection may be more commonly associated with asymptomatic bacteriuria during pregnancy than m age-matched controls. Single dose regimens expose the developing fetus to less antibacterial agent and identify women with renal infection who need careful follow-up during the pregnancy to reduce complications of bacteriuria. Despite the plethora of information on single dose treatment and its efficacy in published studies, most physicians continue to treat acute cystitis and asymptomatic infection in women with conventional 7- to 14-day regimens. Why have the apparent advantages of this trealment and diagnostic modality not been more widely accepted by physicians m practice? 1. The risk of undertreating renal infection is of continuing concern. If patients do not comply with follow-up culture o f the urine at 1 to 2 weeks, some patients who would have been cured of their renal infection with conventional therapy, will have persisting bacteriuria. Although the risks of asymptomatic bacteriuria in adult women are uncertain. most infectious diseases physicians will treat asymptomatic infection in otherwise healthy women. Moreover. progression of acute cystitis to symptomatic upper tract infection following failure of a single dose treatment regimen has been documented. 2. Many physicians have a laissezfaire attitude toward acute cystitis and treat with the assumption that such UTI are self-limited and respond to a variety of therapeutic
initiatives including water diuresis. acidification, and time. One recent study of a placebo and another or water diuresis without antibacterial treatment both demonstrated that symptoms, bacteriuria, and pyurm continued in the absence of effective treatment, Antibacterial treatment is ~mportant to limit the duration of symptoms and to eradicate bacteria from the urinary tract+ Although persistent bacteriuria with or without symptoms, rarely, if ever. leads to progressive renal damage after infanc~ and childhood, It is an emit5 that +ustifies an exam diagnosis and a specific treatment plan 3. Advertisements directed at physmians by the pharmaceutical industry have not identified single dose treatment as an effective, preferred alternative to conventional treatment regimens 4. Initial studies showed that amoxicillin. 3 g as a single peroral dose. was effective. However. the recent dissemination of ampicillin resistance among communityacquired urinary pathogens negates this regimen. Trimet hoprim-sulfamethoxazole in a dose of 2 double strength tablets (320 mg of trimethoprim plus ! 600 mg of sulfamethoxazole) has been the regimen studied most widely. Although investigated less, trimethopnm alone, prescribed in a dose of 400 mg, presumably is also effective and can be used if patmnts have a history of adverse effects to sulfonamides. 5. Patient acceptance of single dose therapy has not been uniformly favorable. Marly women continue to have symptoms for 12 to 48 hours alter cure of bacteriuria. Resolution of acute inflammation is gradual. Unless reassu-
hll~'~tlou~ fJt~'u~{~ Ne~'xh,tter I I S S N O27R-2316) is ixsued m o m h l v m o n e indexed ~ o l u m e per Near by Elsevmr Selcnce P u b h s h m g C o . I n c . 52 ~ a n d e r b l l t A v e n u e New Y o r k. N'~ (HIl 7 P r i m e d in U S A a! R o u t e 115, (;uilderland+ N Y 12{)84 S u b s c r i p t i o n price per-year- m~tlmtlon~. $ 1 1 2 0 0 : indi~qduals. $56.00. F o r air mini +o Europe. a d d S 2 1 00. for air m a d elsewhere, a d d $24 (X) Second-class p o s t a g e p e n d i n g at N e ~ Y(~rk. N Y . a n d a[ zJdditlonal m a i h n g othces P o s t m a s t e r : ,'Send address c h a n g e s to h~te, erom Dnsea~e~ N e w s l e t t e r . Elsewe[ Science P u b l i s h i n g ( ' o Inc . 52 V a n d e r b i l t A ~ e n u e N e ~ Y~rk N~t I(R~I-
©
1986 Elsevier
Science
0278-2316
Publishing
86'$0.00+220
Co.,
Ira
43 Infectious Diseases Newsletter 5(6)
June 1986 rance is offered, patients may request continuing medication for ongoing symptoms. Unfortunately, few studies comparing single dose with conventional treatment regimens have used a placebo in order to assess objectively the rate of resolution of symptoms. 6. In at least one study, it appeared that patients may reinfect more frequently following single dose treatment regimens. In our experience, a 10-day treatment regimen with trimethoprim alone, or in combination with a sulfonamide, substantially reduces the reservoir for reinfections due to the elimination of Escherichia coli and other aerobic gramnegative rods from the colon and perineum. However, patients with very frequent reinfections do not require a prolonged course of conventional therapy, but rather continuing prophylaxis with a regimen designed to prevent recurrences. 7. All published studies have a relatively small sample size and it is possible that single dose therapy is not as effective as conventional treatment. A type II or fl error is unlikely but until a large, blinded study, with localization, is completed, the concept will be vulnerable to criticism.
