If you thought you knew all about the modern and up-to-date treatment of acute cystitis in women, think again. Times have changed, as have treatment regimens and the profile of infecting organisms. The overuse of antibiotics has culled out resistant bacteria that used to be easily controlled with even one or two doses of simple antibiotics, such as amoxicillin.
E. coli would readily die when the first few molecules of antibiotics filtered into the infected urinary bladder. But if you haven't reviewed this topic in the past few years and continue to use the same antibiotics you did when you were an intern, you're behind the times. Updated clinical practice guidelines for treating acute uncomplicated cystitis in women were published in 2010 by some prestigious infectious diseases societies. This month: garden-variety acute cystitis; next month: -pyelonephritis. Also read last month's column on the emergence of bacteria that produce extended spectrum -B-lactamase (ESBL), substances that inactivate once-invincible antibiotics, making some E. coli and Klebsiella -infections impossible to cure without using some rather exotic antimicrobials.
International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update
Gupta K, Hooton TM
Clin Infect Dis
Acute uncomplicated cystitis remains one of the most common indications for antibiotic prescriptions in otherwise healthy women. The Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) updated their practice guidelines in 2010. Prescribing habits still vary widely despite published guidelines for the optimal selection of the best antimicrobial agent and proper duration of therapy. Last updated in 1999, the clinical practice guidelines changed because of antimicrobial resistance among uropathogens and development of newer agents with different durations of therapy.
Complicating empirical treatment choices is the fact that women with uropathogens resistant to various medications have been included in some studies. Run-of-the-mill ED cystitis is rarely cultured so hospital antibiograms do not reflect simple outpatient infections. Sensitivity reporting lumps together inpatients and samples skewed by more complicated infections, some treated with multiple antibiotics for extended periods. Because empirical therapy is often prescribed without a urine culture, the true community susceptibility and bacterial pathogen profile of women seeking relief in the ED, office, or clinic from the signs and symptoms of acute cystitis is often unknown. Of course, antibiotics concentrate significantly in the urine so the laboratory is not the most ideal place to determine efficacy in real life.
Uncomplicated cystitis occurs rather commonly in premenopausal, nonpregnant women with no known urological abnormalities or comorbidities. Occasionally postmenopausal women or those with well controlled diabetes have been included in the uncomplicated category. Recurrent cystitis and UTI in pregnancy garner different treatment guidelines. And, of course, the divergence between in vitro resistance versus in vivo efficacy often makes treatment choices difficult to reconcile, even when a culture is obtained.
Optimal Treatment for Acute Uncomplicated Cystitis: Per current evidence and guidelines, a limited number of antibiotics should be chosen for empirically treating uncomplicated acute cystitis. Because of minimal resistance and little collateral damage, nitrofurantoin (Macrodantin) 100 mg BID for five days is an appropriate empirical choice. Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-strength tablet twice a day for three days, is also appropriate and guideline-recommended therapy. TMP-SMZ has proven efficacy in numerous clinical trials, but increasing resistance may alter this thinking in the future. As an overall guide, if resistance is greater than 20 percent, a drug is no longer recommended. So far, TMP-SMZ has not crossed this cutoff, but many fluoroquinolones have long been above that line. Interestingly, TMP-SMZ prescribed within the past three to six months is an independent risk factor for resistance to this antibiotic in women with uncomplicated cystitis.
A newer drug, fosfomycin (Monurol), is a UTI medication largely unknown to emergency physicians. It is given as a 3 g single dose, and is considered appropriate therapy because of minimal resistance and relative safety. -Fosfomycin has somewhat slightly -inferior efficacy compared with the five-day nitrofurantoin and three-day TMP-SMZ regimens. The cost of about $50 a dose prohibits its widespread.
Most fluoroquinolones (ofloxacin, ciprofloxacin, and levofloxacin) can be highly efficacious in a three-day regimen. Resistance and numerous side effects attributed to fluoroquinolones, however, have prompted the IDSA/-ESCMID to withdraw a previous recommendation for the initial use of these antibiotics for uncomplicated cystitis. Currently, no fluoroquinolones is considered alternative first-line therapy for acute uncomplicated -cystitis. Essentially, forget about ciprofloxacin for outpatient treatment of acute cystitis.
