Utility of initial procalcitonin values to predict urinary tract infection

Accepted Manuscript Utility of initial procalcitonin values to predict urinary tract infection

Alexander R. Levine, Midori Tran, Jonathan Shepherd, Edgar Naut PII: DOI: Reference:

S0735-6757(18)30178-5 doi:10.1016/j.ajem.2018.03.001 YAJEM 57352

To appear in: Received date: Revised date: Accepted date:

13 November 2017 22 February 2018 2 March 2018

Please cite this article as: Alexander R. Levine, Midori Tran, Jonathan Shepherd, Edgar Naut , Utility of initial procalcitonin values to predict urinary tract infection. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yajem(2017), doi:10.1016/j.ajem.2018.03.001

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ACCEPTED MANUSCRIPT Title: Utility of initial procalcitonin values to predict urinary tract infection Running title: Use of procalcitonin to predict urinary tract infection Alexander R. Levine PharmD 1,2, Midori Tran PharmD 3, Jonathan Shepherd MD, MSc 4, Edgar Naut MD 5,6 Assistant Professor, Department of Pharmacy Practice, University of Saint Joseph School of Pharmacy

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Clinical Pharmacist, Department of Pharmacy, Saint Francis Hospital and Medical Center

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Pharmacy Resident, Department of Pharmacy, Kingsbrook Jewish Medical Center

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Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Saint

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Francis Hospital and Medical Center

Academic Hospitalist, Department of Medicine, Saint Francis Hospital and Medical Center

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Assistant Professor, Site Director, UConn Health

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Corresponding Author:

Department of Pharmacy Practice

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Alexander R. Levine

229 Trumbull Street

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Hartford, Connecticut 06103

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University of Saint Joseph School of Pharmacy

Phone: 860-231-6896

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Fax: 860-231-5876

[email protected]

Abstract Background: Urinary tract infections (UTIs) are one of the most common reasons women seek treatment in the emergency department (ED). The biomarker procalcitonin (PCT) has gained popularity over the last decade to improve the diagnosis of bacterial infections and reduce unnecessary exposure to antibiotics. PCT has been extensively studied in patients with pneumonia and sepsis and may have additional role in UTI. Methods: A retrospective study of patients who presented to the ED in which a urinalysis test and a PCT level was obtained within the first 24 hours of presentation. Signs and symptoms of UTI and urine cultures were reviewed to determine a positive diagnosis of UTI. The area under the receiver operating curve was used

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to calculate the test characteristics of PCT. Different breakpoints were analyzed to determine which PCT level corresponded to the highest sensitivity and specificity. Results: 293 patients were included in this single center, retrospective study. The AUC of PCT to predict UTI was 0.717; 95% CI: 0.643-0.791 (p<0.001). A PCT threshold of 0.25 ng/ml corresponded to the best combination of sensitivity (67%) and specificity (63%), with a positive predictive value and negative predictive value of 26% and 91%, respectively. Conclusions: A PCT threshold < 0.25 ng/ml was a strong predictor of the absence of UTI. The high negative predictive value of PCT may be useful as an adjunct to urinalysis results to rule out UTI and facilitate noninitiation or earlier discontinuation of empiric antibiotics.

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Keywords: Urinary tract infection, procalcitonin, antimicrobial stewardship, biomarker

1. Introduction

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The development of a urinary tract infection (UTI) is one of the leading reasons women seek treatment in the emergency department (ED). In 2007, UTIs led to 2-3 million ED visits in the United States [1]. Accurately

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identifying UTI is challenging, particularly in the elderly patients, who often have atypical clinical

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presentations [2]. Use of urinary biomarkers such as leukocyte esterase and nitrite can aid in the diagnostic process. Leukocyte esterase is highly sensitive at detecting a UTI but lacks specificity. The presence of a

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positive nitrite reaction is more specific but only identifies gram-negative coliforms and will fail to identify atypical pathogens like pseudomonas and gram-positive organisms [2-4]. Utilization of the biomarker

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procalcitonin (PCT) has been shown to improve the diagnosis of bacterial infections and reduce unnecessary antibiotic exposure in patients with sepsis and pneumonia [5-11]. PCT may offer additional benefit in guiding

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antibiotic therapy in UTI patients.

