Session III A. R. R o n a l d , L. E. Nicolle, G. K. M. H a r d i n g
Standards of Therapy for Urinary Tract Infections in Adults Definitions Summary: Therapeutic standards have not been well defined for many forms of bacterial urinary tract infection. In women with uncomplicated infections, these exist for bacterial cystitis and for acute pyelonephritis. For most other categories of illness, among patients with complicated infections, no treatment regimens have been determined. As a result, well-designed clinical trials for these patient populations should be a priority.
Zusammenfassung: Standardisierung der Therapie von Harnwegsinfektionen bet Erwachsenen. Ftir viele Arten von bakteriellen Harnwegsinfektionen gibt es bisher keine standardisierte Therapie, ausgenommen die bakterielle Zystitis und akute Pyetonephritis bet Frauen mit unkomptizierten Infektionen. Ftir die meisten anderen Kategorien von Harnwegsinfektionen, einschlieBtich der Patienten mit komplizierten Infektionen, gibt es kein festgelegtes Therapieregime. Deshalb sollten bet diesen Patienten gut angelegte klinische Studien vorrangig durchgeftihrt werden.
Table 1: Classification of uncomplicated bacterial urinary tract infection in adults. 1. 2. 3. *4. 5. 6. 7. 8.
Acute cystitis in women Acute pyelonephritis in women Asymptomatic bacteriuria in men under 65 years of age. Asymptomatie bacteriuria in non-pregnant women under 65 years of age Asymptomatic bacteriuria in pregnant women Acute cystitis in men under 65 years of age Acute pyelonephritis in men under 65 years of age Post-catheterization bacteriuria in women under 65 years of age
Treatment not proven to alter favourably the natural history.
Introduction Therapeutic standards are essential for professional practice [t]. These are the "norms" which we communicate to our patients and students and use to evaluate quality of care. The therapeutic "norm" becomes the "gold standard" to which alternative or new therapeutic regimens are compared. Many common microbial infections, including bacterial urinary tract infections, lack well-determined therapeutic standards [2]. Poorly designed clinical trials lead to inconclusive and controversial recommendations. As a result, the standards we identify in this review will often be arbitrary and based on our best judgement of the published clinical trials and our own experience. In many instances, we will identify the lack of established or proven therapeutic standards. Optimal therapeutic regimens are scientifically determined by large prospective, well-designed studies which can identify clinically significant differences in efficacy and common adverse effects [ 2 ] . Most investigators determine the efficacy of a treatment regimen within a research milieu. Only rarely are studies carried out in a practice setting in which all patients are entered in order to determine "effectiveness." In the present review, we have categorized groups of patients with urinary tract infection in order to determine subsets in which the majority of adult patients can be placed. S 164
Bacterial infection of the bladder or of the upper urinary tract (kidneys and ureters) is the presence of bacteria in the urinary tract regardless of bacterial numbers or of any host response such as symptoms or p~aria. Optimal cost-effective microbiological strategies to make a diagnosis of infection are currently under review [3]. Urinary infections are further classified by the presence of underlying disease. For this review, an uncomplicated urinary tract infection (UTI) is infection of the bladder or kidney occurring in the normal host without structural or functional abnormalities of the urinary tract (Table 1).
Table 2: Classification of complicated bacterial urinary tract infection in adults. 1. "2. *3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Symptomatic infection in catheterized men or women Asymptomatic bacteriuria in the elderly (over 65 years old) Asymptomatic bacteriuria in catheterized men or women Infection associated With urinary calculi Infection associated with renal impairment (segmental, unilateral or bilateral) Symptomatic urinary tract infection with evidence of a prostatic focus of infection (acute or recurrent) Symptomatic and asymptomatic bacteriuria acquired during intermittent catheterization programmes Post-urological urinary tract infection Symptomatic and asymptomatic bacteriuria in patients with diabetes mellitus Symptomatic and asymptomatic bacteriuria in patients following renal transplant Symptomatic and asymptomatic infection associated with immunosuppression or neutropenia Symptomatic or asymptomatic infection with cystic renal disease
* Treatment not usually recommended.
A. R. Ronald, M.D. FRCPC, Lindsay E. Nicolle, M.D., FRCPC, G. K. 3//. Harding, M.D. FRCPC, Dept. of Medical Microbiology and Internal Medicine, University of Manitoba, St. Boniface General Hospital, 409 Tache Ave., Winnipeg, Manitoba R2H 2A6, Canada. Correspondence to: Dr. Lindsay NicoUe, Dept, of Clinical Microbiology, University of Manitoba, Room MS675D, 820 Sherbrook St., Winn!peg, Manitoba R3A 1R9, Canada.
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Urinary tract infection is "complicated" when one or more anatomical, functional or host abnormalities are present
(Table 2). We classify infections in pregnant patients as uncomplicated in the absence of any of these complications. A cure is defined as eradication of the initial pathogen(s) from the urinary tract. In therapeutic trials, this must be determined by follow-up urine cultures. These cultures should not be obtained during the first week following treatment because cultures at this time may be falsely negative. In our experience, over 90% of women who fail therapy with recurrence of the original pathogen after a course of treatment, do so within 14 days. Men may take weeks or months to relapse if the prostate is the persistent focus of infection. For the purposes of this review, a cure in women is defined as no recurrence of the original infecting pathogen(s) 14 days after completion of therapy and a cure in men is defined as no recurrence after six weeks with negative cultures from prostatic secretions. Uncomplicated infections should be successfully treated with population cure rates that exceed 95%. Complicated infections will "commonly" fail therapy. Why T r e a f f A rationale for treatment is important. Treatment for urinary tract infections is indicated for one or more of the following reasons: - to reduce the duration and severity of symptoms - to prevent bacteraemic sepsis or metastatic infection - to prevent complications during pregnancy - to prevent complications during manipulation of the urinary tract - to prevent stone formation or stone growth - to prevent direct invasion of structures adjacent to the urinary tract, such as the epididymis or the perinephric space - to prevent renal impairment - to prevent infections that would make concomitant illnesses more serious, e.g., diabetes mellitus. In the absence of indications for treatment, we would usually recommend against treatment (Tables 1 and 2). However, few studies have been carried out for most of these categories of infection and the decision to prescribe antimicrobial agents must be based on individual circumstances until adequate treatment studies have determined whether any advantage is to be gained by treatment. Standard Infection
Treatment
Regimens
for
Uncomplicated
costs, increased compliance, and fewer side effects [4-6]. Single-dose regimens have been most thoroughly studied and a cure rate of between 85 and 100% of women has been found if the organism is susceptible [4,5]. However, if recurrence of infection is used as a criterion for further investigation for upper tract pathology, unwarranted additional investigation and treatment may occur. Also, Fihn et al. have shown that a recent history of UTI, the use of a diaphragm and a spermicide, and the presence of more than 105 cfu/ml of the pathogen all predict a significantly increased failure rate with single-dose regimens [7]. Based on these observations, single-dose regimens may no longer be the preferred treatment option for women with acute cystitis. Norrby and Hooton et al. suggest that three-day regimens should be recognized as the empirical choice for this syndrome [4,8]. The combination of trimethoprim/sutphamethoxazole (TMP/SMX) prescribed as 160 mg/800 mg twice daily for three days is our preferred regimen. At least 95% of women will be predictably cured clinically and microbiologically. Less than 5% of patients will have significant side effects that require medical attention. If patients are allergic to sulphonamides, trimethoprim, 200 mg twice daily for three days, is an acceptable alternative. If resistance to trimethoprim is present in more than 5% of isolates from women with acute cystitis, equally effective and well-tolerated but less well-studied regimens are available and can be prescribed for three days. Amoxycillin or ampicillin are no longer useful antimicrobial agents because of the emergence of resistance in 15-30% of isolates in most parts of the world [8]. Oral cephalosporins such as cephalexin are effective, although [3-1actam drugs may have an increased rate of recurrence in comparison with other regimens [9,10]. Other single-dose or three-day regimens successfully used for treatment of acute cystitis include the trometamol salt of fosfomycin and the fluoroquinolones [11-13]. Parenteral regimens such as ceftriaxone or the aminoglycosides also cure more than 95% of women with acute cystitis when prescribed as a single-dose regimen but these are more expensive [14]. The fluoroquinolones are contraindicated in pregnancy. Trimethoprim- sulphonamide combinations have been used frequently in pregnancy and have not been associated with any reported adverse effects to the fetus other than the theoretical risk of kernicterus at term. Cephalexin is our agent of choice for pregnant women with uncomplicated acute cystitis who cannot tolerate trimethoprim/sulfamethoxazole or are near term [t0].