In conclusion, single dose treatment for acute cystitis and asymptomatic bacteriuria in females, using the 2 double strength tablet trimethoprim-sulfamethoxazole regimen, is an established therapeutic alternative to conventional 7- to 14day regimens, and should be the treatment of choice. Women who have a previous history of UTI and no risk factors for sexually transmitted pathogens can be treated without investigation, and selfinitiated treatment is an acceptable alternative. A dipstick urine culture, or perhaps, a leukocyte esterase test for pyuria, is an inexpensive followup procedure at 2 weeks to ensure cure. As most reinfections are symptomatic, it can be argued that a test of cure is unnecessary. However, asymptomatic relapse of renal infection may occur and should be searched for. Larger, definitive studies are required to determine the sensitivity and specificity of single dose regimens in various population groups, and to provide predictive value for successful use. Bibliography
Avner ED, Ingelfinger JR, Herrin JT, et al: Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections. J Ped 102:623-627, 1983. Bailey RR: Single dose therapy of uri-
Current Status and Future Trends of Methods for Detection of Exposure to the AIDS Virus (HTLV-III/LAV) William M. Mitchell, MD, .hD Vanderbilt University School of Medicine, Nashville, Tennessee The current tests for the presence of antibodies in the serum against H T L V - I I I / L A V (AIDS virus) have provided significant, although imperfect, protection against the inad-
vertent transmission of AIDS through the nation's blood supply system. In an effort to maximize sensitivity, the Food and Drug Administration (FDA) approved
© 1986Elsevier Science Publishing Co., Inc. 0278-2316/86~$0.00 + 2.20
nary tract infection. ADIS Health Science Press, Sydney, Australia, 1983. Buckwold FJ, Ludwig P, Harding GH, et al: Therapy for acute cystitis in adult women. Randomized comparison of single-dose sulfisoxazole vs trimethoprim-sulfamethoxazole. J Amer Med Assoc 247:1839-1842, 1982. Fang LST, Tolkoff-Rubin NE, Rubin RH: Efficacy of single-dose and conventional amoxicillin therapy in urinary tract infection localized by the antibody-coated bacteria technic. N Engl J Med 298:413-416, 1978. Harding GKM, Buckwold F J, Marrie TJ, et al: Prophylaxis of recurrent urinary tract infection in females: efficacy of low-dose thrice weekly therapy with trimethoprim/sulfamet hoxazole. J Amer Med Assoc 242:1975-1977, 1979. Masterton RG, Evans DC, Strike PW: Single-dose amoxycillin in the treatment of bacteriuria in pregnancy and the puerperium--a controlled clinical trial. Br J Obstet Gynecol 92:498-505, 1985. Philbrick JT, Bracikowski JP: Singledose antibiotic treatment for uncomplicated urinary tract infections. Arch Intern Med 145:1672-1678, 1985. Ronald AR, Boutros P, Mourtada H: The correlation between localisation of bacteriuria and response to single dose therapy in adult females. J Amer Med Assoc 235:1854-1856, 1976. Wong ES, McKevitt M, Running K, et al: Management of recurrent urinary tract infections with patientadministered single-dose therapy. Ann Intern Med 102:302-307, 1985.