PCT is the peptide precursor of the hormone calcitonin that is produced in the thyroid gland and the lung. In healthy individuals under normal physiological conditions, PCT is undetectable in the blood. However, in the presence of a bacterial infection, PCT is released throughout the body resulting in a concentration that increases several thousand-fold in the blood [12, 13]. In patients with UTI, PCT blood concentrations that exceed 0.5 ng/ml have a sensitivity of 58% and specificity of 76% to distinguish acute pyelonephritis (APN) from a lower UTI [14]. PCT is also a strong predictor of the severity of UTI [15-20]. Higher PCT levels are

ACCEPTED MANUSCRIPT associated with a greater risk of renal scarring in pediatric patients, bacteremia in patients with urosepsis, 30-day mortality in febrile UTI patients, and severity of sepsis in adult women with APN [15-18]. Most of the current studies have focused on the ability of PCT to differentiate the type of UTI and predict the severity of UTI in patients with APN, urosepsis, or bacteremia. Only one randomized controlled trial has utilized PCT as a tool to deescalate antibiotics in UTI [21]. The purpose of this study is to evaluate the value of

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PCT to differentiate a positive and negative lower UTI and determine its role in optimizing antibiotic

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stewardship in these patients.

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2. Material and methods

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2.1 Study setting and population

This study was approved by the institutional review board, which waived the need for informed consent.

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This is a single center, retrospective study in consecutive adult patients, at least 18 years of age, who presented to the ED over a 4 month period in which a urinalysis with reflex culture and a PCT level was

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obtained within the first 24 hours of presentation. If patients who presented with more than 1 episode of

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lower UTI during the study period, only the first episode was included. PCT is most commonly ordered among UTI patients in the ED who present with signs of systemic illness such as fever or leukocytosis. Patients who

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were pregnant, had a primary infection other than a UTI, evidence of APN, urethritis, prostatitis, or past medical history of a thyroid disorder, spinal cord injury resulting in paralysis, immunocompromised condition, or kidney transplantation were excluded. Several non-infectious conditions can cause an elevation of PCT including trauma, burn, surgery, malignancy and chronic kidney disease [22-24]. Therefore, these patient populations were also excluded from the analysis. 2.2 Data extraction protocol

ACCEPTED MANUSCRIPT The medical chart was reviewed to determine the presence of signs and symptoms of lower UTI and urine culture to meet criteria for a positive UTI. A positive lower UTI diagnosis was defined as patients who were symptomatic and had a positive urine culture result. Signs and symptoms of a lower UTI were defined as acute onset of any of the following symptoms (dysuria, hematuria, frequency, urgency, urinary retention, suprapubic pain). Positive urine culture in non-catheterized patients was defined as a single, clean-catch,

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voided urine specimen with 1 bacterial species isolated in a quantitative count ≥ 10 5 cfu/mL (24). A positive

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urine culture in catheterized patients was defined as a single catheterized urine specimen with 1 bacterial

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negative urine cultures were designated as negative for a UTI.

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species isolated in a quantitative count of ≥ 103 cfu/mL (24). Patients who were asymptomatic or had

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2.3 Statistical analysis

The primary endpoint of the study is the area under the receiver operating curve (AUC) to predict UTI

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corresponding to PCT level. A receiver operating curve (ROC) was constructed to determine the AUC. The

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sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were analyzed for different PCT breakpoints and Youden’s index was calculated to determine the best PCT

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threshold to predict a positive UTI diagnosis. This generates the PCT cut-point where the combined sensitivity and specificity are maximized. Independent t-tests were utilized to analyze continuous outcomes

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and Wilcoxon Signed-Rank tests were used to assess non-parametric data. Pearson Chi-Square tests were

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used to summarize categorical outcomes. All statistical tests were 2-tailed and a p < 0.05 met statistical significance. A multivariate logistic regression was used to calculate the odds ratio (OR) with 95% confidence intervals (CI) for each covariate that predicted a positive UTI. Covariates with a p value < 0.1 were eligible for inclusion in the final model using a backward selection method. Statistical analyses were performed using SPSS version 25.0 (IBM Corp, 2017).