Women with Acute Cystitis
Women with Acute Uncomplicated Pyelonephritis
Regulatory agencies often require, and many practitioners continue to prescribe, a 7-14 day regimen for this common syndrome. Shorter courses of therapy have been shown to be equally effective and have the advantages of lower
Recent studies suggest that most women can be managed with oral regimens as outpatients [15]. The standard oral regimen as determined by prospective studies in ambulatory patients should be TMP 160 mg/SMX 800 mg
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A. IL Ronald et al.: Standards for Urinary Tract Infection prescribed twice daily for 14 days [16]. ~aanpicillin and amoxycillin are less effective on account of the prevalence of resistant organisms. Pivampicillin was much less effective when prescribed for one week as compared to three weeks [17]. For this reason, we favour a regimen of two weeks of therapy as the routine standard for acute uncomplicated pyelonephritis. Other oral regimens including ciprofloxacin and norfloxacin have also been used for the oral treatment of acute pyelonephritis. However, these have been less well investigated to date. Numerous parenteral regimens have been used for the initial therapy of hospitalized women with acute uncomplicated pyelonephritis. We have favoured ampicillin and gentamicin as an initial, inexpensive, empirical parenteral treatment, to be modified once the susceptibility of the infecting organism is known [18]. Johnson et al. randomized 85 women to ampicillin or TMP/SMX, both intravenously [19]. Both were combined initially with gentamicin [19]. No patient treated with TMP/SMX required modification of therapy. Fourteen of the 42 women treated with ampicillin and gentamicin were infected with ampicillin-resistant isolates and required treatment modification [19]. No treatment failures occurred in either group following a two-week treatment regimen. At present there is no evidence to continue parenteral therapy beyond the initial response with resolution of fever and local symptoms. In most instances we choose TMP/SMX and complete a two-week course of therapy. Ceftriaxone prescribed in a dose of 1 g/day is a suitable alternative regimen and is particularly well adapted for parenteral use at home. Women with uncomplicated acute pyelonephritis should have a urine culture two weeks following completion of therapy. If recurrence with the same infecting pathogen has occurred, further investigation is indicated with possible reclassification as a "complicated" urinary tract infection. Acute pyelonephritis in pregnancy should be managed in hospital. Although not proven, it is presumed that all patients should be initially prescribed parenteral therapy until a therapeutic response has occurred. It is hoped, although unproven, that this will prevent untoward complications of pregnancy. With the exception of the fluoroquinolones and TMP/SMX in the third trimester, the treatment regimen suggested for acute pyelonephritis in the non-pregnant patient is appropriate during pregnancy.
Asymptomatic Bacteriuria during Pregnancy Single-dose and three-day treatment regimens cure the majority of patients with this diagnosis [10,20]. As most patients will have a culture with susceptible results at the time therapy is initiated, a drug effective in vitro should be prescribed. ~aanoxycillin, 500 mg three times a day for three days, or other regimens identified as suitable for S 166
women with acute cystitis are, with the exception of the ftuoroquinolones, probably also appropriate for asymptomatic bacteriuria in pregnancy. Cephalexin has been prescribed as a single-dose, 2 g regimen with a good therapeutic outcome [t4].
Asymptomatic Infection following Catheter Removal in Women Large numbers of women who have required indwelling catheters for varying periods of time, will have bacteriuria following catheter removal. It has been assumed that many of these infections resolve spontaneously without specific therapy. A recent study by Harding et al. suggests that this premise is incorrect [21]. Almost a quarter of untreated Patients become symptomatic with either upper or lower tract illness within two weeks of catheter removal. As a result, these patients should be treated routinely. Harding et al. used TMP/SMX prescribed as either a single-dose regimen or twice daily for ten days [21]. Both regimens were equally effective in women under the age of 65 with cure rates in excess of 90%. However, older women failed both short and longer courses of therapy. Until further information is available, all women with catheter-acquired infections should be treated when the catheter is removed with either a single dose of an effective regimen such as TMP/SMX or a three-day regimen similar to that identified earlier for women with acute cystitis. Patients with catheter-associated bateriuria should not be left untreated following catheter removal.
Uncomplicated Infection in Men (Cystitis or Pyelonephritis) Acute symptomatic and asymptomatic infection in men with no evidence of obstruction, prostatic disease by rectal examination, or underlying renal disease occur with an incidence of about 0.3% per year in men 20-60 years of age [22]. Although it has been traditional to identify all male patients as complicated urinary infections with the assumption that extensive investigation is necessary, this has not been proven [22]. After the age of 60, the incidence of UTI rises dramatically. We presume that a greater proportion of elderly men have obstructive uropathy. At present, we prescribe regimens for these patients that are identical to those used in women with acute pyelonephritis. A 14-day course of parenteral and oral therapy or, in less acutely ill men, a 14-day course of oral therapy is appropriate. Standards of treatment must be determined by prospective studies. TMP/SMX or the fluoroquinolones are appropriate choices. Follow-up cultures, including prostatic secretion cultures, are warranted for study pruposes, and should be obtained at six weeks following completion of therapy. If patients are cured without any recurrence, further investigation is unnecessary. Patients who relapse should be identified as a "complicated urinary' infection" and investigated urologically and radiologically.
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Urinary Tract Infections in Patients with Diabetes
Few natural history or treatment studies or urinary infection have been stratified by the complicating factors. As a result, there are few standards of therapy and most regimens are empirical and will require revision once studies are carried out. Several categories of complicated infections are infrequent and can only be studied through multicentre trials. Well-defined, prospective, longitudinal studies should be a priority with planned intervention to treat, prevent or suppress infection as appropriate. In patients with asymptomatic bacteriuria, placebo controls are essential and, in most instances, are ethically acceptable. In Table 2, we have starred categories of patients with complicated infection for whom we consider treatment to be relatively contraindicated because of the absence of studies that suggest that treatment alters the natural history of these infections or prevents complications. Long treatment courses in patients with complicated infections frequently select out multiply-resistant pathogens that are difficult to eradicate.
Several possible synergistic interactions occur between diabetes and urinary infection. These include metabolic disturbances, urinary bladder dysfunction and renal microangiopathy. Histologically, post mortem evaluation prior to the antimicrobial era, documented "pyelonephritis" in one-fifth of patients, an occurrence five times that of non-diabetic patients [26]. At present, no evidence proves that the treatment of asymptomatic infection in men or women with diabetes leads to improved outcomes. Only one controlled study exists. Forland and Thomas, in a study of 45 adults, were unable to show that six weeks of trimethopritrd sulphamethoxazote was superior to two weeks [27]. However, on account of the serious consequences of invasive symptomatic infection in patients with diabetes, many experts treat asymptomatic infections in ambulatory patients. Prospective longitudinal studies are necessary to validate this approach. Acute pyelonephritis is common in patients with diabetes. At present, there are no studies to suggest that any treatment regimens are preferable and we recommend that the treatment regimens selected should be those previously identified for uncomplicated pyelonephritis in both men and women.
