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Am J Med. Author manuscript; available in PMC 2017 October 08.
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Published in final edited form as:

Am J Med. 2017 July ; 130(7): 842–845. doi:10.1016/j.amjmed.2017.01.025.

A Seven-Day Course of Trimethoprim-Sulfamethoxazole May Be

as Effective as a Seven-Day Course of Ciprofloxacin for the
Treatment of Pyelonephritis
Miriam T. Fox,
The Johns Hopkins University School of Medicine, Department of Medicine

Michael T. Melia, MD,

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The Johns Hopkins University School of Medicine, Department of Medicine, Division of Infectious
Diseases

Rebecca G. Same, MD,

The Johns Hopkins University School of Medicine, Department of Pediatrics

Anna T. Conley, BA, and

The University of Maryland School of Medicine, Department of Medicine

Pranita D. Tamma, MD, MHS

The Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric
Infectious Diseases, 200 North Wolfe Street, Suite 3149, Baltimore, MD 21087, Tel (410)
614-1491
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Abstract
Introduction—The Infectious Diseases Society of America guidelines recommend either 14 days
of trimethoprim-sulfamethoxazole (TMP-SMX) or 7 days of ciprofloxacin for the treatment of
pyelonephritis. Antibiotic courses of 7 days of TMP-SMX versus 7 days of ciprofloxacin for
pyelonephritis have not been previously compared. We evaluated the odds of a subsequent,
symptomatic urinary tract infection (UTI) for women with E. coli pyelonephritis receiving a 7-day
course of TMP-SMX versus a 7-day course of ciprofloxacin.

Methods—Women ages 16 and older with Escherichia coli pyelonephritis presenting to 5

healthcare facilities in the greater Maryland area between 2010 and 2016 receiving either TMP-
SMX or ciprofloxacin were included. Patients were excluded if they met any of the following
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criteria: (a) pregnancy, (b) dialysis dependency, (c) E. coli not susceptible to the treatment
prescribed, (d) polymicrobial urine culture, or (e) greater than 48 hours of antibiotic therapy other
than TMP-SMX or ciprofloxacin.

Results—Of 272 women meeting eligibility criteria, 81 (30%) and 191 (70%) received 7 days of
TMP-SMX and 7 days of ciprofloxacin, respectively. In an adjusted model, the likelihood of a
recurrent UTI within 30 days for the TMP-SMX and ciprofloxacin groups was similar (aOR: 2.30,
95% confidence interval: 0.72–7.42).

Correspondence to: Pranita D. Tamma.

None of the authors report any conflicts of interest.
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Conclusions—Our findings suggest that 7 days of TMP-SMX therapy may result in similar
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clinical outcomes compared with 7 days of ciprofloxacin for the treatment of pyelonephritis.
Considering the frequency of pyelonephritis and risks of antibiotic resistance and associated
toxicities, decreasing the duration of antibiotic therapy for pyelonephritis may impact a large
number of women.

Keywords
UTI; urine; E. coli; antibiotics; infection

Introduction
There are over 250,000 cases of pyelonephritis in the United States each year, resulting in
direct and indirect costs approximating 2.1 billion US dollars per year [1,2]. Pyelonephritis
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is one of the most common reasons women visit emergency departments or ambulatory care
clinics, frequently resulting in hospitalization [3,4].

The Infectious Diseases Society of America (IDSA) guidelines recommend treating

pyelonephritis with either 14 days of oral trimethoprim-sulfamethoxazole (TMP-SMX) or 7
days of oral ciprofloxacin based on a randomized controlled trial that showed equivalence
between these two regimens, when the causative pathogen was susceptible to these agents
[5,6]. Data comparing the efficacy of a 7-day TMP-SMX regimen and a 7-day regimen of
ciprofloxacin are lacking. If 7 days of TMP-SMX were to produce equivalent clinical
outcomes to 7 days of ciprofloxacin, this shorter duration of therapy could have the potential
to reduce TMP-SMX-associated adverse drug reactions, the emergence of antibiotic resistant
organisms, and healthcare costs, while improving patient satisfaction. Our objective was to
compare the odds of subsequent symptomatic urinary tract infections (UTIs) for women
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with pyelonephritis treated with a 7-day course of TMP-SMX versus a 7-day course of
ciprofloxacin.

Methods
This was a multicenter, retrospective study of women at least 16 years of age who presented
to the Johns Hopkins Hospital, Bayview Medical Center, Sibley Memorial Hospital, Howard
County General Hospital, Suburban Hospital or their affiliated ambulatory care practices
with Escherichia coli pyelonephritis between 2010 and 2016. Pyelonephritis was defined as
the presence of fever (temperature ≥39°C), rigors, or costovertebral angle tenderness in
addition to pyuria (>10 white blood cells/high powered field [WBC/hpf]) and ≥100,000
colony forming units per milliliter (CFU/mL) of E. coli in the urine.
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The primary exposure was 7 days of TMP-SMX or 7 days of ciprofloxacin (± 2 days).