3. Results

ACCEPTED MANUSCRIPT 2093 patients were reviewed during the study time frame with 293 patients meeting the inclusion criteria (Fig. 1). Forty-eight of the 293 patients (16%) were positive for UTI. Of the 293 patients, 155 patients (53%) had a urine culture result. Of these, 148 patients had a urine culture secondary to reflex testing from a positive urinalysis and 7 were ordered for a urine culture regardless of the urinalysis results. Among the 155 patients ordered for urine cultures, 70 patients (45%) had a positive urine culture and 48 of these patients

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(69%) were also symptomatic and met the criteria for a positive UTI. The baseline demographics and

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admitting clinical characteristics of the positive and negative UTI groups are presented in Table 1. Patients

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with a negative UTI diagnosis were more likely to be younger, have significantly lower PCT values, WBC count, peak temperature, and less likely to be initiated on antibiotics.

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The AUC of PCT to predict UTI was 0.717; 95% CI: 0.643-0.791 (p<0.001) (Fig. 2). The Youden’s index

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method demonstrated the best PCT threshold was 0.235 ng/ml with a sensitivity and specificity equal to 69% and 63%, respectively. The cutoffs of different PCT levels are listed in Table 2. These were common

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thresholds recognized in the literature for their ability to discriminate between differing infectious outcomes. Of the commonly used thresholds, a PCT of 0.25 ng/ml demonstrated the highest combination of sensitivity

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and specificity equal to 67% and 63%, respectively. The PPV and NPV using this threshold are 26% and 91%,

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respectively. This corresponded to a positive likelihood ratio of 1.81 and negative likelihood ratio of 0.524. Clinical variables approaching significance for predicting UTI with a p-value < 0.1 on univariable

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regression included age ≥ 65, sex, initial PCT ≥ 0.25 ng/ml, urine WBC count ≥ 6/hpf, positive nitrite reaction, and ≥ small leukocyte esterase. These were entered in a multivariable logistic regression. Urine WBC count ≥

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6/hpf (OR 19.7 95% CI: 7.68-50.5, p<0.001), PCT ≥ 0.25 ng/ml (OR 3.89; 95% CI 1.75-8.65, p=0.001), and age ≥ 65 (OR 3.66; 95% CI 1.40-9.61, p=0.008) were significant predictors of UTI after adjusting for confounders.

4. Discussion Among patients who presented to the emergency department with suspicion of UTI, the AUC of PCT to predict UTI was 0.717. A perfect test has an AUC of 1 and AUC=0.5 has no predictive value. The AUC in this study demonstrates that PCT is significantly better than chance alone in predicting UTI. A PCT threshold <

ACCEPTED MANUSCRIPT 0.25 ng/ml was identified as a reasonable threshold below which a UTI could be ruled out. We feel this value is better than 0.235 ng/ml which was identified using the Youden index since 0.25 ng/ml corresponds to previously identified cut-points in the literature. This choice offers the benefit of simplicity with minimal impact on sensitivity and specificity. While PCT > 0.25 ng/ml was still a poor predictor in determining the likelihood of a positive UTI diagnosis, values less than this threshold were a strong predictor of the absence of

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UTI. Of the 173 patients who presented with a PCT < 0.25 ng/ml, 91% of patients were negative for UTI. The

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high NPV of this threshold may be useful as an adjunct to urinalysis to appropriately withhold or discontinue

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antibiotics in UTI. In clinical practice, if patients have lower UTI symptoms and either equivocal urinalysis results or only meet one criteria for a positive urinalysis, PCT levels < 0.25 ng/ml would strengthen the

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decision to hold or stop antibiotics.

