US Pharm. 2012;37(9):56-60.
Uncomplicated urinary tract infections (UTIs) are one of
the most common reasons for antibiotic use among otherwise healthy
women.1 In 2011, the Infectious Diseases Society of America
(IDSA) published an update to its clinical practice guidelines for the
treatment of uncomplicated UTIs (i.e., cystitis).1 Twelve
years had passed since the original guidelines were published, and not
surprisingly, there have been a number of changes in treatment
recommendations. Such a shift in current practice warrants review of the
appropriate diagnosis and treatment of this common women’s health
UTIs develop by either ascending or descending bacterial
invasion into the urinary tract. The more common mode of infection is
the ascending pathway, where fecal flora gain access to the urinary
tract via colonization of the urethra. Rarely, a UTI occurs by way of
the descending pathway. Descending infections are the result of
hematogenous spread of bacteria from a primary source located elsewhere
in the body.2 By far, the most common uropathogen identified in uncomplicated UTIs is Escherichia coli, accounting for about 85% of all cases. The remaining 15% are caused primarily by Staphylococcus saprophyticus and Klebsiella and Proteus species.1
Signs and symptoms of a UTI vary depending on the extent
of the infection. Lower UTIs can involve the urethra, bladder, and/or
prostate (in men), and tend to present with localized symptoms such as
dysuria, urinary frequency, urgency, and suprapubic pain or heaviness.3
A UTI extending to the ureter or kidneys (i.e., pyelonephritis) often
involves more systemic signs and symptoms, such as leukocytosis, fever,
chills, abdominal pain, flank pain, and nausea/vomiting. Certain patient
populations may present atypically. For example, elderly patients are
less likely to have urinary symptoms and more likely to present with
altered mental status, changes in eating habits, and gastrointestinal
There are a number of diagnostic tools that can be
utilized to confirm a diagnosis of UTI. In the outpatient setting, the
most convenient tool is the urine dipstick, which provides two important
markers for UTI detection—leukocyte esterase and nitrite. Leukocyte
esterase is indicative of white blood cells in the urine (pyuria).
Nitrite indicates bacteriuria and has a higher specificity for UTI than
does leukocyte esterase (95%-98% versus 59%-96%).4 However, the sensitivity is limited by bacteria that do not reduce nitrate, such as S saprophyticus and Enterococcus and Pseudomonas
species. The most reliable method for confirming UTI is the urine
culture. The preferred method for collection is the midstream clean
catch, as it is the least invasive. The traditional cut-off for
significant bacteriuria in this case is 105 CFU/mL, though some sources cite 102 CFU/mL as diagnostic for a symptomatic patient.2,3
UTIs are classified as either complicated or
uncompli-cated. What distinguishes a complicated UTI is the presence of a
structural or functional abnormality in the urinary tract. By default,
infections in men, children, and pregnant women are considered
complicated, as most of these cases involve some type of urologic
abnormality. Other characteristics that denote a complicated infection
include immunosuppressive conditions, diabetes, catheterization, renal
transplantation, and neurogenic bladder.1-3 Consequently, uncomplicated UTIs occur in otherwise healthy, adult, nonpregnant females.
Lower UTI Treatment
In the original IDSA guidelines from 1999, the recommended
treatment for uncomplicated lower UTI in the United States was
primarily trimethoprim-sulfamethoxazole (TMP-SMX).5 Since
that time, new clinical data and a greater emphasis on the potential for
antibiotics to propagate antimicrobial resistance (i.e., “collateral
damage”) has led to a number of changes in the treatment recommendations
within the guideline update (TABLE 1).1 In addition
to TMP-SMX, nitrofurantoin and fosfomycin are now also considered
appropriate empiric treatment options due to their reasonable efficacy
and low risk for collateral damage.1 Fluoroquinolones and
beta-lactams remain alternative treatment options due to concerns for
antimicrobial resistance and inferior efficacy, respectively.
TMP-SMX: Overall, clinical trials for
UTIs evaluate two primary outcomes, the resolution of bacteriuria
(microbiological cure) and the resolution of symptoms (clinical cure).