Patients were excluded if they met any of the following criteria: (a) pregnancy, (b) dialysis
dependency, (c) E. coli not susceptible to the treatment prescribed, (d) polymicrobial urine
culture, or (e) greater than 48 hours of antibiotic therapy prior to conversion to TMP-SMX
or ciprofloxacin. The primary outcome was a subsequent, symptomatic UTI (cystitis or
pyelonephritis) with ≥100,000 CFU E. coli within 30 days of initiation of antibiotic therapy.

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Cystitis was defined as dysuria, urgency, frequency, or suprapubic pain with pyuria (>10
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WBC/hpf) and ≥100,000 CFU/mL of E. coli.

Demographic data, pre-existing medical conditions, hospital or ICU admission,

microbiological data, treatment data, and outcomes were collected by electronic medical
chart review. The EPIC Care Everywhere Network, which includes several hundred hospital
networks nationwide (https://www.epic.com/CareEverywhere/) was used to determine
whether patients presented to outside ambulatory care or acute care facilities with recurrent
UTI symptoms subsequent to their initial pyelonephritis presentation. This study was
approved by the Johns Hopkins University School of Medicine Institutional Review Board,
with a waiver of informed consent.

Baseline categorical data were compared using Pearson χ2 or Fisher’s exact test, as
appropriate. Continuous data were evaluated using the Wilcoxon rank-sum test. Unadjusted
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odds ratios and 95% confidence intervals were calculated for the analysis of a recurrent UTI
within 30 days. Variables which changed the point estimate of the association between 7-
days of TMP-SMX and UTI recurrence by at least 10% were included in a multivariable
model. Statistical significance was defined as p-value <0.05. Statistical analysis was
completed using STATA version 13.0.

Results
There were 272 women with pyelonephritis who met eligibility criteria. Of these, 81 patients
(30%) received 7 days of TMP-SMX and 191 patients (70%) received 7 days of
ciprofloxacin. Both groups were generally similar with respect to baseline characteristics
(Table 1). Although the majority of women were otherwise healthy, the most common pre-
existing condition in both groups was diabetes mellitus.
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Fewer women in the TMP-SMX group had concomitant E. coli bloodstream infections (9%
vs. 21%; p<0.01) or were hospitalized (22% vs. 36%; p=0.01). Overall, 43% of patients
received intravenous (IV) antibiotics on day 1 and 57% received oral antibiotics on day 1 of
therapy (Table 2). For women receiving TMP-SMX, 86% were infected with E. coli
susceptible to ciprofloxacin. For women receiving ciprofloxacin, 69% were infected with E.
coli susceptible to TMP-SMX.

There were 6 (7%) patients in the TMP-SMX group and 12 (6%) patients in the
ciprofloxacin group with symptomatic UTIs within 30 days of starting antibiotic therapy;
odds ratio (OR) 1.19 (95% CI 0.43–3.30). Adjustment for hospitalization and concomitant
E. coli bloodstream infections yielded an aOR of 2.30 (95% CI 0.71–7.42). Two patients in
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the ciprofloxacin group developed Clostridium difficile infections at 7 days and 9 days,
respectively, after initiating antibiotic therapy and both were readmitted to an acute care
facility. One patient in the TMP-SMX group developed a pruritic rash after receiving 5 days
of TMP-SMX.

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Discussion
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Our findings suggest that a 7-day course of TMP-SMX may be as effective as a 7-day course
of ciprofloxacin for women with E. coli pyelonephritis. Previous data suggest that 14 days of
TMP-SMX yielded similar outcomes to 7 days of ciprofloxacin, if the pathogen was
susceptible in vitro, but a comparison of 7 days of each regimens for pyelonephritis has not
been conducted [6]. Unlike the previous study [6], we included women with a variety of
medical concerns in our analysis such as those with diabetes, immunocompromising
conditions, urologic abnormalities, and severe sepsis. Clinicians appear more likely to
prescribe ciprofloxacin to women requiring hospitalization or those with concomitant E. coli
bloodstream infections, but even after adjustment for these variables, no differences in the
outcomes between the groups was observed.

