E D I T O R I A L C O M M E N T A R Y

Including the X-Factor: Toward Patient-Centered

Prevention of Urinary Tract Infection
Kalpana Gupta
1,2
and Nahid Bhadelia
3,4
1
Infectious Diseases, Veterans Affairs Boston Healthcare System, West Roxbury,
2
Infectious Diseases, Boston University School of Medicine,
3
Hospital
Epidemiology, Boston Medical Center, and
4
Section of Infectious Diseases, Boston University School of Medicine, Massachusetts
(See the Major Article by Eells et al on pages 14760.)
Keywords. UTI; non-antimicrobial prevention; self-initiated therapy; patient-centered.
Urinary tract infection (UTI) is a common and costly
infection; a recent study estimated that the number of
patients treated for UTIs in US emergency rooms was
2.0 million in 2006 and 2.3 million in 2009. The overall
estimated annual direct and indirect cost of UTI in the
United States in 2010 was $2.3 billion [1]. The excess
cost of emergency room care, when compared to
healthcare services provided in the outpatient setting, is
>$1.5 billion annually [2].
Beyond direct healthcare costs, the human cost of re-
current UTIs is broader and more difcult to quantify
in term of dollars and cents. Recurrent UTIs have a
considerable impact on quality of life, not only due
to pain and discomfort but also by disrupting sexual
activity [3]. Furthermore, patients and employers may
suffer signicantly from lost revenue due to missed
work resulting from symptoms and the time needed to
access medical care. Reduction of UTI has the potential
to decrease healthcare and societal costs by billions of
dollars annually.
There is no consensus regarding a single superior
strategy for the prevention of UTIs. Prior Cochrane
reviews demonstrated a decrease in UTIs through use
of continuous low-dose antibiotics compared to
placebo; however, the treatment arm also experienced
higher rates of adverse events [4]. A similar review
comparing cranberry juice to no intervention failed to
demonstrate a clear benet [5]. Moreover, there are no
trials comparing the relative efcacy of all of the pre-
vention and management options with an evaluation of
their relative benets to both individual patients and
the healthcare system as a whole.
Eells et al present a well-organized decision analysis
addressing the comparative effectiveness of different
prevention options [6]. They evaluate the impact of 5
strategies, chosen based on the availability of adequate
published data, on reducing recurrent UTIs in women.
Strategies evaluated in the model include daily nitrofur-
antoin prophylaxis, topical estrogen prophylaxis, daily
cranberry prophylaxis, monthly acupuncture sessions,
and self-directed treatment with ciprooxacin at the
earliest symptom. The authors evaluate the reduction
in the absolute number of UTIs, as well as improve-
ment in quality-adjusted life-days (QALDs) and cost
per QALD gained. The models are constructed from
both the payer and the patient perspectives and evalu-
ate both high (>8 UTIs per year) and moderate (>3
UTIs per year) recurrence rates.
Daily prophylactic use of nitrofurantoin resulted in
the lowest number of UTIs per year (0.4) and the
highest payer cost, but also the most QALDs gained per
year. Surprisingly, acupuncture resulted in the second-
highest QALDs gained and decreased UTIs to 0.7. The
authors remark that this could be secondary to publica-
tion bias resulting from the relatively small number of
studies on acupuncture. Cranberry juice and estrogen
Received 10 September 2013; accepted 12 September 2013; electronically
published 24 September 2013.
Correspondence: Kalpana Gupta, MD, MPH, VA Boston HCS, 1400 VFW Parkway,
MED 111, West Roxbury, MA (kalpana.gupta@va.gov).
Clinical Infectious Diseases 2014;58(2):1613
Published by Oxford University Press on behalf of the Infectious Diseases Society of
America 2013. This work is written by (a) US Government employee(s) and is in the
public domain in the US.
DOI: 10.1093/cid/cit648
EDITORIAL COMMENTARY CID 2014:58 (15 January) 161

