Acute Uncomplicated Pyelonephritis
Patients with clear-cut symptomatic pyelonephritis have deep-tissue infection, have (or are at risk for) bacteremia, and merit antimicrobial therapy. Two requirements guide the initial choice of antimicrobial regimens for pyelonephritis: the probability that the infecting organism is sensitive to the regimen should be at least 99%, and therapeutic blood levels should be quickly achievable. Depending on the severity of illness and the presence of comorbid conditions, pyelonephritis can be initially managed with oral outpatient therapy or with parenteral inpa-tient therapy. Patients with mild disease (low-grade fever and no signs of sepsis) who are otherwise healthy and do not have significant nausea or vomiting can be managed as outpatients with an oral fluoroquinolone or TMP-SMX [see Figure 3 and Table 4].4,29,50 A randomized clinical trial demonstrated that 7 days of therapy with oral ciprofloxacin (with or without an initial intra venous dose of the drug) was highly effective for the initial management of pyelonephritis in the outpatient setting.50 Oral TMP-SMX is also very effective but should not be used unless the prevalence of TMP-SMX resistance in the area is very low or the strain is known to be susceptible.29 An initial I.V. dose of ceftriax-one should be considered when oral TMP-SMX is being used, because in one study, patients receiving this combination regimen had high success rates even when the infecting strain was resistant to TMP-SMX.51 Amoxicillin-clavulanate should be considered if the Gram stain suggests enterococci. Regardless of which outpatient oral regimen is chosen, an initial I.V. dose of a fluoroquinolone or a third-generation cephalosporin in an observed setting may be of benefit.33
Figure 3 Clinical approach to acute uncomplicated pyelonephritis in a woman.
Patients who are severely ill, cannot tolerate oral medication, or have complicating medical conditions should be hospitalized for parenteral therapy. Various regimens can be used, such as ampicillin plus gentamicin; fluoroquinolones; the third-generation cephalosporins (e.g., ceftriaxone); or, for susceptible strains, TMP-SMX. Combinations of a ^-lactam and a ^-lactamase inhibitor (e.g., ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam) or imipenem-cilastatin can be used in patients with more complicated histories, previous episodes of pyelonephritis, or recent urinary tract manipulations. After the patient has been afebrile for 24 hours (usually within 72 hours of initiating therapy), there is no benefit in maintaining parenteral therapy. Currently, prescription of oral TMP-SMX or a fluoro-quinolone to complete a 14-day course of outpatient therapy appears to be the most effective means of eradicating both tissue infection and residual clones of uropathogens present in the GI tract that could cause early recurrence if allowed to remain.
UTI during Pregnancy
There are three major differences between the approach to UTI in pregnant women and that in nonpregnant women. First, in pregnant women, asymptomatic bacteriuria is actively sought and is as aggressively treated and followed as symptomatic infection; this is clearly not the case in nonpregnant women, for whom screening for asymptomatic bacteriuria is not recommended. Second, although short-course therapy is also the cornerstone of treatment during pregnancy for patients with uncomplicated cystitis (as well as those with asymptomatic bacteri-uria), the drugs that can be safely used are far more limited for pregnant women. Third, follow-up of patients with bacteriuria during pregnancy is more intense, with a more rapid deployment of prophylactic strategies in pregnant women with recurrent bacteriuria.11
Nitrofurantoin, ampicillin, and the cephalosporins have been considered relatively safe in early pregnancy. Sulfonamides should be avoided in the first trimester because of possible ter-atogenic effects and avoided near term because of a possible role in the development of kernicterus. Trimethoprim is usually avoided because of evidence of fetal toxicity at high doses in animals, although it has been used successfully in humans during pregnancy without evidence of toxicity or teratogenicity. Fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. Nitrofurantoin, ampicillin, and the cephalosporins have been used most extensively in pregnancy and are the regimens of choice for the treatment of asymptomatic or minimally symptomatic UTI [see Table 3]. For pregnant women with overt pyelonephritis, admission to the hospital for parenteral therapy should be the standard of care; ^-lactams with or without aminoglycosides are the cornerstone of therapy.
Prevention of UTI, including pyelonephritis, can be accomplished during pregnancy with nitrofurantoin or cephalexin taken prophylactically after coitus or at bedtime without relation to coitus. Such prophylaxis should be considered for patients who have had acute pyelonephritis during pregnancy, patients with bacteriuria during pregnancy who have had a recurrence after a course of treatment, and patients who had recurrent UTI before pregnancy that required prophylaxis.