Considering the incidence of pyelonephritis, decreasing the length of antibiotic therapy

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could have widespread implications beyond simply reducing antibiotic use. Every additional
day of antibiotics prescribed has been associated with an increased risk of C. difficile
infections, adverse drug events, and antibiotic resistance. The prevalence of resistance to
both TMP-SMX and ciprofloxacin in uropathogens continues to rise globally [7,8].
Reducing the duration of TMP-SMX treatment may help slow the development of resistance
to this agent. In addition, shorter antibiotic regimens decrease healthcare costs and may
increase patient compliance and satisfaction with medical care. Furthermore, a 7-day course
of TMP-SMX provides an attractive alternative to fluoroquinolone therapy, which has been
associated with a high risk of community-acquired C. difficile infections, amongst other
negative sequelae [9]. In July 2016, the US Food and Drug Administration disseminated the
results of a safety review outlining the association between fluoroquinolones and a number
of disabling side effects involving tendons, muscles, nerves, and the central nervous system
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[10]. Although fluoroquinolones have an excellent track-record for treating UTIs, providing
an alternative antibiotic for the same duration of therapy may prevent some of these
potentially incapacitating side effects, particularly in high-risk populations.

There are several limitations to our study. First, as this was an observational study, it is
possible that there were important differences influencing the decision to prescribe TMP-
SMX or ciprofloxacin that we failed to consider in our analysis. Additionally, our sample
size may have precluded the ability to effectively evaluate for differences in adverse events
between the groups. Third, despite our best attempt to capture subsequent symptomatic UTIs
across health networks in the Epic Care Everywhere network, we were not able to capture
visits to primary care physicians, urgent care centers, and emergency rooms that do not use
the Epic system. To our knowledge, however, missing data should have similarly impacted
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both groups.

Despite the limitations of this study, our findings suggest that a 7-day course of TMP-SMX
may produce equivalent clinical outcomes to a 7-day course of ciprofloxacin for women
with pyelonephritis and provide support for re-evaluation of the recommended 14-day
regimen of TMP-SMX. A randomized controlled trial comparing outcomes associated with
these two regimens would be helpful to validate our findings. With the large number of
pyelonephritis cases annually, a 50% reduction in the duration of antibiotic treatment could

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result in an important decrease in antibiotic use and the downstream effects associated with
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antibiotic overuse.

Acknowledgments
Funding

The work was supported by funding from the NIH (1K23AI127935) awarded to PDT.

References
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6. Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Jravani A, Reuning-Scherer J, Church DA.
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1583–90.
7. Khawcharoenporn T, Vasoo S, Ward E, et al. High rates of quinolone resistance among urinary tract
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infections in the ED. Am J Emerg Med. 2012; 30(1):68–74. [PubMed: 21075586]

8. Kahlmeter G, Poulsen HO. Antimicrobial susceptibility of Escherichia coli from community-
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2012; 39(1):45–51. [PubMed: 22055529]
9. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of
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Table 1

Baseline Characteristics of 272 Women with Escherichia coli Pyelonephritis Treated with 7 Days of
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Trimethoprim-Sulfamethoxazole (TMP-SMX) versus 7 Days of Ciprofloxacin from 2010 to 2016

Variable TMP-SMX Ciprofloxacin p-value

(n=81; 30%) (n=191; 70%)
Age (median, IQR) 37 (29–48) 41 (26–59) 0.33

Race/Ethnicity
Caucasian 36 (43%) 77 (40%) 1.00

African American 37 (46%) 80 (42%) 0.59

Latino 2 (2%) 8 (4%) 0.73

Asian/Pacific Islander 2 (2%) 13 (7%) 0.24

Multiracial/Unknown 6 (7%) 13 (7%) 0.80

Pre-existing conditions
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Diabetes 12 (15%) 30 (16%) 1.00

Human immunodeficiency virus 2 (2%) 6 (3%) 1.00

Chemotherapy in past 6 months 1 (1%) 4 (2%) 1.00

Renal transplant 1 (1%) 4 (2%) 1.00

End-stage liver disease 1 (1%) 4 (2%) 1.00

Immunomodulators within the past 30 days 2 (2%) 11 (6%) 1.00

Indwelling or intermittent urinary catheterization 2 (2%) 6 (3%) 1.00

Serum creatinine on day of positive urine culture (median, IQR) 1 (0.7–1) 1 (0.8–1) 0.22

Escherichia coli bacteremia 7 (9%) 40 (21%) <0.01

Hospitalized 18 (22%) 69 (36%) 0.01

Extended spectrum beta-lactamase producing E. coli 3 (4%) 4 (2%) 0.43

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Table 2

Antibiotics Prescribed on Day One of Therapy for 272 Women with Pyelonephritis
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Antibiotic Prescribed on Day 1 Final Antibiotic: Final Antibiotic:

TMP-SMX ciprofloxacin
(n=81) (n=191)
Ceftriaxone 19 (24%) 53 (28%)

Ciprofloxacin 0 105 (55%)

Trimethoprim-sulfamethoxazole 57 (70%) 0

Piperacillin-tazobactam 1 (1%) 4 (2%)

Cefepime 4 (5%) 19 (10%)

Aztreonam 0 10 (5%)
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