screening tests that yield a significant number of false positives (currently estimated at 17-89% of all positive samples, depending on the prevalence of true AIDS viral antibodies and the apparent specificity of each commercial method). All current F D A approved screening tests use enzyme-linked immunosorbent assays (ELISA) for detection of IgG reactive against relatively crude preparations of whole, detergent-disrupted AIDS virus (eg,
Editor P a u l D. H o e p r i c h , MD Division of Infectious and Immunologic Diseases University of California, Davis Medical Center
Associate Editors R u t h M. L a w r e n c e , MD
Larry K. Pickering, MD
C h a r l e s W. Stratton, MD
Division of Infectious Diseases Texas Tech University Health Sciences Center
Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston
Department of Pathology Vanderbilt University Medical Center
Single Dose Treatment of Urinary Tract Infection in Females
~?lmtent~
Single Dose Treatment of Urinary Tract Infection in Females
Allan R. Ronald, MD 41
University of Manitoba, Department of Medicine, Winnepeg, Manitoba, Canada
A l l a n R. R o n a l d
Current Status and Future Trends of Methods for Detecting Exposure to the AIDS Viruses (LAV/HTLVIII/ARV)
43
W i l l i a m M. Mitchell
CASE REPORT
45
Larry Corman
COMMENTS
ON C U R R E N T
PUBLICATIONS
Elsevier 0278-2316,86'$0.00+220
46
Early evaluations (1967-1975) of single dose therapy in the treatment of urinary tract infections (UTI) were largely noncontributory because the site of infection was not identified. However, when UTI confined to the bladder were treated by irrigation with neomycin, cure resulted. In 1976, we reported the first study in which the results of single dose therapy were correlated with site of UTI as determined by a bladder washout procedure. We localized 119 episodes of bacteriuria in 115 adult women most of whom were asymptomatic. A number had minor lower tract symptoms that did not demand immediate treatment; none was actually ill with invasive upper tract disease. Fiftyfour of the 119 episodes were confined to the bladder, and 15 of these were cured by the washout test itself. The 39 patients with continuing infection after localization were each treated with a single dose of
500 mg of kanamycin given by IM injection. Thirty-six of these 39 were cured. In the past decade, over 50 publications have appeared on single dose treatment of acute cystitis or asymptomatic bacteriuria. All but 4 of these studies have concluded that single dose treatment is equivalent in efficacy to more prolonged treatment regimens for acute cystitis in adult women. Among females with asymptomatic bacteriuria, between 50 and 80% are cured with single dose treatment. In 6 studies of adult females in whom radiographic investigation was carried out, single dose failure predicted the overwhelming majority of patients in whom radiographic abnormalities were subsequently detected. However, in a pediatric study, a number of patients cured with single dose treatment did have significant renal abnormalities. From prospective studies, between 10 and 40% of women with
ISSN0278-2316
IDINDN 5(6) 41-48, 1986
42
Infectious Diseases Newslelter 516~ .lunc
acute cystitis have asymptomatic renal involvement. Failure of cure with single dose treatment identifies many of these patients. Women cured with single dose therapy do not need radiographic investigation. In one study, two-thirds of patients with upper tract infection as determined by a positive antibody coated bacteria (ACB) test were cured with a single dose regimen. Presumably, these patients, despite ACB evidence of renal infection, had only superficial colonization of the upper tract. Another study in adult women has shown not only that single dose treatment fails to cure many women with asymptomatic renal infection but also that many of these patients will relapse after a conventional 10 day course of treatment. The diagnosis of upper tract infection, using the criteria of immediate relapse, appears to be as specific and, perhaps, as sensinve as any other readily performed test to identify women that require a more prolonged course of therapy and. perhaps, additional investigation. Additional advantages of single dose treatment have been shown in a number of prospective studies. In one study, significant adverse effects occurred in 27% of patients treated with a conventional course of trimethoprim-sulfamet hoxazole, but in only 4% of patients treated with a single dose regimen. The drug costs are substantially lower for single dose therapy and patient compliance is assured. Patients presenting with acute cystitis with low count bacteriuria, are cured with single dose regimens. Also. single dose therapy results in less emergence of resistance within the colonic flora. with less opportunity for subsequent reinfections with resistant organisms.