Treatment of Men with UTI
It is uncommon for men to have UTI that is analogous to acute uncomplicated cystitis in women. Even when seemingly uncomplicated UTI does occur, men should never be treated with short-course therapy, because of a high rate of early relapse. Instead, 7- to 14-day regimens of a fluoroquinolone should be prescribed. TMP-SMX is the best alternative drug, assuming susceptibility of the strain.
In men older than 50 years with UTI, bacterial invasion of the prostate and possibly the kidneys should be considered, even in the absence of overt signs of infection at these sites. Acute bacterial prostatitis should be treated with a fluoroquinolone for 2 weeks or with TMP-SMX for at least 4 weeks. Recurrence is common and usually connotes a sustained focus in the prostate that has not been eradicated. Several factors make eradication of prostatic foci difficult. Many antimicrobial agents do not diffuse well across the prostatic epithelium into the prostatic fluid, where the infection lies. The prostate may harbor calculi, which can block drainage of portions of the prostate gland or act as foreign bodies in which persistent infection can reside. An enlarged (and inflamed) prostate gland can cause bladder outlet obstruction, resulting in pools of stagnant urine in the bladder that are difficult to sterilize.28
In view of these factors, intensive therapy for at least 4 to 6 weeks is recommended for chronic bacterial prostatitis. The drugs of choice for this purpose, assuming the organisms are susceptible, are the fluoroquinolones. The best alternative agent is TMP-SMX. Prolonged treatment with any of these drugs has a greater than 60% probability of eradicating infection. Most therapeutic failures result from either anatomic factors or infection by Enterococcus faecalis or P. aeruginosa; these two organisms are particularly likely to cause relapse after treatment with the antimicrobial agents currently recommended. Relapses should be treated for 12 weeks. If this therapy fails, long-term antimicrobial suppression or repeated treatment courses for each relapse are often needed.28
Complicated UTI
Complicated UTI occurs in a heterogeneous group of patients with a wide variety of structural and functional abnormalities of the urinary tract and kidneys. The range of antimicrobial species and their susceptibility to antimicrobial agents are likewise heterogeneous. As a consequence, therapy for patients with complicated UTI requires individualization, although the following guidelines appear to be useful54:
• As a rule, only symptomatic UTI requires therapy.
• If symptoms of UTI are present, a urine culture and susceptibilities should always be obtained.
• If the antimicrobial susceptibilities of the infecting organism are not known and symptomatic infection requires immediate therapy, consideration of previous microbiology or recent antimicrobial exposures can help guide initial empirical therapy.
• In patients with mild disease [see Pyelonephritis, above]), an oral regimen with a fluoroquinolone, or possibly TMP-SMX, is appropriate and can be given in the outpatient or inpatient setting depending on other patient factors.
• In patients who cannot take oral regimens or who have more severe disease, intravenous therapy with fluoroquinolones or broad-spectrum agents such as ampicillin plus gentamicin, imipenem-cilastatin, or piperacillin-tazobactam should be considered until the susceptibilities of the invading organism are identified [see Table 4].
• Whenever possible, every effort should be made to correct the underlying complicating factor in conjunction with the antimicrobial therapy.
Asymptomatic Bacteriuria
Bacteriuria detected in the absence of symptoms referable to the urinary tract does not warrant antimicrobial therapy except in specific settings. These include during pregnancy, before surgery or instrumentation of the urinary tract, and after renal transplantation. Treatment of asymptomatic bacteriuria in patients who are immunosuppressed because of transplantation other than renal (i.e., other solid organ or bone marrow) or because of neutropenia has not been well studied and is not currently recommended as standard practice.
In women with diabetes and asymptomatic bacteriuria, a large randomized trial of antimicrobial treatment versus no antimicrobials found no difference in the time to first symptomatic UTI between the groups. The authors conclude that there is no benefit to screening for asymptomatic bacteriuria or treating it in women with diabetes.
Radiologic evaluation to rule out functional abnormalities
A final consideration in the management of UTI is the role of radiologic evaluation. Intravenous pyelography, ultrasonogra-phy, or CT should be carried out expeditiously to rule out obstruction in any patient with acute pyelonephritis who does not respond to an effective antimicrobial agent and in any patient in whom a persistent bacteremia has been demonstrated. Contrast-enhanced helical CT is the radiologic study of choice for imaging and evaluation of renal infections. The study should be performed without contrast when renal calculi are suspected.
