TREATMENT Urinary Tract Infections
Antimicrobial therapy is warranted for any symptomatic UTI. The choice of antimicrobial agent and the dose and duration of therapy depend on the site of infection and the presence or absence of complicating conditions. Each category of UTI warrants a different approach based on the particular clinical syndrome.
Antimicrobial resistance among uropathogens varies from region to region and impacts the approach to empirical treatment of UTI. E. coli ST131 is the predominant multilocus sequence type found worldwide as the cause of multidrug-resistant UTI. Recommendations for treatment must be considered in the context of local resistance patterns and national differences in some agents’ availability. For example, fosfomycin and pivmecillinam are not available in all countries but are considered first-line options where they are available because they retain activity against a majority of uropathogens that produce extended-spectrum β-lactamases. Thus, therapeutic choices should depend on local resistance, drug availability, and individual patient factors such as recent travel and antimicrobial use. UNCOMPLICATED CYSTITIS IN WOMEN
Since the species and antimicrobial susceptibilities of the bacteria that cause acute uncomplicated cystitis are highly predictable, many episodes of uncomplicated cystitis can be managed over the telephone (Fig. 33-4). Most patients with other UTI syndromes require further diagnostic evaluation. Although the risk of serious complications with telephone management appears to be low, studies of telephone management algorithms generally have involved otherwise healthy white women who are at low risk for complications of UTI.
In 1999, TMP-SMX was recommended as the first-line agent for treatment of uncomplicated UTI in the published guidelines of the Infectious Diseases Society of America. Antibiotic resistance among uropathogens causing uncomplicated cystitis has since increased, appreciation of the importance of collateral damage (as defined below) has increased, and newer agents have been studied. Unfortunately, there is no longer a single best agent for acute uncomplicated cystitis.
Collateral damage refers to the adverse ecologic effects of antimicrobial therapy, including killing of the normal flora and selection of drug-resistant organisms. Outbreaks of Clostridium difficile infection offer an example of collateral damage in the hospital environment. The implication of collateral damage in this context is that a drug that is highly efficacious for the treatment of UTI is not necessarily the optimal first-line agent if it also has pronounced secondary effects on the normal flora or is likely to change resistance patterns. Drugs used for UTI that have a minimal effect on fecal flora include pivmecillinam, fosfomycin, and nitrofurantoin. In contrast, trimethoprim, TMP-SMX, quinolones, and ampicillin affect the fecal flora more significantly; these drugs are notably the agents for which rising resistance levels have been documented.
Several effective therapeutic regimens are available for acute uncomplicated cystitis in women (Table 33-1). Well-studied first-line agents include TMP-SMX and nitrofurantoin. Second-line agents include fluoroquinolone and β-lactam compounds. Single-dose fosfomycin treatment for acute cystitis is widely used in Europe but has produced mixed results in randomized trials. There is increasing experience with the use of fosfomycin against UTIs (including complicated infections) caused by multidrug-resistant E. coli. Pivmecillinam is not currently available in the United States or Canada but is a popular agent in some European countries. The pros and cons of other therapies are discussed briefly below.
Traditionally, TMP-SMX has been recommended as first-line treatment for acute cystitis, and it remains appropriate to consider the use of this drug in regions with resistance rates not exceeding 20%. TMP-SMX resistance has clinical significance: in TMP-SMX-treated patients with resistant isolates, the time to symptom resolution is longer and rates of both clinical and microbiologic failure are higher. Individual host factors associated with an elevated risk of UTI caused by a strain of E. coli resistant to TMP-SMX include recent use of TMP-SMX or another antimicrobial agent and recent travel to an area with high rates of TMP-SMX resistance. The optimal setting for empirical use of TMP-SMX is uncomplicated UTI in a female patient who has an established relationship with the practitioner and who can thus seek further care if her symptoms do not respond promptly.
Resistance to nitrofurantoin remains low despite >60 years of use. Since this drug affects bacterial metabolism in multiple pathways, several mutational steps are required for the development of resistance. Nitrofurantoin remains highly active against E. coli and most non–E. coli isolates. Proteus, Pseudomonas, Serratia, Enterobacter, and yeasts are all intrinsically resistant to this drug. Although nitrofurantoin has traditionally been prescribed as a 7-day regimen, similar microbiologic and clinical efficacies are noted with a 5-day course of nitrofurantoin or a 3-day course of TMP-SMX for treatment of women with acute cystitis; 3-day courses of nitrofurantoin are not recommended for acute cystitis. Nitrofurantoin does not reach significant levels in tissue and cannot be used to treat pyelonephritis.