1986
Pregnant patients with asymptomanc infection can also be managed with single dose regimens. Renal infection may be more commonly associated with asymptomatic bacteriuria during pregnancy than m age-matched controls. Single dose regimens expose the developing fetus to less antibacterial agent and identify women with renal infection who need careful follow-up during the pregnancy to reduce complications of bacteriuria. Despite the plethora of information on single dose treatment and its efficacy in published studies, most physicians continue to treat acute cystitis and asymptomatic infection in women with conventional 7- to 14-day regimens. Why have the apparent advantages of this trealment and diagnostic modality not been more widely accepted by physicians m practice? 1. The risk of undertreating renal infection is of continuing concern. If patients do not comply with follow-up culture o f the urine at 1 to 2 weeks, some patients who would have been cured of their renal infection with conventional therapy, will have persisting bacteriuria. Although the risks of asymptomatic bacteriuria in adult women are uncertain. most infectious diseases physicians will treat asymptomatic infection in otherwise healthy women. Moreover. progression of acute cystitis to symptomatic upper tract infection following failure of a single dose treatment regimen has been documented. 2. Many physicians have a laissezfaire attitude toward acute cystitis and treat with the assumption that such UTI are self-limited and respond to a variety of therapeutic
initiatives including water diuresis. acidification, and time. One recent study of a placebo and another or water diuresis without antibacterial treatment both demonstrated that symptoms, bacteriuria, and pyurm continued in the absence of effective treatment, Antibacterial treatment is ~mportant to limit the duration of symptoms and to eradicate bacteria from the urinary tract+ Although persistent bacteriuria with or without symptoms, rarely, if ever. leads to progressive renal damage after infanc~ and childhood, It is an emit5 that +ustifies an exam diagnosis and a specific treatment plan 3. Advertisements directed at physmians by the pharmaceutical industry have not identified single dose treatment as an effective, preferred alternative to conventional treatment regimens 4. Initial studies showed that amoxicillin. 3 g as a single peroral dose. was effective. However. the recent dissemination of ampicillin resistance among communityacquired urinary pathogens negates this regimen. Trimet hoprim-sulfamethoxazole in a dose of 2 double strength tablets (320 mg of trimethoprim plus ! 600 mg of sulfamethoxazole) has been the regimen studied most widely. Although investigated less, trimethopnm alone, prescribed in a dose of 400 mg, presumably is also effective and can be used if patmnts have a history of adverse effects to sulfonamides. 5. Patient acceptance of single dose therapy has not been uniformly favorable. Marly women continue to have symptoms for 12 to 48 hours alter cure of bacteriuria. Resolution of acute inflammation is gradual. Unless reassu-
hll~'~tlou~ fJt~'u~{~ Ne~'xh,tter I I S S N O27R-2316) is ixsued m o m h l v m o n e indexed ~ o l u m e per Near by Elsevmr Selcnce P u b h s h m g C o . I n c . 52 ~ a n d e r b l l t A v e n u e New Y o r k. N'~ (HIl 7 P r i m e d in U S A a! R o u t e 115, (;uilderland+ N Y 12{)84 S u b s c r i p t i o n price per-year- m~tlmtlon~. $ 1 1 2 0 0 : indi~qduals. $56.00. F o r air mini +o Europe. a d d S 2 1 00. for air m a d elsewhere, a d d $24 (X) Second-class p o s t a g e p e n d i n g at N e ~ Y(~rk. N Y . a n d a[ zJdditlonal m a i h n g othces P o s t m a s t e r : ,'Send address c h a n g e s to h~te, erom Dnsea~e~ N e w s l e t t e r . Elsewe[ Science P u b l i s h i n g ( ' o Inc . 52 V a n d e r b i l t A ~ e n u e N e ~ Y~rk N~t I(R~I-
©
1986 Elsevier
Science
0278-2316
Publishing
86'$0.00+220
Co.,
Ira
43 Infectious Diseases Newsletter 5(6)
June 1986 rance is offered, patients may request continuing medication for ongoing symptoms. Unfortunately, few studies comparing single dose with conventional treatment regimens have used a placebo in order to assess objectively the rate of resolution of symptoms. 6. In at least one study, it appeared that patients may reinfect more frequently following single dose treatment regimens. In our experience, a 10-day treatment regimen with trimethoprim alone, or in combination with a sulfonamide, substantially reduces the reservoir for reinfections due to the elimination of Escherichia coli and other aerobic gramnegative rods from the colon and perineum. However, patients with very frequent reinfections do not require a prolonged course of conventional therapy, but rather continuing prophylaxis with a regimen designed to prevent recurrences. 7. All published studies have a relatively small sample size and it is possible that single dose therapy is not as effective as conventional treatment. A type II or fl error is unlikely but until a large, blinded study, with localization, is completed, the concept will be vulnerable to criticism.