Symptomatic Infection in Patients with an Indwelling Catheter Patients with indwelling catheters have a mean of one febrile episode per 100 days of catheterization [23] and about one-half of the febrile episodes in these patients appear to arise from the urinary tract [23]. In women, many episodes resolve without antimicrobial therapy. On the other hand, autopsies reveal acute pyelonephritis in one-third of these patients [24]. Patients with catheters in place in one study were 40 times as likely to be bacteraemic with a febrile episode as those without catheters [23]. In the same study, 16 of 20 patients catheterized for one year had at least one episode of bacteraemia [23]. Avoiding catheterization or replacing the indwelling catheter with an intermittent catheterization programme should be considered in patients who have recurrent symptomatic infections associated with an indwelling catheter. Otherwise, treatment regimens in patients with indwelling catheters and symptomatic infection depend upon the antimicrobial susceptibility of the infecting pathogen. The goals of therapy are to reduce symptoms, treat invasive infection early, and to prevent superinfection with more resistant pathogens that are difficult to eradicate. In most instances a parenteral regimen of ampicillin and gentamicin is a satisfactory initial choice. The duration of therapy is unknown. We usually stop therapy after the patient has been afebrile for 48-72 h. Oral regimens may be equally satisfactory [25]. Long courses of oral therapy have not been shown to be of value in patients with an indwelling catheter and symptomatic urinary tract infection. Further treatment studies are necessary in this patient population.
Urinary Tract Infection Complicating Renal or Bladder Calculi Treatment will usually fail in patients with underlying urinary tract calculi. As a result, the therapeutic preference in these patients is to treat symptomatic infection and, in some instances, to suppress persistent infections in patients whose calculi cannot be removed [281. Acutely symptomatic infections should be treated with regimens similar to those identified for uncomplicated infections. However, with the initiation of treatment, a decision needs to be made about subsequent care. ObstrUction needs to be excluded. If infection is promoting stone growth, particularly in patients with urea splitting organisms, long-term suppressive therapy should be prescribed [28]. Stone removal is always the optimal course to follow in all patients with calculi.
Bacteriuria and Renal Impairment Urinary tract infection is a common accompaniment of renal impairment. In most instances, the impairment is unrelated to the bacteriuria but it may provoke concern because of either symptoms, or anxiety that infection is further endangering residual renal function. Renal impairment may be either unilateral or bilateral. Patients with unilateral renal impairment and infection in the involved kidney are difficult to treat. Few studies have been carried out. However, drugs rapidly eliminated by the healthy kidney to not achieve sufficient concentration in diseased renal tissue to achieve adequate bacterial cure
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A. R. Ronald et al.: Standards for Urinary Tract Infection or suppression of infection in the impaired infected kidney [29]. In the absence of careful studies, we prescribe therapeutic regimens which are not in themselves nephrotoxic and which achieve effective serum and tissue levels. Bilateral renal impairment adds a further concern with regard to inadequate renal tissue and urine levels. Although most antimicrobial agents are reasonably well studied prior to marketing with regard to renal handling in patients with impaired function, similar studies demonstrating treatment effectiveness for bacteriuria are not available. Careful, prospective, well-designed studies of therapeutic efficacy in patients with both unilateral and bilateral renal impairment are required. We would encourage trials with both the quinolones and broad-spectrum [3-1actams.
Symptomatic Infection with Evidence of a Prostatic Focus (Acute or Recurrent) Treatment studies are inadequate for both acute and chronic bacterial prostatitis due in part to the difficulties inherent in establishing an accurate diagnosis of prostatic infection. Oral or parenteral TMP/SMX is the drug of first choice for patients with acute bacterial prostatitis [34]. Although there are no careful studies, it is recommended that the treatment be continued for six weeks. A fluoroquinolone would be an appropriate alternative regimen for patients unable to tolerate TMP/SMX [31]. Recurrent or chronic bacterial prostatitis is diagnosed in patients with positive prostatic secretion cultures and negative urine cultures. TMP/SMX should be prescribed for 12 weeks in patients with positive prostatic secretion cultures with an organism susceptible to both TMP and SMX. Patients with resistant pathogens or intolerance of TMP/SMX should be treated with a fluoroquinolone. The duration of therapy is still uncertain but we recommend a 12-week course of treatment. The expected outcome is a 50--60% cure rate. Many patients with relapsing bacterial prostatic infection can be managed with continuous suppressive therapy using low doses of either TMP/SMX or a fluoroquinolone and maintained free of symptoms for years. Our understanding of prostatic infections remains limited with no useful advances over the past two decades other than the introduction of the fluoroquinolones. Basic and applied research is required to understand the pathogenesis and management of microbial invasion in the prostate.
Infections Acquired during Intermittent Catheterization in Patients with a Neurogenic Bladder (Symptomatic or Asymptomatic) No studies have proven that treatment is necessary in these patients in the absence of symptoms. However, S 168
because of recurring manipulation during catheter insertion, we treat these infections. Treatment regimens have not been adequately studied. Patients on intermittent catheterization should probably be followed with a urine culture whenever symptoms occur or at three monthly intervals. We would treat for three days in women and for two weeks in men, whenever asymptomatic infection is noted. Perhaps infections with gram-positive bacteria do not require treatment unless symptoms are present. Our regimen of choice is TMP/SMX if the organism is susceptible. A fluoroquinolone is an appropriate alternative if the organism is resistant to TMP/SMX. Symptomatic patients should be treated with an empirical regimen, presumably TMP/SMX unless resistance or intolerance are known to be present. The goal of treatment in these patients is eradication of the current infection and avoidance of reinfections with multi-resistant pathogens that are difficult to eradicate.
Urinary Tract Infection following Urological Procedures in Patients without Foreign Bodies or Catheters Infection is commonly present following prostatectomy and may also b e present after urological procedures. These infections should be seen as a failure to prevent infection. Post-urological infections appear to be difficult to treat because of postoperative changes in the urinary tract. However, in the absence of specific information, we would routinely treat hospital-acquired infections related to urological procedures regardless of symptoms. An empirical treatment regimen for women is a two-week course of TMP/SMX if the organism is susceptible. The fluoroquinolones are an acceptable alternative. Men who fall into this category can be treated with a six-week regimen of TMP/SMX or a quinolone. Follow-up cultures including culture of prostate secretions should be carried out at six weeks following completion of therapy to ensure cure.
Urinary Tract Infections following Renal Transplant Urinary infections commonly occur after renal transplant with an incidence of between 30 and 50%. Urinary infections also recur with increased frequency during prolonged follow-up [32,33]. Careful prospective studies have not been carried out in patients with a renal transplant. In the absence of these studies we would use a two-week regimen of TMP/SMX in women and a six-week TMP/SMX regimen in men [32,33]. A fluoroquinolone would be an acceptable alternative regimen. We would initiate treatment for both men and women with the diagnosis of infection regardless of symptoms. Follow-up would also be carried out in order to diagnose recurrences. Bacteriuria is potentially dangerous in
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patients with a transplant and should be eradicated if possible.