Several studies support the efficacy of TMP-SMX in uncomplicated
cystitis, with an estimated clinical cure rate of 93%.1
Moreover, TMP-SMX maintains reasonable efficacy at resistance rates of
14% to 15%. In one trial, TMP-SMX was noninferior to ciprofloxacin
despite a resistance rate of 15%, with a clinical cure rate of 86%.6 Another trial comparing TMP-SMX to nitrofurantoin had similar resistance and a clinical cure rate for TMP-SMX of 79%.7
Not surprisingly, patients treated with TMP-SMX with a uropathogen
sensitive to the antibiotic had a much higher clinical cure rate than
those with a resistant organism. However, it is worth noting that the
clinical cure rate was still 41% in those patients with a TMP-SMX
resistant pathogen, likely reflecting spontaneous resolution via host
One advantage that TMP-SMX has over other antibiotics is
sufficient evidence from clinical, in vitro, and mathematical modeling
data to support a threshold of 20% resistance below which the antibiotic
is still considered appropriate for empiric use.1 This
recommendation may be more practical to implement in the hospital
setting, as community antibiograms (antibiotic sensitivity reports) are
often not available, and the IDSA guidelines caution against
extrapolating hospital antibiograms to resistance patterns in the
community. However, one study examining E coli antimicrobial
resistance among outpatient urinary isolates revealed several U.S.
regions where resistance to TMP-SMX exceeded 20%,8 which calls into question the appropriateness of this antibiotic for empiric treatment in the outpatient setting.
There are several pitfalls to using TMP-SMX. Intolerance
to sulfa medications is fairly common, with about 3% of hospital
inpatients experiencing a drug rash.9 Less common but still
of concern is drug hypersensitivity syndrome, which can involve
hematologic abnormalities, renal dysfunction, and life-threatening skin
reactions such as Stevens-Johnson syndrome. Renal insufficiency is
another issue that may prohibit the use of this agent, primarily due to
concern for causing hyperkalemia. For patients on warfarin, TMP-SMX
poses a significant interaction via both alteration in protein binding
and inhibition of warfarin metabolism, and avoidance of even short-term
use may be advisable to avoid potentially dramatic prolongation of the
international normalized ratio (INR).
Nitrofurantoin: In the previous IDSA
guidelines, nitrofurantoin had scant evidence to support its use in
uncomplicated cystitis. Over the past decade, however, a number of
clinical trials have revealed excellent microbiological and clinical
cure rates with this agent, with an overall estimated clinical cure rate
of 93%.1 Traditionally, nitrofurantoin has been used for a
total of 7 days, but recent literature indicates a 5-day course to be
noninferior to TMP-SMX, with a clinical cure rate of 84%.7 Though clinical benefit data are lacking at varying levels of resistance, U.S. surveillance data indicate E coli resistance to nitrofurantoin at 0% to 5%.8
Pitfalls associated with nitrofurantoin use are mostly
related to loss of efficacy in the setting of renal dysfunction. As
creatinine clearance (CrCl) declines, urinary excretion of
nitrofurantoin is reduced, with little to no excretion occurring when
the CrCl falls below 20 mL/min.10 However, there is minimal
evidence to delineate the level of renal dysfunction that negates the
drug’s clinical efficacy. Several references recommend avoiding
nitrofurantoin in patients with a CrCl less than 50 to 60 mL/min due to
an increased risk of neurotoxicity and pulmonary toxicity.11,12
Whether or not this is a relevant concern for the short courses used in
UTIs is highly debatable, as these rare toxicities are typically seen
after accumulation from chronic use.13
Fosfomycin: Fosfomycin is a
phosphonic acid derivative and currently the only antibiotic in its
class. A small amount of evidence suggests it has comparable clinical
efficacy to nitrofurantoin (90% vs. 95%), although with a lower
microbiological cure rate (78% vs. 86%).14 Its convenience as
a single-dose regimen makes it a particularly attractive treatment
option from a medication adherence perspective.
The main drawbacks with fosfomycin are related to cost and
availability. Despite its being the shortest treatment for UTI, it is
the most expensive at around $40 to $50 for a single dose. Moreover,
with UTI as its only indication in the U.S. and the very recent
endorsement of its use by the IDSA, the availability of fosfomycin at
community pharmacies is variable. Lastly, susceptibility testing of this
antibiotic is not routinely performed, which makes surveillance of
resistance rates a challenge. However, E coli resistance to fosfomycin in Europe has remained low despite frequent use of this agent,15 suggesting that routine testing may not be required.
Fluoroquinolones: Numerous trials have
demonstrated the efficacy of fluoroquinolones at producing both
microbiological and clinical cure in the treatment of uncomplicated
lower UTI.1 With ciprofloxacin and levofloxacin both
available as generic formulations, this antibiotic class represents an
efficacious and inexpensive treatment option. Despite these advantages,
the IDSA has recommended reserving use of these agents as an alternative
rather than a preferred treatment option due to their high propensity
for collateral damage. Fluoroquinolone use is directly correlated with
fluoroquinolone resistance, and hospital resistance rates are on the
rise. One study examining hospital resistance rates across 10 years
found an overall 25% relative decline in Pseudomonas aeruginosa susceptibility and a 7% decline in E coli susceptibility to fluoroquinolones.16 In the community setting, U.S. surveillance data indicate that overall E coli resistance to fluoroquinolones is fairly low (~5%).8
However, caution is warranted in interpreting national resistance rates
due to significant regional variation. In fact, the same surveillance
study found fluoroquinolone resistance rates at 11% and 20% in the
mid-Atlantic and west south-central regions, respectively.