Table 4 Treatment Regimens for Acute Pyelonephritis4
|
Patient Status |
Regimen |
Comment |
|
Outpatient |
Fluoroquinolones x 7-14 days* |
Fluoroquinolones can be given orally throughout the entire course, if patient can tolerate oral intake |
|
Ciprofloxacin, 250-500 mg q. 12 hr |
||
|
Ciprofloxacin XR, 1,000 mg q.d. |
||
|
Gatifloxacin, 400 mg q.d. |
||
|
Levofloxacin, 250-500 mg q.d. |
||
|
TMP-SMX, 160/800 mg q. 12 hr x 14 days |
If strain is likely to be susceptible |
|
|
Amoxicillin, 500 mg q. 8 hr or 875 mg q. 12 hr |
||
|
Amoxicillin-clavulanate, 875/125 mg q. 12 hr x 14 days |
If Enterococcus is suspected |
|
|
Inpatient |
I.V. fluoroquinolones x 14 days |
Patients can be switched to oral therapy after they have been afebrile for 24 hr |
|
Ciprofloxacin, 200-400 mg q. 12 hr |
||
|
Gatifloxacin, 400 mg q.d. |
Particularly useful if enterococcal infection is suspected |
|
|
Levofloxacin, 250-500 mg q.d. |
||
|
Ceftriaxone,* 1-2 g I.V. q. 24 hr, or other third- or fourth-generation cephalosporin |
||
|
Ampicillin, 1 g I.V q. 6 hr plus gentamicin, 1 mg/kg I.V. q. 8 hr or 3-5 mg/kg I.V. q. 24 hr |
||
|
Ampicillin-sulbactam |
||
|
Ticarcillin-clavulanate |
||
|
Piperacillin-tazobactam |
Useful in complicated cases |
|
|
Imipenem-cilastatin |
*First dose of a fluoroquinolone or ceftriaxone may be given intravenously.
TMP-SMX—trimethoprim-sulfamethoxazole
For ambulatory patients who have UTI, guidelines are less clear. Radiographic evaluation, usually with intravenous pyel-ography and voiding cystourethrography, is carried out for delineation of surgically correctable lesions that might predispose patients to recurrent infection or progressive renal disease. Because congenital anatomic anomalies are particularly prevalent in young children who have a first or second UTI, such studies are obligatory for patients in this age group. In addition, careful prostatic examination and assessment of postvoiding residual urine volume should be considered in males with UTI at any stage of life because such infection is highly unlikely in this population unless anatomic anomalies or specific risk factors are present55 [see Young Men, above]. In women with uncomplicated UTI, the incidence of correctable anatomic lesions is so low that radiologic and urologic evaluation should be restricted to patients who have rapid recurrence of infection or recurrent pyelonephritis despite adequate therapy.26
Catheter-Associated UTI
UTIs are the most common nosocomial infections, representing 40% of all such infections. Most nosocomial UTIs are related to bladder catheterization. Catheter-associated UTIs are associated with increased mortality and costs.56,57 Multiple risk factors for catheter-associated UTIs have been identified, including the duration of catheterization, lack of systemic antibiotic therapy, female sex, age older than 50 years, and azotemia.57 Risk factors for bacteremia related to catheter-associated UTI are not well established.
Several guidelines can be followed to minimize the occurrence of catheter-related infection [see Table 5]. Most important, the catheter should be inserted with strict aseptic technique by trained persons. In addition, a closed system should be used at all times. Even with optimal care, however, catheter use for 1 month or longer will eventually result in bladder infection. Apparently, little additional protection is provided by antibiotic rinses for the bladder, antibiotic ointments applied to the ure-thral meatus, and instillation of disinfectants such as hydrogen peroxide into the urinary collection bag. Although systemic antibiotics are of no value when the closed system is to be in place for an extended period, antibiotics may be protective when the catheter is in place for only a few days.56 However, this advantage should be balanced against the risk of selecting for resistant flora if catheterization must be prolonged unexpectedly. In patients who require urethral catheterization for 2 to 10 days, use of a silver alloy-coated urinary catheter may offer some protection against infection.58-60 In one randomized study of hospitalized patients, the use of a silver alloy-coated urinary catheter resulted in a lower rate of UTIs and a significant cost savings.59 A nitrofurazone-impregnated catheter also has been shown to decrease the incidence of UTIs caused by gram-negative organisms.60
Treatment of catheter-associated UTI depends on the clinical circumstances.