Urinary Tract Infection in Immunosuppressed Patients Urinary infections are more common in patients with organ transplants, the acquired immunodeficiency syndrome and a variety of other immunosuppressed states due to disease or treatment. Studies of optimal treatment regimens in these patients have not been adequately carried out. We consider that these infections should be treated regardless of symptoms and that follow-up cultures should be performed routinely to diagnose and treat recurrences. Our treatment regimen of choice is TMP/SMX with a course of therapy of two weeks in women and six weeks in men. Studies are needed to determine the efficacy of these treatment regimens.
Urinary Tract Infection in Patients with Polycystic Renal Disease or Nonfunctioning Renal Segments Bacteriuria is very common in patients with polycystic renal disease, occurring in about one-half of the patients followed longitudinally over 10 to 20 years. Bacteriuria in these patients can lead to serious complications including perinephric abscess. Patients with infectious cysts are often chronically ill with both local pain and systemic symptoms of infection. Treatment response is usually
poor. Many antibiotics such as the IMactams and aminoglycosides are not transferred across the cystic epithelial barrier [34]. Additional studies are required to evaluate lipophilic agents such as TMP/SMX and the fluoroquinolones. Until there is more information, we treat patients with symptomatic or asymptomatic infection in the presence of polycystic renal disease or a nonfunctioning renal segment. We prescribe TMP/SMX for six weeks. The fluoroquinolones may be good alternatives. If infections recur following treatment, we would continue long-term suppressive regimens for months and even years. The data demonstrating that this is of value are not available. Conclusion
Bacterial urinary tract infections in adults are treated daily by a variety of practitioners including urologists, infectious disease physicians, family practitioners and general physicians. Despite their frequency, we have not identified optimal therapeutic regimens for most categories of complicated urinary tract infection. As a result, most treatment regimens identified in this review are empirical and unproven. We urge physicians who frequently treat these patients to establish well-designed prospective studies of various treatment regimens and establish a scientific basis for the optimal management of urinary tract infection. Our patients should not expect less.
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6. Buckwold, F. J., Ludwig, P., Harding, G. K. M., Thompson, L, Slutchuk, M., Shaw, J., Ronald, A. R.: Therapy for acute cystitis in adult women. Randomized comparison of single-dose sulfisoxazole vs. trimethoprim- sulfamethoxazole. JAMA 247 (1982) 1839-1842.
7. Fihn, S. D., Johnson, C., Roberts, P. L, Running, K., Stature, W. E.: Trimethoprim-sulfamethoxazole for acute dysuria in women: a double blind randomized trial of single dose versus 10 day treatment. Ann. Intern. Med. 108 (1988) 350-357. 8. Hooten, T. M., Stature, W. E.: Management of acute uncomplicated urinary tract infection in adults. Med. Clin. N. Amer. 75 (1991) 333-357. 9. Greenberg, R. N., Sanders, C. V., Lewis, A. C., Marier, R. L : Single dose cefaclor therapy of urinary tract infection. Evaluation of antibody-coated bacteria test and C-reactive protein assay as predictors of cure. Amer. J. Med. 71 (1981) 841-845.
10. Cardenas, J. V., Quinn, E. L, Rooker, G. H., Bavinger, J. V., Pohlod, D. J.: Single dose cephalexin therapy of acute bacterial urinary tract infections and the acute urethral syndrome with bladder bacteriuria. Antimicrob. Agents Chemother. 29 (1986) 383.
11. Naber, K. G.: Efficacy and safety of fosfomycin trometamol in the treatment of uncomplicated urinary tract infection. In: Neu, H. C., Williams, J. 1). (eds.): New trends in urinary tract infections. Karger, Basel, Switzerland 1988, pp. 312-315. 12. Garlando, F., Rietiker, S., Tanher, M. G., Flepp, M., Meier, B., Luthy, R.: Single-dose ciprofloxacin at 100 versus 250 mg for treatment of uncomplicated urinary tract infections in women. Antimicrob. Agents Chemother. 31 (1987) 354-356. 13. Inter-Nordic Urinary Infection Group: Double blind comparison of 3 day vs. 7 day treatment with norfloxacin in symptomatic urinary tract infection. Scar@ J. Infect. Dis. 20 (1988) 619. 14. lrvani, A., Richard, G. A.: Single dose ceftriaxone versus multiple dose trimethoprim-sulfamethoxazole in the treatment of acute urinary infections. Antimicrob. Agents Chemother. 27 (1985) 158-161. 15. Safrin, S., Siegel, D., Black, D.: Pyelonephritis in adult women: Inpatient versus outpatient therapy. Amer. J. Med. 85 (1988) 793. 16. Stamm, W. E., McKevitt, M., Counts, 13. W.: Acute renal infection in women: treatment with trimethoprim sulfamethoxazole or ampicillin for 2 or 6 weeks. Ann. Intern. Med. 106 (1987) 341. 17. Jernelius, H., Zbornik, J., Bauer, C.: One or three week treatment of acute pyelonephritis: a double blind comparison using a fixed combination of pivampicitlin plus pivmecillinan. Acta Med. Scand. 223 (1988) 469. 18. Sheehan, G., Harding, G. K. M., Ronald, A. R.: Advances in the treatment of urinary tract infection. Amer. J. Med. 76 (1984) 141-147. 19. Johnson, J. R., Lions, M. F. II, Pearce, W., Gorman, P., Roberts, P.
L., White, N., Brust, P., Olsen, R., Gnann Jr., J. W., Stamm, W. E.: Therapy for women hospitalized with acute pyelonephritis: a
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randomized trial of ampiciUin vs. trimethoprim sutfamethoxazole for 14 days. J. Infect. Dis. 163 (1991) 325-330. 20. Ronald, A. R., Boutros, P., Mourtada, H.: Bacteriuria localization and response to single dose therapy in women. JAMA 235 (1976) 1854-1856.
21. Harding, G. K. M., Nicolle, L. E., Ronald, A. R., Preiksaitis, J. K., Forward, K. R., Low, D. E., Cheang, M.: How long should catheter-acquired urinary infection in women be treated? Ann. Intern. Med. 114 (1991) 713-719. 22. Lipsky, B. A.: Urinary tract infections in men: epidemiology, pathophysiology, diagnosis and treatment. Ann. Intern. Med. 110 (1989) 138-150.
23. Warren, J. W., Damrom, D., Tenney, J. H., Hoopes, J. M., Deforge, B., Muncie Jr., H. L.: Fever, bacteremia and death as complications of bacteriuria in women with long term urethral catheters. J. Infect. Dis. 155 (1987) 1151-1158. 24. Warren, J. W., Muncie Jr., H. L, Hall-Craggs, M.: Acute pyelonephritis associatedwith the bacteriuria of long-term catheterization: a prospective clinical pathological study. J. Infect. Dis. 158 (1988) 1341-1346.
25. Warren, J. W., Anthony, W. C., Hoopes, J. M, Muncie Jr., H. L: Cephalexin for susceptible bacteriuria in afebrile, long-term catheterized patients. JAMA 248 (1982) 454-458.