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replacement each also reduced recurrent UTI rates with slightly
more modest gains in QALDs. Symptomatic self-treatment was
the cheapest to both payers and patients as it resulted in de-
creased utilization of the healthcare system, but it did not result
in signicant QALDs gained as there was no reduction in the
number of UTIs per year. It would be interesting to assess if the
inclusion of economic costs to the consumer through workdays
missed would improve the overall attractiveness of this strategy.
Furthermore, these studies did not evaluate the psychological
benet to the patient of being able to exercise control over a painful
and capricious illness, as permitted by self-initiated therapy.
As the authors suggest, daily antibiotic use is the most
studied and effective prevention strategy. If we take these nd-
ings at face value, many of our patients who have opted for
other nonantimicrobial management strategies would start
using regular prophylactic antibiotics instead. The impact of
this shift is difcult to quantitate, but includes increased rates
of antibiotic-related adverse events, antimicrobial resistance
(direct as well as collateral), and possibly other as yet undeter-
mined outcomes associated with alterations of the microbiome
related to antibiotic use.
Antimicrobial resistance is an escalating problem in the am-
bulatory setting, even with apparently simple clinical problems,
such as uncomplicated cystitis [7, 8]. Although the frequency of
resistant organisms varies by patient population and geography,
multidrug-resistant uropathogens including extended-spectrum
-lactamase (ESBL)producing gram-negative bacteria raise
considerable concern about the ability of clinicians to treat
UTIs with orally available agents in the outpatient setting [9].
Currently, a signicant percentage of ESBL and enterococcal
isolates remain sensitive to nitrofurantoin [1012]. The barrier
to development of nitrofurantoin resistance is high. However,
widespread adoption of daily nitrofurantoin therapy among a
large cohort of women might lead to rapid emergence of resis-
tance. Other classes of antimicrobials such as cephalosporins,
uoroquinolones, or trimethoprim-sulfamethoxazole that are
frequently used for UTI prophylaxis certainly have a propensity
for propagating resistance, even with short-term use.
Eells model is constructed to account for a certain number
of treatment failures, which lead to further healthcare costs
due to subsequent visits or hospitalizations. In reality, the per-
centage of failures will increase with time as rates of resistance
rise; hence, whether the strategy remains cost effective in the
long run is unclear. Certainly, the attractiveness of the use of
chronic suppressive antimicrobials will worsen over time. Fur-
thermore, the daily antimicrobial prophylaxis strategy is
mired with the possibility of adverse reactions secondary to
the antimicrobial itself, an outcome not easily captured in the
model [13]. Variations in dosing (daily vs less frequent post-
coital or thrice-weekly regimens) and in the agents used for
prophylaxis and treatment are also not easily incorporated
into the model, in part due to limited availability of compara-
tive data.
How do we balance the UTI reduction benets garnered by
daily antibiotic prophylaxis with the societal cost of resistance or
adverse drug reactions? Before adopting this strategy en masse,
we should recall the insight of famed statistician George E. Box:
Essentially, all models are wrong, but some are useful [14].
Fundamentally, all models, even the best ones, are based on
estimates and approximations. Although they may provide
powerful, thought-provoking information, we should proceed
with caution prior to incorporating modeling results into clini-
cal practice.
Instead of interpreting the work of Eells et al as a call for antibi-
otic prophylaxis as the optimal prevention strategy, we must think
beyond the decision model and consider approaches to prevention
that are novel and informed by the model. Results of decision
analysis models are driven by publicly available data from individ-
ual clinical trials and epidemiological studies. Hence, only single
or studied combinations of interventions or strategies can be reli-
ably incorporated into the analyses. However, clinicians are not
limited to using only approaches evaluated in the decision model.
In real-world practice, clinicians often use mixed combinations of
strategies. Combining approaches may result in additive or
perhaps even synergistic benets to patients. For example, in an
individual case, a clinician and patient working together may opt
to use acupuncture in combination with cranberry juice and self-
directed therapy at the rst sign of symptoms.
Further complicating the issue is that different payers may
choose to cover varied aspects of the prevention strategies avail-
able in the clinical toolbox. The overall efcacy and QALDs
yielded from each of these combination approaches is unknown,
and may differ according to both the risk of UTI and patient ac-
ceptance of complementary and alternative medical treatments.
The decision model presented in this issue provides esti-
mates for each strategy and serves as a starting point for patient
counseling; less predictable Xfactors such as patient beliefs,
preferences, and values will ultimately determine the best
option for an individual. This integrated approach is similar to
the bundle concept directed toward the prevention of health-
care-associated infections, with the notable difference that the
bundle in this case is modied based on individual patient
inputperhaps best termed a patient-centered bundle for
UTI prevention. The work of Eells and colleagues contributes
to this patient-centered decision making being a more in-
formed and effective process, while illustrating the importance
of additional clinical trials examining bundled strategies for
this common clinical problem.
Notes
Acknowledgments. We greatly appreciate the critical review of the
manuscript draft by Dr Westyn Branch-Elliman.
162 CID 2014:58 (15 January) EDITORIAL COMMENTARY

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Potential conicts of interest. K. G. has served as a consultant for
Paratek Pharmaceutical and is an equity holder in Aegis Womens Health
Technologies, Inc. N. B. reports no potential conicts.
Both authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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EDITORIAL COMMENTARY CID 2014:58 (15 January) 163

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