Most fluoroquinolones are highly effective as short-course therapy for cystitis; the exception is moxifloxacin, which may not reach adequate urinary levels. The fluoroquinolones commonly used for UTI include ofloxacin, ciprofloxacin, and levofloxacin. The main concern about fluoroquinolone use for acute cystitis is the propagation of fluoroquinolone resistance, not only among uropathogens but also among other organisms causing more serious and difficult-to-treat infections at other sites. Fluoroquinolone use is also a factor driving the emergence of C. difficile outbreaks in hospital settings. Most experts now call for restricting fluoroquinolones to specific instances of uncomplicated cystitis in which other antimicrobial agents are not suitable. Quinolone use in certain populations, including adults >60 years of age, has been associated with an increased risk of Achilles tendon rupture.
Except for pivmecillinam, β-lactam agents generally have not performed as well as TMP-SMX or fluoroquinolones in acute cystitis. Rates of pathogen eradication are lower and relapse rates are higher with β-lactam drugs. The generally accepted explanation is that β-lactams fail to eradicate uropathogens from the vaginal reservoir. A proposed role for intracellular biofilm communities is intriguing. Many strains of E. coli that are resistant to TMP-SMX are also resistant to amoxicillin and cephalexin; thus, these drugs should be used only for patients infected with susceptible strains.
Urinary analgesics are appropriate in certain situations to speed resolution of bladder discomfort. The urinary tract analgesic phenazopyridine is widely used but can cause significant nausea. Combination analgesics containing urinary antiseptics (methenamine, methylene blue), a urine-acidifying agent (sodium phosphate), and an antispasmodic agent (hyoscyamine) also are available. PYELONEPHRITIS
Since patients with pyelonephritis have tissue-invasive disease, the treatment regimen chosen should have a very high likelihood of eradicating the causative organism and should reach therapeutic blood levels quickly. High rates of TMP-SMX-resistant E. coli in patients with pyelonephritis have made fluoroquinolones the first-line therapy for acute uncomplicated pyelonephritis. Whether the fluoroquinolones are given orally or parenterally depends on the patient’s tolerance for oral intake. A randomized clinical trial demonstrated that a 7-day course of therapy with oral ciprofloxacin (500 mg twice daily, with or without an initial IV 400-mg dose) was highly effective for the initial management of pyelonephritis in the outpatient setting. Oral TMP-SMX (one double-strength tablet twice daily for 14 days) also is effective for treatment of acute uncomplicated pyelonephritis if the uropathogen is known to be susceptible. If the pathogen’s susceptibility is not known and TMP-SMX is used, an initial IV 1-g dose of ceftriaxone is recommended. Oral β-lactam agents are less effective than the fluoroquinolones and should be used with caution and close follow-up. Options for parenteral therapy for uncomplicated pyelonephritis include fluoroquinolones, an extended-spectrum cephalosporin with or without an aminoglycoside, or a carbapenem. Combinations of a β-lactam and a β-lactamase inhibitor (e.g., ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam) or imipenem-cilastatin can be used in patients with more complicated histories, previous episodes of pyelonephritis, or recent urinary tract manipulations; in general, the treatment of such patients should be guided by urine culture results. Once the patient has responded clinically, oral therapy should be substituted for parenteral therapy. UTI IN PREGNANT WOMEN
Nitrofurantoin, ampicillin, and the cephalosporins are considered relatively safe in early pregnancy. One retrospective case-control study suggesting an association between nitrofurantoin and birth defects has not been confirmed. Sulfonamides should clearly be avoided both in the first trimester (because of possible teratogenic effects) and near term (because of a possible role in the development of kernicterus). Fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. Ampicillin and the cephalosporins have been used extensively in pregnancy and are the drugs of choice for the treatment of asymptomatic or symptomatic UTI in this group of patients. For pregnant women with overt pyelonephritis, parenteral β-lactam therapy with or without aminoglycosides is the standard of care. UTI IN MEN
Since the prostate is involved in the majority of cases of febrile UTI in men, the goal in these patients is to eradicate the prostatic infection as well as the bladder infection. A 7- to 14-day course of a fluoroquinolone or TMP-SMX is recommended if the uropathogen is susceptible. If acute bacterial prostatitis is suspected, antimicrobial therapy should be initiated after urine and blood are obtained for cultures. Therapy can be tailored to urine culture results and should be continued for 2–4 weeks. For documented chronic bacterial prostatitis, a 4- to 6-week course of antibiotics is often necessary. Recurrences, which are not uncommon in chronic prostatitis, often warrant a 12-week course of treatment. COMPLICATED UTI
Complicated UTI (other than that discussed above) 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 species and their susceptibility to antimicrobial agents are likewise heterogeneous. As a consequence, therapy for complicated UTI must be individualized and guided by urine culture results. Frequently, a patient with complicated UTI will have prior urine culture data that can be used to guide empirical therapy while current culture results are awaited. Xanthogranulomatous pyelonephritis is treated with nephrectomy. Percutaneous drainage can be used as the initial therapy in emphysematous pyelonephritis and can be followed by elective nephrectomy as needed. Papillary necrosis with obstruction requires intervention to relieve the obstruction and to preserve renal function. ASYMPTOMATIC BACTERIURIA
Treatment of ASB does not decrease the frequency of symptomatic infections or complications except in pregnant women, persons undergoing urologic surgery, and perhaps neutropenic patients and renal transplant recipients. Treatment of ASB in pregnant women and patients undergoing urologic procedures should be directed by urine culture results. In all other populations, screening for and treatment of ASB are discouraged. The majority of cases of catheter-associated bacteriuria are asymptomatic and do not warrant antimicrobial therapy. CATHETER-ASSOCIATED UTI
Multiple institutions have released guidelines for the treatment of CAUTI, which is defined by bacteriuria and symptoms in a catheterized patient. The signs and symptoms either are localized to the urinary tract or can include otherwise unexplained systemic manifestations, such as fever. The accepted threshold for bacteriuria to meet the definition of CAUTI is ≥103 CFU/mL, while the threshold for bacteriuria to meet the definition of ASB is ≥105 CFU/mL.