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26. Robbins, S. L , Tucker, A. W.: The cause of death in diabetes. New Engl. J. Med. 231 (1944) 865. 27. Forland, M., Thomas, V. L.: The treatment of urinary tract infections in women with diabetes meUitus. Diabetes Care 8 (1985) 499-506. 28 Hugosson, J., Grenabo, L, Hedelin, H., Lincoln, K~, Pettersson, S.: Chronic urinary tract infection and renal stones. Scand. J. Urol. Nephrol. 23 (1989) 61-66. 29. Saitoh, H., Nakamura, K., Hida, M., Satoh, T.: Urinary tract infection in oliguric patient with chronic renal failure. J. Urol. 133 (1985) 990-993. 30. Meares Jr., E. M.: Prostatitis. Med. Clin. N. Amer. 75 (1991) 405-424. 31. Naber, K. G.: Use of quinolones in urinary tract infections and prostatitis. Rev. Infect. Dis. 11 (.1989) S1321. 32. Ruhin, R. H., Wolfsan, J. S., Cosimi, A. B., Tolkoff-Rnhin, M. E.: Infections in the renal transplant recipient. Amer. J. Med. 70 (1981) 405-411. 33. Peterson, P. K., Anderson, R. C.: Infection in renal transplant recipients: current approaches to diagnosis, therapy and prevention. Amer. J. Med. 81 (1986) 2. 34. Sldar, A. H., Caruana, IL J., Lammers, J. E., Strauser, G. D.: Renal infections in autosomal dominant polycystic kidney disease. Amer. J. Kid. Dis. 10 (1987) 81-88.
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Standards of Therapy for Urinary Tract Infections in Adults Definitions Summary: Therapeutic standards have not been well defined for many forms of bacterial urinary tract infection. In women with uncomplicated infections, these exist for bacterial cystitis and for acute pyelonephritis. For most other categories of illness, among patients with complicated infections, no treatment regimens have been determined. As a result, well-designed clinical trials for these patient populations should be a priority.
Zusammenfassung: Standardisierung der Therapie von Harnwegsinfektionen bet Erwachsenen. Ftir viele Arten von bakteriellen Harnwegsinfektionen gibt es bisher keine standardisierte Therapie, ausgenommen die bakterielle Zystitis und akute Pyetonephritis bet Frauen mit unkomptizierten Infektionen. Ftir die meisten anderen Kategorien von Harnwegsinfektionen, einschlieBtich der Patienten mit komplizierten Infektionen, gibt es kein festgelegtes Therapieregime. Deshalb sollten bet diesen Patienten gut angelegte klinische Studien vorrangig durchgeftihrt werden.
Table 1: Classification of uncomplicated bacterial urinary tract infection in adults. 1. 2. 3. *4. 5. 6. 7. 8.
Acute cystitis in women Acute pyelonephritis in women Asymptomatic bacteriuria in men under 65 years of age. Asymptomatie bacteriuria in non-pregnant women under 65 years of age Asymptomatic bacteriuria in pregnant women Acute cystitis in men under 65 years of age Acute pyelonephritis in men under 65 years of age Post-catheterization bacteriuria in women under 65 years of age
Treatment not proven to alter favourably the natural history.
Introduction Therapeutic standards are essential for professional practice [t]. These are the "norms" which we communicate to our patients and students and use to evaluate quality of care. The therapeutic "norm" becomes the "gold standard" to which alternative or new therapeutic regimens are compared. Many common microbial infections, including bacterial urinary tract infections, lack well-determined therapeutic standards [2]. Poorly designed clinical trials lead to inconclusive and controversial recommendations. As a result, the standards we identify in this review will often be arbitrary and based on our best judgement of the published clinical trials and our own experience. In many instances, we will identify the lack of established or proven therapeutic standards. Optimal therapeutic regimens are scientifically determined by large prospective, well-designed studies which can identify clinically significant differences in efficacy and common adverse effects [ 2 ] . Most investigators determine the efficacy of a treatment regimen within a research milieu. Only rarely are studies carried out in a practice setting in which all patients are entered in order to determine "effectiveness." In the present review, we have categorized groups of patients with urinary tract infection in order to determine subsets in which the majority of adult patients can be placed. S 164
Bacterial infection of the bladder or of the upper urinary tract (kidneys and ureters) is the presence of bacteria in the urinary tract regardless of bacterial numbers or of any host response such as symptoms or p~aria. Optimal cost-effective microbiological strategies to make a diagnosis of infection are currently under review [3]. Urinary infections are further classified by the presence of underlying disease. For this review, an uncomplicated urinary tract infection (UTI) is infection of the bladder or kidney occurring in the normal host without structural or functional abnormalities of the urinary tract (Table 1).
Table 2: Classification of complicated bacterial urinary tract infection in adults. 1. "2. *3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Symptomatic infection in catheterized men or women Asymptomatic bacteriuria in the elderly (over 65 years old) Asymptomatic bacteriuria in catheterized men or women Infection associated With urinary calculi Infection associated with renal impairment (segmental, unilateral or bilateral) Symptomatic urinary tract infection with evidence of a prostatic focus of infection (acute or recurrent) Symptomatic and asymptomatic bacteriuria acquired during intermittent catheterization programmes Post-urological urinary tract infection Symptomatic and asymptomatic bacteriuria in patients with diabetes mellitus Symptomatic and asymptomatic bacteriuria in patients following renal transplant Symptomatic and asymptomatic infection associated with immunosuppression or neutropenia Symptomatic or asymptomatic infection with cystic renal disease
* Treatment not usually recommended.
A. R. Ronald, M.D. FRCPC, Lindsay E. Nicolle, M.D., FRCPC, G. K. 3//. Harding, M.D. FRCPC, Dept. of Medical Microbiology and Internal Medicine, University of Manitoba, St. Boniface General Hospital, 409 Tache Ave., Winnipeg, Manitoba R2H 2A6, Canada. Correspondence to: Dr. Lindsay NicoUe, Dept, of Clinical Microbiology, University of Manitoba, Room MS675D, 820 Sherbrook St., Winn!peg, Manitoba R3A 1R9, Canada.
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Urinary tract infection is "complicated" when one or more anatomical, functional or host abnormalities are present
(Table 2). We classify infections in pregnant patients as uncomplicated in the absence of any of these complications. A cure is defined as eradication of the initial pathogen(s) from the urinary tract. In therapeutic trials, this must be determined by follow-up urine cultures. These cultures should not be obtained during the first week following treatment because cultures at this time may be falsely negative. In our experience, over 90% of women who fail therapy with recurrence of the original pathogen after a course of treatment, do so within 14 days. Men may take weeks or months to relapse if the prostate is the persistent focus of infection. For the purposes of this review, a cure in women is defined as no recurrence of the original infecting pathogen(s) 14 days after completion of therapy and a cure in men is defined as no recurrence after six weeks with negative cultures from prostatic secretions. Uncomplicated infections should be successfully treated with population cure rates that exceed 95%. Complicated infections will "commonly" fail therapy. Why T r e a f f A rationale for treatment is important. Treatment for urinary tract infections is indicated for one or more of the following reasons: - to reduce the duration and severity of symptoms - to prevent bacteraemic sepsis or metastatic infection - to prevent complications during pregnancy - to prevent complications during manipulation of the urinary tract - to prevent stone formation or stone growth - to prevent direct invasion of structures adjacent to the urinary tract, such as the epididymis or the perinephric space - to prevent renal impairment - to prevent infections that would make concomitant illnesses more serious, e.g., diabetes mellitus. In the absence of indications for treatment, we would usually recommend against treatment (Tables 1 and 2). However, few studies have been carried out for most of these categories of infection and the decision to prescribe antimicrobial agents must be based on individual circumstances until adequate treatment studies have determined whether any advantage is to be gained by treatment. Standard Infection
Treatment
Regimens
for
Uncomplicated
costs, increased compliance, and fewer side effects [4-6]. Single-dose regimens have been most thoroughly studied and a cure rate of between 85 and 100% of women has been found if the organism is susceptible [4,5]. However, if recurrence of infection is used as a criterion for further investigation for upper tract pathology, unwarranted additional investigation and treatment may occur. Also, Fihn et al. have shown that a recent history of UTI, the use of a diaphragm and a spermicide, and the presence of more than 105 cfu/ml of the pathogen all predict a significantly increased failure rate with single-dose regimens [7]. Based on these observations, single-dose regimens may no longer be the preferred treatment option for women with acute cystitis. Norrby and Hooton et al. suggest that three-day regimens should be recognized as the empirical choice for this syndrome [4,8]. The combination of trimethoprim/sutphamethoxazole (TMP/SMX) prescribed as 160 mg/800 mg twice daily for three days is our preferred regimen. At least 95% of women will be predictably cured clinically and microbiologically. Less than 5% of patients will have significant side effects that require medical attention. If patients are allergic to sulphonamides, trimethoprim, 200 mg twice daily for three days, is an acceptable alternative. If resistance to trimethoprim is present in more than 5% of isolates from women with acute cystitis, equally effective and well-tolerated but less well-studied regimens are available and can be prescribed for three days. Amoxycillin or ampicillin are no longer useful antimicrobial agents because of the emergence of resistance in 15-30% of isolates in most parts of the world [8]. Oral cephalosporins such as cephalexin are effective, although [3-1actam drugs may have an increased rate of recurrence in comparison with other regimens [9,10]. Other single-dose or three-day regimens successfully used for treatment of acute cystitis include the trometamol salt of fosfomycin and the fluoroquinolones [11-13]. Parenteral regimens such as ceftriaxone or the aminoglycosides also cure more than 95% of women with acute cystitis when prescribed as a single-dose regimen but these are more expensive [14]. The fluoroquinolones are contraindicated in pregnancy. Trimethoprim- sulphonamide combinations have been used frequently in pregnancy and have not been associated with any reported adverse effects to the fetus other than the theoretical risk of kernicterus at term. Cephalexin is our agent of choice for pregnant women with uncomplicated acute cystitis who cannot tolerate trimethoprim/sulfamethoxazole or are near term [t0].
