Procalcitonin, mid-regional proadrenomedullin and C-reactive protein in predicting treatment outcome in community-acquired febrile urinary tract infection

Febrile urinary tract infections (UTI), including acute pyelonephritis and prostatitis, are relatively common in adults, but data on the optimal duration of treatment are limited, especially within men, the elderly and patients with comorbidities. Emerging bacterial resistance calls for more efficient efforts to shorten the duration of antibiotic treatment.

Our previous findings in the FUTIRST trial have shown that patients with community-acquired febrile urinary tract infections, such as women and elderly patients with severe comorbidities, can be safely and efficaciously treated with oral ciprofloxacin for 7 days, irrespective of disease severity upon presentation [1]. In men, however, a short course of therapy can lead to significantly more clinical failures compared to a 14-day course of oral ciprofloxacin.

Previous studies have shown that procalcitonin (PCT) can provide useful guidance for antimicrobial treatment in patients with respiratory tract infections and sepsis [2–4]. However, little is known concerning PCT guided-therapy in patients with urinary tract infections. An earlier subgroup analysis of a randomized trial performed in the intensive care unit (ICU) has shown that the duration of antibiotic treatment was significantly shorter for 24 UTI-patients receiving procalcitonin-guided treatment compared to 18 UTI control-group patients [4]. However further investigations are scarce. Other biomarkers may also be of interest, such as mid-regional proadrenomedullin (MR-proADM), which has been shown to be increased in the early stages of progression towards multiple organ failure [5], and is of value in predicting a complicated course of treatment and the requirement for ICU admission [6–8].

This secondary analysis of the earlier FUTIRST trial [1] therefore hypothesized that procalcitonin measurement on days 0 and 3 could more accurately identify patients at risk of treatment failure and in need a prolonged course of antibiotics compared to either MR-proADM or C-reactive protein.

A total of 249 patients with a presumptive diagnosis of fUTI were analysed (details provided in Fig. 1). Patient characteristics in terms of urologic history, comorbidities and presenting symptoms are outlined in Table 1. Of these, 165 (66%) were randomly assigned to receive antimicrobial treatment for either 7 (N = 85) or 14 (N = 80) days; in the remaining patients the treatment duration was left at the discretion of the treating physician. The majority of patients (N = 175; 70%) were included at the ED, and 73 (29%) patients undergoing existing antimicrobial treatment prior to presentation. Patients had an average age of 60 (45–73) years, with females comprising the majority of enrolled patients (N = 148; 59%).

	All patients (n = 249)
Age (years)	60 (45–73)
Male sex	101 (41)
Urologic history
Indwelling urinary catheter	7 (3)
Urinary tract disordera	75 (30)
Recurrent UTIb	57 (23)
Comorbidity
Diabetes mellitus	33 (13)
Malignancy	17 (7)
Heart failure	21 (8)
Cerebrovascular disease	13 (5)
Chronic renal insufficiency	9 (4)
COPD	27 (11)
Immunocompromised	15 (6)
Presentation
At emergency department	175 (70)
Antibiotic pretreatment	73 (29)
Fever duration, hours	36 (19–72)
Dysuria	188/243 (77)
Flank pain	159/245 (65)
Suprapubic pain	127/242 (52)
Perineal pain	11/241 (5)
Systolic BP, mmHg	130 (116–146)
Diastolic BP, mmHg	74 (64–84)
Heart rate, beats/minute	94 (80–107)
Cultures
Positive urine culture	171 (69)
Escherichia coli	143/171 (84)
Positive blood culture	45/240 (19)
Positive urine and/or blood culture	183 (73)

Data presented as number (%) or median (IQR).

BP blood pressure, AB antibiotics, TMP/SMX trimethoprim-sulfamethoxazole.

^aany functional or anatomical abnormality of urinary tract except urinary catheter

^b≥3 UTIs in past 12 months or ≥ 2 UTIs in past 6 months

Median biomarker concentrations across the total patient population were as follows: PCT: 0.40 [0.12–1.54] ug/mL; MR-proADM: 0.89 [0.63–1.28] nmol/L; and CRP: 118 (52–205) mg/L.

Prediction of treatment outcome

Total patient population

Concentrations of PCT, MR-proADM and CRP, measured at presentation, did not differ between patients with clinical cure or treatment failure (Fig. 2 and Table 3). As shown in Table 3, biomarker levels also did not predict treatment failure when measured after 3 days of treatment. We also assessed cut-offs for PCT as previously used in other studies, such as 0.25 μg/mL [10, 11] and a decrease of PCT concentration by 80% [4].