|
Table 5 Guidelines for Bladder Catheter Care |
|
Use catheters only when absolutely necessary; remove as soon as possible. |
|
Insert catheters aseptically and maintain by trained personnel only. |
|
A sterile closed drainage system is mandatory. The catheter and drainage tube must never be disconnected except when irrigation is necessary to relieve obstruction. Strict aseptic technique is employed under these circumstances. |
|
Obtain urine for culture by aspirating the catheter with a 21-gauge needle after the catheter is prepared with povidone-iodine. |
|
Maintain downhill, nonobstructed flow, with the collection bag always below the level of the bladder and emptied at frequent intervals. |
|
Replace indwelling catheters when obstruction or concretions are demonstrated. |
|
Strict hand-washing precautions should be observed by staff caring for these patients. |
|
Administer prophylactic antibiotics during catheter insertion and removal to patients with cardiac disease (particularly prosthetic valves) that predisposes to bacterial endocarditis. |
Symptomatic patients (e.g., those with fever, chills, dyspnea, and hypotension) require immediate antibiotic therapy [see Complicated UTI, above]. In addition, it may be useful to remove and replace the urinary catheter if it has been in place for a week or longer. This eliminates difficult-to-eradicate organisms in the biofilm on the catheter. In an asymptomatic patient, therapy should be postponed until the catheter can be removed. Patients with persistent asymptomatic bacteriuria and those with lower urinary tract symptoms who have had the catheter removed respond well to short-course therapy.
Patients with long-term indwelling catheters seldom become symptomatic unless the catheter is obstructed or is eroding through the bladder mucosa. In patients who do become symptomatic, appropriate antibiotics should be administered, and the catheter should be changed. Therapy for asymptomatic catheterized patients leads to the selection of increasingly antibiotic-resistant bacteria.56,57,60 Thus, although long-term bladder catheterization carries a significant risk of chronic pyelonephritis (10% or more if the catheter is in place for more than 90 days), there is no way to avoid this event other than by catheter removal.
The appearance of Candida in the urine is an increasingly common complication of indwelling catheterization, particularly for patients in the intensive care unit, on broad-spectrum antimicrobials, or with underlying diabetes mellitus.63 C. albicans is still the most common isolate, although C. glabrata and other non-albicans species are also frequently isolated. The clinical presentation can vary from an asymptomatic laboratory finding to sepsis. In asymptomatic patients, removal of the urethral catheter results in resolution of the candiduria in as many as one third of cases. For patients with symptomatic candiduria (fever with or without cystitis symptoms), oral fluconazole, 200 mg/day for 7 to 14 days, has been shown to be highly effective. This regimen was even effective for non-albicans species of Candida that had reduced susceptibility to fluconazole, possibly because of the high concentrations achieved in the urine. For more severely ill patients, the possibility of pyelonephritis and can-didemia should be evaluated, and systemic antifungal therapy with fluconazole, 6 mg/kg/day, or amphotericin, 0.6 mg/kg or more a day, should be instituted.
Prognosis
Although earlier epidemiologic studies suggested that bac-teriuria, whether symptomatic or asymptomatic, was associated with increased mortality, more recent findings suggest that bac-teriuria does not itself cause an increase in mortality.64 Rather, bacteriuria appears to be a marker for poor health, particularly in elderly patients. Not surprisingly, then, antimicrobial therapy for asymptomatic bacteriuria in the elderly is of no demonstrable clinical benefit.65,66
The relationships between recurrent UTI, chronic pyelonephritis, and renal insufficiency have been widely studied. In the absence of anatomic abnormalities, recurrent infection in children and adults does not lead to chronic pyelonephritis or to renal failure. Also, infection does not play a primary role in chronic interstitial nephritis; the primary etiologic factors in this condition are analgesic abuse, obstruction, reflux, and toxin exposure. In the presence of underlying renal abnormalities, however, infection as a secondary factor can accelerate renal parenchymal damage. In children, the common combination of reflux, congenital anomalies, and infection appears to lead to significant renal parenchymal damage; moreover, kidneys in children appear to be more susceptible to damage than kidneys in adults.23
A retrospective questionnaire study has found that men and women newly diagnosed with renal cell carcinoma were more likely to have a history of cystitis or pyelonephritis sometime in their lifetime and to be smokers than persons without renal cell carcinoma.67 The risk was greater for males than females. Although the study shows a possible association between UTI and renal cell cancer, data on causality, temporal relatedness, dose effect, and putative mechanisms are lacking.