Women with Acute Cystitis
Women with Acute Uncomplicated Pyelonephritis
Regulatory agencies often require, and many practitioners continue to prescribe, a 7-14 day regimen for this common syndrome. Shorter courses of therapy have been shown to be equally effective and have the advantages of lower
Recent studies suggest that most women can be managed with oral regimens as outpatients [15]. The standard oral regimen as determined by prospective studies in ambulatory patients should be TMP 160 mg/SMX 800 mg
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A. IL Ronald et al.: Standards for Urinary Tract Infection prescribed twice daily for 14 days [16]. ~aanpicillin and amoxycillin are less effective on account of the prevalence of resistant organisms. Pivampicillin was much less effective when prescribed for one week as compared to three weeks [17]. For this reason, we favour a regimen of two weeks of therapy as the routine standard for acute uncomplicated pyelonephritis. Other oral regimens including ciprofloxacin and norfloxacin have also been used for the oral treatment of acute pyelonephritis. However, these have been less well investigated to date. Numerous parenteral regimens have been used for the initial therapy of hospitalized women with acute uncomplicated pyelonephritis. We have favoured ampicillin and gentamicin as an initial, inexpensive, empirical parenteral treatment, to be modified once the susceptibility of the infecting organism is known [18]. Johnson et al. randomized 85 women to ampicillin or TMP/SMX, both intravenously [19]. Both were combined initially with gentamicin [19]. No patient treated with TMP/SMX required modification of therapy. Fourteen of the 42 women treated with ampicillin and gentamicin were infected with ampicillin-resistant isolates and required treatment modification [19]. No treatment failures occurred in either group following a two-week treatment regimen. At present there is no evidence to continue parenteral therapy beyond the initial response with resolution of fever and local symptoms. In most instances we choose TMP/SMX and complete a two-week course of therapy. Ceftriaxone prescribed in a dose of 1 g/day is a suitable alternative regimen and is particularly well adapted for parenteral use at home. Women with uncomplicated acute pyelonephritis should have a urine culture two weeks following completion of therapy. If recurrence with the same infecting pathogen has occurred, further investigation is indicated with possible reclassification as a "complicated" urinary tract infection. Acute pyelonephritis in pregnancy should be managed in hospital. Although not proven, it is presumed that all patients should be initially prescribed parenteral therapy until a therapeutic response has occurred. It is hoped, although unproven, that this will prevent untoward complications of pregnancy. With the exception of the fluoroquinolones and TMP/SMX in the third trimester, the treatment regimen suggested for acute pyelonephritis in the non-pregnant patient is appropriate during pregnancy.
Asymptomatic Bacteriuria during Pregnancy Single-dose and three-day treatment regimens cure the majority of patients with this diagnosis [10,20]. As most patients will have a culture with susceptible results at the time therapy is initiated, a drug effective in vitro should be prescribed. ~aanoxycillin, 500 mg three times a day for three days, or other regimens identified as suitable for S 166
women with acute cystitis are, with the exception of the ftuoroquinolones, probably also appropriate for asymptomatic bacteriuria in pregnancy. Cephalexin has been prescribed as a single-dose, 2 g regimen with a good therapeutic outcome [t4].
Asymptomatic Infection following Catheter Removal in Women Large numbers of women who have required indwelling catheters for varying periods of time, will have bacteriuria following catheter removal. It has been assumed that many of these infections resolve spontaneously without specific therapy. A recent study by Harding et al. suggests that this premise is incorrect [21]. Almost a quarter of untreated Patients become symptomatic with either upper or lower tract illness within two weeks of catheter removal. As a result, these patients should be treated routinely. Harding et al. used TMP/SMX prescribed as either a single-dose regimen or twice daily for ten days [21]. Both regimens were equally effective in women under the age of 65 with cure rates in excess of 90%. However, older women failed both short and longer courses of therapy. Until further information is available, all women with catheter-acquired infections should be treated when the catheter is removed with either a single dose of an effective regimen such as TMP/SMX or a three-day regimen similar to that identified earlier for women with acute cystitis. Patients with catheter-associated bateriuria should not be left untreated following catheter removal.
Uncomplicated Infection in Men (Cystitis or Pyelonephritis) Acute symptomatic and asymptomatic infection in men with no evidence of obstruction, prostatic disease by rectal examination, or underlying renal disease occur with an incidence of about 0.3% per year in men 20-60 years of age [22]. Although it has been traditional to identify all male patients as complicated urinary infections with the assumption that extensive investigation is necessary, this has not been proven [22]. After the age of 60, the incidence of UTI rises dramatically. We presume that a greater proportion of elderly men have obstructive uropathy. At present, we prescribe regimens for these patients that are identical to those used in women with acute pyelonephritis. A 14-day course of parenteral and oral therapy or, in less acutely ill men, a 14-day course of oral therapy is appropriate. Standards of treatment must be determined by prospective studies. TMP/SMX or the fluoroquinolones are appropriate choices. Follow-up cultures, including prostatic secretion cultures, are warranted for study pruposes, and should be obtained at six weeks following completion of therapy. If patients are cured without any recurrence, further investigation is unnecessary. Patients who relapse should be identified as a "complicated urinary' infection" and investigated urologically and radiologically.
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Urinary Tract Infections in Patients with Diabetes
Few natural history or treatment studies or urinary infection have been stratified by the complicating factors. As a result, there are few standards of therapy and most regimens are empirical and will require revision once studies are carried out. Several categories of complicated infections are infrequent and can only be studied through multicentre trials. Well-defined, prospective, longitudinal studies should be a priority with planned intervention to treat, prevent or suppress infection as appropriate. In patients with asymptomatic bacteriuria, placebo controls are essential and, in most instances, are ethically acceptable. In Table 2, we have starred categories of patients with complicated infection for whom we consider treatment to be relatively contraindicated because of the absence of studies that suggest that treatment alters the natural history of these infections or prevents complications. Long treatment courses in patients with complicated infections frequently select out multiply-resistant pathogens that are difficult to eradicate.