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The host’s immune response to UTI is variable and influenced by many factors including the origin of the infecting strain and virulence factor expression [25]. The variation in the host’s response limits the ability

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of diagnostic biomarkers such as PCT to consistently predict a positive infection. Therefore, the role of PCT in antimicrobial stewardship is shifting towards its use as a tool to de-escalate antibiotics rather than guiding

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initiation [11, 26, 27]. The current Infectious Diseases Society of America Guidelines (IDSA) for hospital acquired pneumonia recommends using PCT in combination with clinical criteria to guide the discontinuation

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of antibiotics [26]. Similarly, the recent Surviving Sepsis Campaign Guidelines suggest PCT can be used to

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shorten the duration of antibiotics or discontinue empiric antibiotics in patients who initially appeared septic, but subsequently had limited clinical evidence of infection [27]. The current IDSA guideline for diagnosis and

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treatment of asymptomatic bacteriuria in adults does not discuss the role of biomarkers, but an update is in progress, which may address this issue [28]. Our results demonstrate that initial PCT values, even at higher thresholds, poorly predict the presence of UTI and therefore, we support the notion that PCT > 0.25 ng/ml should not be used to guide initiation of antibiotics in these patients. Only one randomized controlled trial has examined the utility of PCT to guide antibiotic therapy in UTI [21]. In this trial, patients with community-acquired, non-catheter UTI were randomized to current guidelines or a PCT-pyuria based algorithm to guide initiation and duration of antibiotics. The algorithm recommended antibiotics to be stopped if the PCT < 0.25 ng/ml or PCT decreased by ≥ 80% of the peak value

ACCEPTED MANUSCRIPT and pyuria normalized or pyuria decreased by ≥ 90% of the peak value. Patients randomized to the PCT pyuria algorithm had significantly less overall antibiotic exposure of 7 vs. 10 days, p=0.011. While our study was limited to those with no signs or symptoms of ascending infections, our findings are consistent with this trial and support using PCT < 0.25 ng/ml as the best threshold to potentially withhold or discontinue antibiotics.

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Urinalysis is the most common screening test used to predict positive urine cultures. This test evaluates the presence of urine biomarkers, nitrite and leukocyte esterase, and urinary sediment to

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determine the probability of UTI. The advantages include its low cost and quick turnaround time, but some studies question the reliability of the test [29-34]. A positive nitrite reaction is highly specific for the presence

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of a positive UTI diagnosis with a reported specificity between 75%-98%. However, the absence of a positive

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nitrite reaction cannot definitively exclude a UTI due its lower sensitivity between 36%-57% and negative predictive value [30, 31]. Leukocyte esterase is more sensitive at detecting a UTI with a reported sensitivity

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between 72%-94%, but has a lower specificity of 9%-83% since many other conditions can cause pyuria leading to false positive leukocyte esterase results [31]. The combination of a positive nitrite reaction or

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positive leukocyte esterase plus positive urine leukocytes further improves the sensitivity and specificity of the test [29]. If both biomarkers are negative, this cannot definitively rule out a UTI [32-34]. One study in

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1,993 women with acute uncomplicated UTI demonstrated that approximately 50% of samples that were

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negative for both nitrite and leukocyte esterase produced positive urine cultures [34]. In patients with both negative nitrite and leukocyte esterase results, the addition of PCT may further distinguish between UTI and

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asymptomatic bacteriuria. PCT could also be utilized in patients who have equivocal urinalysis results. For instance, if leukocyte esterase is positive, but nitrite and urine leukocytes are negative, a PCT level <0.25 ng/ml would further support the decision to withhold or discontinue empiric antibiotic treatment. At our institution, PCT is an in-house laboratory test with an average turn-around time of 1-2 hours and costs $25 per test. A previous study demonstrated that PCT-guided antibiotic therapy is cost-effective in patients with bacterial infections or sepsis since the added costs of the test were outweighed by the significant reduction in days of antibiotic therapy and antibiotic-related adverse events [35]. Using a PCTguided approach with moderate treatment algorithm compliance predicted a cost-savings of $65 per patient.