Many beta-lactams, including amoxicillin-clavulanate in three- to seven-day regimens, although not often considered, are appropriate choices, but only when other regimens cannot be used. Cephalexin, another commonly used alternative beta-lactam, has not been well studied, but it appears to be well tolerated and appropriate. Generally, however, the beta-lactams have somewhat inferior efficacy and more adverse effects when compared with these UTI-specific antibiotics. The old standards of amoxicillin or ampicillin should not be used for empirical treatment given their poor efficacy and very high resistance rates.
Antimicrobial Resistance: By far the most common cause of uncomplicated cystitis is E. coli, accounting for about 75–95 percent of infections. Occasionally, acute cystitis is caused by Proteus mirabilis, Klebsiella pneumoniae, and Staphylococcus saprophyticus. Other gram-negative or gram-positive species are rarely isolated in urine collected from those with uncomplicated cystitis, so the local -antibiotic sensitivity to E. coli is a general touchstone for therapy decisions. Considerable geographic variance and varying susceptibility of E. coli to many antibiotics exists, and local patterns should dictate use.
Currently the empirical treatment of acute uncomplicated cystitis is quite acceptable. Antibiotics become highly concentrated in the urine. It is likely that many patients may be successfully treated with an antibiotic that would not demonstrate in vitro laboratory activity against the isolated uropathogen.
Collateral Damage: Antibiotic therapy is not without consequences. The most common unintended outcome is selecting out drug-resistant -organisms and increasing the incidence of infections with multiresistant bacteria. This has been attributed to the use of broad-spectrum cephalosporins and fluoroquinolones, a cogent argument for why these drugs should not be a first-line choice for cystitis. The emergence of extended spectrum beta-lactamase-producing E. coli and Klebsiella is a perfect example of this phenomenon. The increasing incidence of Pseudomonas infections following the gargantuan use of fluoroquinolones is well known.
It is interesting to note that 30–40 percent of patients with clinical cystitis demonstrates a clinical cure with placebo therapy or with an antibiotic without laboratory-corroborated activity against the uropathogen. It's not clear that even a bacteria-laden uncomplicated cystitis requires antibiotics at all. The spontaneous resolution of an uncomplicated cystitis again muddies true scientific analysis. Failure to treat cystitis, however, can lead to the development of pyelonephritis. It is -estimated that approximately one of 38 women treated with placebo for acute cystitis will develop pyelonephritis. About half of all women experience at least one UTI in their lifetime, and those with symptoms will be treated for acute cystitis with an antibiotic. Overall, these organizational guidelines do not recommend withholding antimicrobial therapy for clinical acute cystitis.
Comment: The resistance of E. coli to ciprofloxacin, one of the most widely prescribed antimicrobials for UTI in the United States, increased fivefold between 2000 and 2010. This has been directly related to the overuse of this very potent broad-spectrum antibiotic for simple uncomplicated cystitis. Currently, about a quarter of E. coli infections are laboratory-resistant to TMP-SMZ, the second most prescribed drug for urinary tract infections.
There is no easy answer. The message from the ISDA-ESCMID is that no single agent is the optimal choice for managing uncomplicated cystitis. Nonetheless, these organizations currently recommend only three specific antimicrobials for uncomplicated cystitis in women: TMP-SMZ, nitrofurantoin, and fosfomycin. One of the strongest new guidelines is that no fluoroquinolones should be used for acute cystitis unless all of the other recommended antimicrobials are contraindicated.
Many clinical characteristics of acute cystitis have not changed over the years, and are worth reviewing. Cystitis is still most common in sexually active young women, and risk factors include sexual intercourse, spermicide use, and of course, prior UTIs. The pathogenesis includes colonization of the vagina by uropathogens from fecal flora, with ascension of the bacteria into the bladder via the short female urethra. Symptoms of urgency, frequency, urinary burning, and suprapubic pain drive most women to the ED in search of a cure. No women will eschew an ED visit after the first episodes of bright red urine or the stinging and burning of dysuria. Of course, such symptoms may also be a manifestation of vaginitis or urethritis caused by yeast, Trichomonas, or bacterial vaginosis. The causes of urethritis include Chlamydia, gonorrhea, herpes simplex, and noninfectious irritants such as contraceptive gel. Every woman who has the classic lower UTI symptoms does not have a bona fide bladder infection.
Fever, CVA tenderness, weakness, and significant abdominal pain should cause one to suspect that cystitis is not present. Whether every woman with typical cystitis symptoms requires a pelvic examination to evaluate for vaginitis or urethritis is unknown. When classic cystitis symptoms predominate and complaints of copious or abnormal vaginal discharge are absent, most clinicians will eschew the pelvic exam. This appears to be standard of care. The general consensus is that urine cultures are not required if the symptoms are classic, and it is not considered standard if the symptoms are compatible with simple cystitis unless there is reason to suspect resistance or other complicating issues.