Several possible synergistic interactions occur between diabetes and urinary infection. These include metabolic disturbances, urinary bladder dysfunction and renal microangiopathy. Histologically, post mortem evaluation prior to the antimicrobial era, documented "pyelonephritis" in one-fifth of patients, an occurrence five times that of non-diabetic patients [26]. At present, no evidence proves that the treatment of asymptomatic infection in men or women with diabetes leads to improved outcomes. Only one controlled study exists. Forland and Thomas, in a study of 45 adults, were unable to show that six weeks of trimethopritrd sulphamethoxazote was superior to two weeks [27]. However, on account of the serious consequences of invasive symptomatic infection in patients with diabetes, many experts treat asymptomatic infections in ambulatory patients. Prospective longitudinal studies are necessary to validate this approach. Acute pyelonephritis is common in patients with diabetes. At present, there are no studies to suggest that any treatment regimens are preferable and we recommend that the treatment regimens selected should be those previously identified for uncomplicated pyelonephritis in both men and women.
Symptomatic Infection in Patients with an Indwelling Catheter Patients with indwelling catheters have a mean of one febrile episode per 100 days of catheterization [23] and about one-half of the febrile episodes in these patients appear to arise from the urinary tract [23]. In women, many episodes resolve without antimicrobial therapy. On the other hand, autopsies reveal acute pyelonephritis in one-third of these patients [24]. Patients with catheters in place in one study were 40 times as likely to be bacteraemic with a febrile episode as those without catheters [23]. In the same study, 16 of 20 patients catheterized for one year had at least one episode of bacteraemia [23]. Avoiding catheterization or replacing the indwelling catheter with an intermittent catheterization programme should be considered in patients who have recurrent symptomatic infections associated with an indwelling catheter. Otherwise, treatment regimens in patients with indwelling catheters and symptomatic infection depend upon the antimicrobial susceptibility of the infecting pathogen. The goals of therapy are to reduce symptoms, treat invasive infection early, and to prevent superinfection with more resistant pathogens that are difficult to eradicate. In most instances a parenteral regimen of ampicillin and gentamicin is a satisfactory initial choice. The duration of therapy is unknown. We usually stop therapy after the patient has been afebrile for 48-72 h. Oral regimens may be equally satisfactory [25]. Long courses of oral therapy have not been shown to be of value in patients with an indwelling catheter and symptomatic urinary tract infection. Further treatment studies are necessary in this patient population.
Urinary Tract Infection Complicating Renal or Bladder Calculi Treatment will usually fail in patients with underlying urinary tract calculi. As a result, the therapeutic preference in these patients is to treat symptomatic infection and, in some instances, to suppress persistent infections in patients whose calculi cannot be removed [281. Acutely symptomatic infections should be treated with regimens similar to those identified for uncomplicated infections. However, with the initiation of treatment, a decision needs to be made about subsequent care. ObstrUction needs to be excluded. If infection is promoting stone growth, particularly in patients with urea splitting organisms, long-term suppressive therapy should be prescribed [28]. Stone removal is always the optimal course to follow in all patients with calculi.
Bacteriuria and Renal Impairment Urinary tract infection is a common accompaniment of renal impairment. In most instances, the impairment is unrelated to the bacteriuria but it may provoke concern because of either symptoms, or anxiety that infection is further endangering residual renal function. Renal impairment may be either unilateral or bilateral. Patients with unilateral renal impairment and infection in the involved kidney are difficult to treat. Few studies have been carried out. However, drugs rapidly eliminated by the healthy kidney to not achieve sufficient concentration in diseased renal tissue to achieve adequate bacterial cure
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A. R. Ronald et al.: Standards for Urinary Tract Infection or suppression of infection in the impaired infected kidney [29]. In the absence of careful studies, we prescribe therapeutic regimens which are not in themselves nephrotoxic and which achieve effective serum and tissue levels. Bilateral renal impairment adds a further concern with regard to inadequate renal tissue and urine levels. Although most antimicrobial agents are reasonably well studied prior to marketing with regard to renal handling in patients with impaired function, similar studies demonstrating treatment effectiveness for bacteriuria are not available. Careful, prospective, well-designed studies of therapeutic efficacy in patients with both unilateral and bilateral renal impairment are required. We would encourage trials with both the quinolones and broad-spectrum [3-1actams.
Symptomatic Infection with Evidence of a Prostatic Focus (Acute or Recurrent) Treatment studies are inadequate for both acute and chronic bacterial prostatitis due in part to the difficulties inherent in establishing an accurate diagnosis of prostatic infection. Oral or parenteral TMP/SMX is the drug of first choice for patients with acute bacterial prostatitis [34]. Although there are no careful studies, it is recommended that the treatment be continued for six weeks. A fluoroquinolone would be an appropriate alternative regimen for patients unable to tolerate TMP/SMX [31]. Recurrent or chronic bacterial prostatitis is diagnosed in patients with positive prostatic secretion cultures and negative urine cultures. TMP/SMX should be prescribed for 12 weeks in patients with positive prostatic secretion cultures with an organism susceptible to both TMP and SMX. Patients with resistant pathogens or intolerance of TMP/SMX should be treated with a fluoroquinolone. The duration of therapy is still uncertain but we recommend a 12-week course of treatment. The expected outcome is a 50--60% cure rate. Many patients with relapsing bacterial prostatic infection can be managed with continuous suppressive therapy using low doses of either TMP/SMX or a fluoroquinolone and maintained free of symptoms for years. Our understanding of prostatic infections remains limited with no useful advances over the past two decades other than the introduction of the fluoroquinolones. Basic and applied research is required to understand the pathogenesis and management of microbial invasion in the prostate.
Infections Acquired during Intermittent Catheterization in Patients with a Neurogenic Bladder (Symptomatic or Asymptomatic) No studies have proven that treatment is necessary in these patients in the absence of symptoms. However, S 168
because of recurring manipulation during catheter insertion, we treat these infections. Treatment regimens have not been adequately studied. Patients on intermittent catheterization should probably be followed with a urine culture whenever symptoms occur or at three monthly intervals. We would treat for three days in women and for two weeks in men, whenever asymptomatic infection is noted. Perhaps infections with gram-positive bacteria do not require treatment unless symptoms are present. Our regimen of choice is TMP/SMX if the organism is susceptible. A fluoroquinolone is an appropriate alternative if the organism is resistant to TMP/SMX. Symptomatic patients should be treated with an empirical regimen, presumably TMP/SMX unless resistance or intolerance are known to be present. The goal of treatment in these patients is eradication of the current infection and avoidance of reinfections with multi-resistant pathogens that are difficult to eradicate.
Urinary Tract Infection following Urological Procedures in Patients without Foreign Bodies or Catheters Infection is commonly present following prostatectomy and may also b e present after urological procedures. These infections should be seen as a failure to prevent infection. Post-urological infections appear to be difficult to treat because of postoperative changes in the urinary tract. However, in the absence of specific information, we would routinely treat hospital-acquired infections related to urological procedures regardless of symptoms. An empirical treatment regimen for women is a two-week course of TMP/SMX if the organism is susceptible. The fluoroquinolones are an acceptable alternative. Men who fall into this category can be treated with a six-week regimen of TMP/SMX or a quinolone. Follow-up cultures including culture of prostate secretions should be carried out at six weeks following completion of therapy to ensure cure.