There is also a concern for developing resistance to
nonquinolone antibiotic classes. For example, fluoroquinolone exposure
is an independent risk factor for extended-spectrum beta-lactamase
(ESBL)–producing E coli,17 and it has also been associated with methicillin-resistant Staphylococcus aureus (MRSA) isolation.18
As a result, it is recommended to reserve the use of this class for
more serious infections for which broad-spectrum coverage is warranted.
Beta-lactams: There is a lack of
high-quality evidence with beta-lactams in the treatment of
uncomplicated lower UTI. Most trials are either underpowered or use an
inappropriate comparator arm. Studies to date of reasonable quality
suggest inferiority of beta-lactams to fluoroquinolones.1 Though a small trial comparing cefpodoxime to TMP-SMX suggested comparable cure rates,19 a more recent trial with this cephalosporin resulted in inferior clinical cure rates compared to ciprofloxacin (82% vs. 93%).20
Additionally, there are similar concerns for collateral damage with the
third-generation cephalosporins as for fluoroquinolones, particularly
with regard to ESBL resistance.17 First-generation
cephalosporins, on the other hand, may have a lower propensity for
collateral damage, and clinical trials to explore their efficacy in
uncomplicated UTI are needed.
The IDSA guidelines segregate antibiotic recommendations for pyelonephritis into outpatient and inpatient treatment (TABLES 2 and 3).
Regardless of the location of treatment, a urine culture should always
be sent to evaluate the appropriateness of empiric therapy and allow for
streamlining when possible. For outpatient treatment, the
fluoroquinolones have the most data to support empiric use.1
This antibiotic class is the only one endorsed by the guidelines for
empiric outpatient treatment. There is a paucity of literature with
regard to alternative agents.
One study found TMP-SMX to be inferior to ciprofloxacin (clinical cure of 83% vs. 95%).21
However, the cure rate for TMP-SMX specifically in patients with
susceptible isolates was close to that of ciprofloxacin (92%),
indicating TMP-SMX as an acceptable treatment option when the pathogen
is known to be sensitive. TMP-SMX–resistant isolates were much less
likely to be effectively treated with TMP-SMX, with a clinical cure rate
of only 35%. However, patients in the TMP-SMX arm who received one dose
of ceftriaxone at the start of treatment had significantly higher
microbiological cure rates, and so it is recommended to give a one-time
dose of an IV antibiotic when TMP-SMX is used empirically.21
Similarly, it is recommended to administer one IV antibiotic dose in
addition to treatment with an oral fluoroquinolone when local resistance
rates exceed 10%, though this recommendation is based solely on expert
Since the previous guidelines, no new clinical literature
has been published examining the role of beta-lactams in pyelonephritis.
Thus, current recommendations are based on limited and outdated
literature, mostly with aminopenicillins (e.g., amoxicillin). Because
these data have demonstrated inferior efficacy and higher relapse rates
than standard therapy, beta-lactams remain an alternative treatment
Inpatient treatment is reserved for those patients with
severe pyelonephritis and/or the inability to tolerate oral medications.
Due to the absence of clinical literature, recommendations for
inpatient treatment are largely based on expert opinion, and include a
wide variety of broad-spectrum IV antimicrobials (TABLE 3). In
this case, local resistance rates and individual patient risk factors
for drug-resistant pathogens should be taken into account when
determining an appropriate empiric agent.1
While the advent of new IDSA guidelines has broadened the
treatment options available for lower UTI in women, each antibiotic has
its own advantages and pitfalls, requiring therapy tailored to the
individual patient. When possible, fluoroquinolones should be avoided to
minimize the potential for collateral damage. Evidence-based treatment
options for pyelonephritis remain limited, underscoring the importance
of utilizing a hospital or community antibiogram, when available, to
guide empiric treatment.
1. Gupta K, Hooton TM, Naber KG, et al. International
clinical practice guidelines for the treatment of acute uncomplicated
cystitis and pyelonephritis in women: a 2010 update by the Infectious
Diseases Society of America and the European Society for Microbiology
and Infectious Diseases. Clin Infect Dis. 2011;52:e103-e120.
2. Dipiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: The McGraw-Hill Companies; 2008:1899-1910.
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antimicrobial treatment of uncomplicated acute bacterial cystitis and
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6. Arredondo-Garcia JL, Figueroa-Damian R, Rosas A, et al.
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women. Arch Intern Med. 2007;167:2207-2212.
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to fluoroquinolones of selected pathogens in 10 United States teaching
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18. Weber SG, Gold HS, Hooper DC, et al. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis. 2003;9:1415-1422.
19. Kavatha D, Giamarellou H, Alexiou Z, et al.
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