The formation of biofilm—a living layer of uropathogens—on the urinary catheter is central to the pathogenesis of CAUTI and affects both therapeutic and preventive strategies. Organisms in a biofilm are relatively resistant to killing by antibiotics, and eradication of a catheter-associated biofilm is difficult without removal of the device itself. Furthermore, because catheters provide a conduit for bacteria to enter the bladder, bacteriuria is inevitable with long-term catheter use.
The typical signs and symptoms of UTI, including pain, urgency, dysuria, fever, peripheral leukocytosis, and pyuria, have less predictive value for the diagnosis of infection in catheterized patients. Furthermore, the presence of bacteria in the urine of a patient who is febrile and catheterized does not necessarily predict CAUTI, and other explanations for the fever should be considered.
The etiology of CAUTI is diverse, and urine culture results are essential to guide treatment. Fairly good evidence supports the practice of catheter change during treatment for CAUTI. The goal is to remove biofilm-associated organisms that could serve as a nidus for reinfection. Pathology studies reveal that many patients with long-term catheters have occult pyelonephritis. A randomized trial in persons with spinal cord injury who were undergoing intermittent catheterization found that relapse was more common after 3 days of therapy than after 14 days. In general, a 7- to 14-day course of antibiotics is recommended, but further studies on the optimal duration of therapy are needed.
In the setting of long-term catheter use, systemic antibiotics, bladder-acidifying agents, antimicrobial bladder washes, topical disinfectants, and antimicrobial drainage-bag solutions have all been ineffective at preventing the onset of bacteriuria and have been associated with the emergence of resistant organisms. The best strategy for prevention of CAUTI is to avoid insertion of unnecessary catheters and to remove catheters once they are no longer necessary. Evidence is insufficient to recommend suprapubic catheters and condom catheters as alternatives to indwelling urinary catheters as a means to prevent CAUTI. However, intermittent catheterization may be preferable to long-term indwelling urethral catheterization in certain populations (e.g., spinal cord–injured persons) to prevent both infectious and anatomic complications. Antimicrobial catheters impregnated with silver or nitrofurazone have not been shown to provide significant clinical benefit in terms of reducing rates of symptomatic UTI. CANDIDURIA
The appearance of Candida in the urine is an increasingly common complication of indwelling catheterization, particularly for patients in the intensive care unit, those taking broad-spectrum antimicrobial drugs, and those with underlying diabetes mellitus. In many studies, >50% of urinary Candida isolates have been found to be non-albicans species. The clinical presentation varies from an asymptomatic laboratory finding to pyelonephritis and even sepsis. Removal of the urethral catheter results in resolution of candiduria in more than one-third of asymptomatic cases. Treatment of asymptomatic patients does not appear to decrease the frequency of recurrence of candiduria. Treatment is recommended for patients who have symptomatic cystitis or pyelonephritis and for those who are at high risk for disseminated disease. High-risk patients include those with neutropenia, those who are undergoing urologic manipulation, those who are clinically unstable, and low-birth-weight infants. Fluconazole (200–400 mg/d for 14 days) reaches high levels in urine and is the first-line regimen for Candida infections of the urinary tract. Although instances of successful eradication of candiduria by some of the newer azoles and echinocandins have been reported, these agents are characterized by only low-level urinary excretion and thus are not recommended. For Candida isolates with high levels of resistance to fluconazole, oral flucytosine and/or parenteral amphotericin B are options. Bladder irrigation with amphotericin B generally is not recommended.