Urinary Tract Infections following Renal Transplant Urinary infections commonly occur after renal transplant with an incidence of between 30 and 50%. Urinary infections also recur with increased frequency during prolonged follow-up [32,33]. Careful prospective studies have not been carried out in patients with a renal transplant. In the absence of these studies we would use a two-week regimen of TMP/SMX in women and a six-week TMP/SMX regimen in men [32,33]. A fluoroquinolone would be an acceptable alternative regimen. We would initiate treatment for both men and women with the diagnosis of infection regardless of symptoms. Follow-up would also be carried out in order to diagnose recurrences. Bacteriuria is potentially dangerous in
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patients with a transplant and should be eradicated if possible.
Urinary Tract Infection in Immunosuppressed Patients Urinary infections are more common in patients with organ transplants, the acquired immunodeficiency syndrome and a variety of other immunosuppressed states due to disease or treatment. Studies of optimal treatment regimens in these patients have not been adequately carried out. We consider that these infections should be treated regardless of symptoms and that follow-up cultures should be performed routinely to diagnose and treat recurrences. Our treatment regimen of choice is TMP/SMX with a course of therapy of two weeks in women and six weeks in men. Studies are needed to determine the efficacy of these treatment regimens.
Urinary Tract Infection in Patients with Polycystic Renal Disease or Nonfunctioning Renal Segments Bacteriuria is very common in patients with polycystic renal disease, occurring in about one-half of the patients followed longitudinally over 10 to 20 years. Bacteriuria in these patients can lead to serious complications including perinephric abscess. Patients with infectious cysts are often chronically ill with both local pain and systemic symptoms of infection. Treatment response is usually
poor. Many antibiotics such as the IMactams and aminoglycosides are not transferred across the cystic epithelial barrier [34]. Additional studies are required to evaluate lipophilic agents such as TMP/SMX and the fluoroquinolones. Until there is more information, we treat patients with symptomatic or asymptomatic infection in the presence of polycystic renal disease or a nonfunctioning renal segment. We prescribe TMP/SMX for six weeks. The fluoroquinolones may be good alternatives. If infections recur following treatment, we would continue long-term suppressive regimens for months and even years. The data demonstrating that this is of value are not available. Conclusion
Bacterial urinary tract infections in adults are treated daily by a variety of practitioners including urologists, infectious disease physicians, family practitioners and general physicians. Despite their frequency, we have not identified optimal therapeutic regimens for most categories of complicated urinary tract infection. As a result, most treatment regimens identified in this review are empirical and unproven. We urge physicians who frequently treat these patients to establish well-designed prospective studies of various treatment regimens and establish a scientific basis for the optimal management of urinary tract infection. Our patients should not expect less.
References 1. Ronald, A. R.: Clinical trials of antimicrobial agents following licensure. J. Infect. Dis. 159 (1989) 3-6. 2. Fihn, S. D., Stature, W. E.: Interpretation and comparison of treatment studies for uncomplicated urinary tract infection in women. Rev. Infect. Dis. 7 (1985) 468-478. 3. Johnson, J. R., Stature, W. E.: Diagnosis and treatment of acute urinary tract infection. Infect. Dis. Clin. N. Amer. 1 (1987) 773. 4. Norrby, S. R.: Short-term treatment of uncomplicated lower urinary tract infections in women. Rev. Infect. Dis. 12 (1990) 458. 5. Johnson, J. R., Stature, W. E.: Urinary tract infection in women: diagnosis and treatment. Ann. Intern. Med. 111 (1989) 906.
6. Buckwold, F. J., Ludwig, P., Harding, G. K. M., Thompson, L, Slutchuk, M., Shaw, J., Ronald, A. R.: Therapy for acute cystitis in adult women. Randomized comparison of single-dose sulfisoxazole vs. trimethoprim- sulfamethoxazole. JAMA 247 (1982) 1839-1842.
7. Fihn, S. D., Johnson, C., Roberts, P. L, Running, K., Stature, W. E.: Trimethoprim-sulfamethoxazole for acute dysuria in women: a double blind randomized trial of single dose versus 10 day treatment. Ann. Intern. Med. 108 (1988) 350-357. 8. Hooten, T. M., Stature, W. E.: Management of acute uncomplicated urinary tract infection in adults. Med. Clin. N. Amer. 75 (1991) 333-357. 9. Greenberg, R. N., Sanders, C. V., Lewis, A. C., Marier, R. L : Single dose cefaclor therapy of urinary tract infection. Evaluation of antibody-coated bacteria test and C-reactive protein assay as predictors of cure. Amer. J. Med. 71 (1981) 841-845.
10. Cardenas, J. V., Quinn, E. L, Rooker, G. H., Bavinger, J. V., Pohlod, D. J.: Single dose cephalexin therapy of acute bacterial urinary tract infections and the acute urethral syndrome with bladder bacteriuria. Antimicrob. Agents Chemother. 29 (1986) 383.
11. Naber, K. G.: Efficacy and safety of fosfomycin trometamol in the treatment of uncomplicated urinary tract infection. In: Neu, H. C., Williams, J. 1). (eds.): New trends in urinary tract infections. Karger, Basel, Switzerland 1988, pp. 312-315. 12. Garlando, F., Rietiker, S., Tanher, M. G., Flepp, M., Meier, B., Luthy, R.: Single-dose ciprofloxacin at 100 versus 250 mg for treatment of uncomplicated urinary tract infections in women. Antimicrob. Agents Chemother. 31 (1987) 354-356. 13. Inter-Nordic Urinary Infection Group: Double blind comparison of 3 day vs. 7 day treatment with norfloxacin in symptomatic urinary tract infection. Scar@ J. Infect. Dis. 20 (1988) 619. 14. lrvani, A., Richard, G. A.: Single dose ceftriaxone versus multiple dose trimethoprim-sulfamethoxazole in the treatment of acute urinary infections. Antimicrob. Agents Chemother. 27 (1985) 158-161. 15. Safrin, S., Siegel, D., Black, D.: Pyelonephritis in adult women: Inpatient versus outpatient therapy. Amer. J. Med. 85 (1988) 793. 16. Stamm, W. E., McKevitt, M., Counts, 13. W.: Acute renal infection in women: treatment with trimethoprim sulfamethoxazole or ampicillin for 2 or 6 weeks. Ann. Intern. Med. 106 (1987) 341. 17. Jernelius, H., Zbornik, J., Bauer, C.: One or three week treatment of acute pyelonephritis: a double blind comparison using a fixed combination of pivampicitlin plus pivmecillinan. Acta Med. Scand. 223 (1988) 469. 18. Sheehan, G., Harding, G. K. M., Ronald, A. R.: Advances in the treatment of urinary tract infection. Amer. J. Med. 76 (1984) 141-147. 19. Johnson, J. R., Lions, M. F. II, Pearce, W., Gorman, P., Roberts, P.
L., White, N., Brust, P., Olsen, R., Gnann Jr., J. W., Stamm, W. E.: Therapy for women hospitalized with acute pyelonephritis: a
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21. Harding, G. K. M., Nicolle, L. E., Ronald, A. R., Preiksaitis, J. K., Forward, K. R., Low, D. E., Cheang, M.: How long should catheter-acquired urinary infection in women be treated? Ann. Intern. Med. 114 (1991) 713-719. 22. Lipsky, B. A.: Urinary tract infections in men: epidemiology, pathophysiology, diagnosis and treatment. Ann. Intern. Med. 110 (1989) 138-150.
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Infection 20 (1992) Suppl. 3 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1992