It is acceptable simply to dipstick-test urine, discuss the symptoms, and write a prescription for antibiotics. A urine dipstick is easy to perform, and often provides confirmation. Pyuria is omnipresent, and its absence strongly suggests an alternative diagnosis. An abnormal result is considered greater than 10 leukocytes per microL in an unspun voided midstream urine. If the leukocyte esterase dipstick is positive, it generally correlates with the greater than 10 WBC per high-power field. Blood-tinged urine or even gross hematuria is common with uncomplicated acute cystitis. Hematuria itself is not a predictor of a complicated infection, and does not warrant extended therapy or additional testing. The nitrite test is sensitive and specific for Enterobacteriaceae, but it lacks adequate sensitivity for detection of other organs. The negative nitrite test does not mean that a UTI is absent.
A culture is indicated, as is a referral for a workup for other urinary problems, in women with recurrent infections. Few are ever found, however. Follow-up visits or urine cultures are not considered standard of care for the occasional bout of acute cystitis if symptoms resolve. The clinical symptoms should respond to antibiotics within about 48 hours. Some physicians prefer to use a urinary analgesic such as phenazopyridine to relieve the discomfort of severe dysuria. A two-day course is usually sufficient, and be sure to tell patients it turns the urine bright orange. It is not considered useful after two days, and it may mask symptoms that require additional evaluation. Our nurses frequently suggest that women with severe dysuria sit in a warm bathtub while urinating for the first day, and that appears to relieve symptoms significantly. I generally prescribe cranberry juice, and although its efficacy is in and out of favor, it's a popular lay treatment and gives the clinician an organic flair.
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Potential Side Effects of Trimethoprim-Sulfamethoxazole (TMP-SMZ)
TMP-SMZ is a ubiquitous antibiotic prescribed for acute cystitis and MRSA skin infections. It is generally a very safe drug, but has been associated with a variety of complications not well known or appreciated by many emergency physicians. TMP-SMZ has known side effects, but they are considered rare with the doses and durations used in the ED for uncomplicated cystitis.
- TMP-SMZ affects bacteria in the gut needed for producing vitamin K and interferes with warfarin metabolism via the P450 pathway. The INR of a patient on warfarin can increase within a few days of TMP-SMZ treatment. With extended use, the INR of as many as 60 percent of patients will increase outside therapeutic range, reported as a 30 percent incidence of an INR of 5 or higher and a 13 percent incidence of bleeding complications. Such warfarin potentiation is common with many antibiotics, but TMP-SMZ is the most frequent offender. A preemptive reduction in warfarin dose by 10–20 percent and an INR check in five to seven days has been suggested, but is not a universal recommendation (J Thromb Thrombolysis 2008;26:44.)
- Hyperkalemia is exacerbated by TMP-SMZ in patients taking ACE inhibitors, ARBs, and potassium-sparing diuretics. TMP-SMZ can reduce urinary potassium excretion by about 40 percent. Hyperkalemia may be severe enough to require hospitalization, and potassium elevations can occur within a few days of beginning antibiotic therapy. It appears prudent to avoid prolonged TMP-SMZ in elderly patients, those with renal impairment, and those managed with an ACE inhibitor or ARB.
- TMP-SMZ is one of the most common antibiotics causing Stevens--Johnson syndrome and toxic epidermal necrolysis.
- Patients taking TMP-SMZ with a sulfonylurea, an oral agent for hyperglycemia, are at risk for developing hypoglycemia, especially if they are malnourished or have renal or hepatic impairment.
- With more prolonged use, TMP-SMZ can cause agranulocytosis, aplastic anemia, or hepatic necrosis.
Potential Side Effects of Fluoroquinolones
Concern is growing over serious adverse effects of fluoroquinolones on a variety of systems, although they are generally safe and well tolerated. A partial list of fluoroquinolone-related side effects include:
- Tendinopathy with tendon rupture. Fluoroquinolones have a black box warning for this complication.
- Development of C. difficile diarrhea and MRSA infections.
- A variety of neurological events including insomnia, mania, seizures, and prolonged, if not permanent, peripheral neuropathies.
- Increase QTC duration, possibly leaning to Torsades de pointes.