ACCEPTED MANUSCRIPT The use of PCT-guided antibiotic therapy in lower UTI patients has the potential for similar cost-savings. In our study, the median length of antibiotic therapy in the 48 patients with a positive lower UTI was 2.97 days. Therefore, patients with PCT <0.25 ng/ml could allow holding or stopping antibiotics on day 1 and potentially reduce the length of antibiotics by 2 days and justify the additional cost of one PCT test. Our current study has the following limitations. First, the retrospective nature potentially introduces

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bias due to incomplete data due to missing patient information in the medical record. For example, we defined a positive UTI based on the presence of signs and symptoms described in the history of present

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illness, physical exam, and review of systems. Depending on the completeness of the note, some of the records may omit positive symptoms and therefore these would be inaccurately diagnosed as a negative UTI. Second,

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we did not record the timing of antibiotics relative to obtaining PCT and cannot confirm if PCT was drawn

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prior to antibiotic administration. Therefore, if antibiotics were administered prior to obtaining PCT, this may lead to lower PCT levels. However, all of the patients included in this study had PCT levels drawn within 24

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hours of presentation to the ED and the concentration of PCT does not peak until 24 to 48 hours [36] . Therefore, if the patient received one dose of antibiotics in the ED prior to obtaining PCT, it is unlikely to

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significantly impact the results of the test. Lastly, our study focused only on the predictive value of PCT for

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5. Conclusions

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urosepsis are warranted.

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lower UTI. Future studies that evaluate PCT in predicting UTI diagnosis among patients with APN and

PCT > 0.25 ng/ml was a poor predictor of UTI and should not be used to guide initiation of antibiotics. An initial PCT value < 0.25 ng/ml was highly predictive of the absence of UTI and may provide a role in facilitating non-initiation or earlier discontinuation of antibiotics.

Funding: This work was supported by the Saint Francis Hospital and Medical Center BestStep Grant.

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Table 1. Patient demographics, admitting clinical characteristics, and urinalysis results

Negative UTI

(n=4 8 )

(n=2 4 5 )

77.1 ± 12.0

67.0 ± 17.4

P value

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P ositive UTI

<0.001

123 (50.2)

1.000

46 (18.8)

0.550

10 (20.8)

65 (26.5)

0.473

9 (18.8)

27 (11.0)

0.150

101.1 (100.1-102.6)

99.4 (98.6-101.1)

<0.001

13.3 (10.0-19.3)

12.0 (8.65-16.4)

0.095

0.525 (0.115-2.41)

0.100 (0.010-0.405)

<0.001

48 (100)

189 (77.5)

<0.001

2.97 (2.03-5.09)

2.81 (1.10-4.71)

0.135

Age, years

24 (50.0)

Nursing home resident

11 (22.9)

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Gender, % female

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Demographics

Diabetes mellitus

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Dementia

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Data are means ± standard deviation or number (%) of patients

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Ad mitting clinical characteristics

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Maximum temperature, degrees Fahrenheit 3

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PCT, ng/ml

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Maximum white blood cell count, 10 /mm

Initiation of antibiotics

Length of antibiotic therapy, days

Data are median (interquartile range) or number (%) of patients

Abbreviation: PCT, procalcitonin

ACCEPTED MANUSCRIPT Urinalysis results Pyuria (≥ 6 urine WBC)

40 (87)

57 (24.5)

<0.001

Positive nitrite

17 (37)

24 (9.9)

<0.001

42 (91.3)

77 (31.8)

<0.001

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≥ Small leukocyte esterase

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Data are number (%) of patients

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Abbreviation: WBC, white blood cell

ACCEPTED MANUSCRIPT Table 2. Sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, and negative likelihood ratio to predict UTI Sensitivity

Spec ific ity

NP V

PPV

LR +

LR -

PCT < 0.1 ng/ml

128 (43%)

81

49

93

24

1.56

0.396

PCT < 0.25 ng/ml

173 (57%)

67

63

91

26

1.81

0.524

PCT < 0.5 ng/ml

216 (72%)

50

77

89

30

2.17

0.649

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No (%)

IP

Abbreviations: PCT, procalcitonin; NPV, negative predictive value; PPV, positive predictive value; LR+, positive

AC

CE

PT

ED

M

AN

US

CR

likelihood ratio; LR-, negative likelihood ratio

Figure 1

Figure 2