In conclusion, single dose treatment for acute cystitis and asymptomatic bacteriuria in females, using the 2 double strength tablet trimethoprim-sulfamethoxazole regimen, is an established therapeutic alternative to conventional 7- to 14day regimens, and should be the treatment of choice. Women who have a previous history of UTI and no risk factors for sexually transmitted pathogens can be treated without investigation, and selfinitiated treatment is an acceptable alternative. A dipstick urine culture, or perhaps, a leukocyte esterase test for pyuria, is an inexpensive followup procedure at 2 weeks to ensure cure. As most reinfections are symptomatic, it can be argued that a test of cure is unnecessary. However, asymptomatic relapse of renal infection may occur and should be searched for. Larger, definitive studies are required to determine the sensitivity and specificity of single dose regimens in various population groups, and to provide predictive value for successful use. Bibliography
Avner ED, Ingelfinger JR, Herrin JT, et al: Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections. J Ped 102:623-627, 1983. Bailey RR: Single dose therapy of uri-
Current Status and Future Trends of Methods for Detection of Exposure to the AIDS Virus (HTLV-III/LAV) William M. Mitchell, MD, .hD Vanderbilt University School of Medicine, Nashville, Tennessee The current tests for the presence of antibodies in the serum against H T L V - I I I / L A V (AIDS virus) have provided significant, although imperfect, protection against the inad-
vertent transmission of AIDS through the nation's blood supply system. In an effort to maximize sensitivity, the Food and Drug Administration (FDA) approved
© 1986Elsevier Science Publishing Co., Inc. 0278-2316/86~$0.00 + 2.20
nary tract infection. ADIS Health Science Press, Sydney, Australia, 1983. Buckwold FJ, Ludwig P, Harding GH, et al: Therapy for acute cystitis in adult women. Randomized comparison of single-dose sulfisoxazole vs trimethoprim-sulfamethoxazole. J Amer Med Assoc 247:1839-1842, 1982. Fang LST, Tolkoff-Rubin NE, Rubin RH: Efficacy of single-dose and conventional amoxicillin therapy in urinary tract infection localized by the antibody-coated bacteria technic. N Engl J Med 298:413-416, 1978. Harding GKM, Buckwold F J, Marrie TJ, et al: Prophylaxis of recurrent urinary tract infection in females: efficacy of low-dose thrice weekly therapy with trimethoprim/sulfamet hoxazole. J Amer Med Assoc 242:1975-1977, 1979. Masterton RG, Evans DC, Strike PW: Single-dose amoxycillin in the treatment of bacteriuria in pregnancy and the puerperium--a controlled clinical trial. Br J Obstet Gynecol 92:498-505, 1985. Philbrick JT, Bracikowski JP: Singledose antibiotic treatment for uncomplicated urinary tract infections. Arch Intern Med 145:1672-1678, 1985. Ronald AR, Boutros P, Mourtada H: The correlation between localisation of bacteriuria and response to single dose therapy in adult females. J Amer Med Assoc 235:1854-1856, 1976. Wong ES, McKevitt M, Running K, et al: Management of recurrent urinary tract infections with patientadministered single-dose therapy. Ann Intern Med 102:302-307, 1985.
screening tests that yield a significant number of false positives (currently estimated at 17-89% of all positive samples, depending on the prevalence of true AIDS viral antibodies and the apparent specificity of each commercial method). All current F D A approved screening tests use enzyme-linked immunosorbent assays (ELISA) for detection of IgG reactive against relatively crude preparations of whole, detergent-disrupted AIDS virus (eg,