	Clinical cure	Clinical failure	P value
All patients (n = 249)	n = 229	n = 20
At presentation
PCT	0.40 (0.13–1.54)	0.36 (0.10–1.46)	0.749
PCT > 0.25	136 (59%)	12 (60%)	0.957
CRP	120 (53–211)	90 (27–223)	0.851
proADM	0.89 (0.62–1.30)	0.86 (0.67–1.20)	0.948
Day 3
PCT	0.18 (0.07–0.87)	0.12 (0.04–0.69)	0.667
PCT ≤ 0.25	122 (60%)	12 (67%)	0.568
PCT ≤ 0.25 or PCT decline ≥80%	144 (71%)	14 (78%)	0.519
proADM	0.66 (0.50–0.91)	0.63 (0.51–0.78)	0.667
Short treatment (n = 92)	n = 82	n = 10
At presentation
PCT	0.34 (0.10–1.68)	0.36 (0.11–1.79)	0.980
PCT > 0.25	47 (57%)	6 (60%)	0.871
CRP	123 (53–194)	77 (15–142)	0.231
proADM	0.76 (0.56–1.04)	0.85 (65–1.25)	0.360
Day 3
PCT	0.12 (0.06–0.42)	0.13 (0.09–0.63)	0.794
PCT ≤ 0.25	51 (66%)	7 (78%)	0.484
PCT ≤ 0.25 or PCT decline ≥80%	62 (80%)	8 (89%)	0.542
proADM	0.56 (0.47–0.76)	0.59 (0.53–0.74)	0.679
Long treatment (n = 157)	n = 147	n = 10
At presentation
PCT	0.48 (0.15–1.49)	0.48 (0.09–3.13)	0.826
PCT > 0.25	89 (60%)	6 (60%)	0.973
CRP	119 (52–224)	181 (37–263)	0.531
proADM	0.98 (0.67–1.44)	0.86 (0.62–1.21)	0.495
Day 3
PCT	0.22 (0.08–1.08)	0.08 (0.04–0.72)	0.358
PCT ≤ 0.25	71 (56%)	5 (56%)	0.984
PCT ≤ 0.25 or PCT decline ≥80%	82 (65%)	6 (67%)	0.899
proADM	0.74 (0.53–1.03)	0.74 (0.47–1.02)	0.609

Data presented as median (IQR) or number (%)

CRP at presentation missing: n = 41 in short treatment and n = 41 in long treatment

ROC analyses were further performed to define the prognostic accuracy of the different biomarkers for predicting treatment outcome. Based on the calculated AUCs, none of the biomarkers had any predictive value for treatment success (Fig. 3). Findings were similar in a selection of patients with culture proven UTI (N = 183); and regarding the long term clinical cure in all patients (data not shown).

Patients treated for 7 days

We assessed the group of patients who received 7 days of antimicrobial treatment separately, because treatment success was lower as compared to those treated for 14 days (89% versus 94%, respectively, p = 0.21). Again, no difference was seen in levels of PCT, MR-proADM and CRP between patients with clinical cure or treatment failure (Table 3).

In the current study we assessed the ability of the biomarkers PCT, MR-proADM and CRP in predicting treatment failure in a randomized trial of antibiotic treatment duration (i.e. 7 versus 14 days) in patients with febrile urinary tract infection. We hypothesized that the biomarker signature, as an objective laboratory proxy of physical status in fUTI, would help the physician in guiding the length of antibiotic therapy. In our study, however, neither PCT nor MR-proADM or CRP were distinctive in identifying upfront those patients at risk for a treatment failure, i.e. who might benefit from a more prolonged antibiotic treatment.

Overall treatment success was high: 94% of the randomized 165 and 88% of 84 non-randomized patients who all were given an identical follow-up reached the endpoint of clinical cure. Of the biomarkers, PCT and MR-proADM were significantly correlated to clinical parameters such as fever, blood pressure and subjective complaints that represent the acute febrile illness of invasive urinary tract infection. Also, the biomarker signature of PCT and MR-proADM correlated with severity of disease, such as presence of bacteraemia and need for initial administration of antibiotics intravenously rather than orally. Finally, the course of biomarkers over the first three days correlated with signs of clinical recovery, such as time to defervescence, intensity of subjective complaints and length of hospital stay. As opposed to PCT and MR-proADM, the currently popular biomarker CRP did not display any correlation to relevant clinical parameters like course of fever or bacteraemia.

The biomarkers we chose are in current use as predictors of morbidity and mortality in a variety of conditions. Procalcitonin is a precursor hormone of calcitonin and is upregulated by cytokines released in response to bacterial infection [4]. MR-proADM has been detected in a variety of tissues, including heart, vessels and the kidneys and has both immune modulating and vasodilating properties [2]. Levels of MR-proADM are elevated in sepsis, contributing to hypotension in these patients. Thus, procalcitonin has shown to be a marker of bacteraemia in patients with febrile UTI [12–14], whereas mid-regional proadrenomedullin (MR-proADM) is a predictor of a complicated course of disease, the need for ICU admission, and mortality [6, 7].

PCT-based algorithms have been developed to aid decisions on the initiation and/or discontinuation of antibiotics in patients with acute respiratory tract infections and in critically ill patients admitted to the intensive care ward [15]. In these specific patient groups, the use of PCT has been shown to be a powerful tool in antibiotic stewardship [16]. Although in the intensive care studies patients with infections originating from the urinary tract were included, numbers were small (e.g. 7% of patients in the PRORATA trial, 3% of patients in the SAPS trial) and these results cannot directly be extrapolated to patients with community-acquired urinary tract infections [4, 17].

Elevation of these biomarkers is a reflection of the systemic inflammatory response to bacterial invasion. This inflammatory response coincides with acute illness, and often in a measurable deviation of vital signs, such as a raised temperature and decreased blood pressure. In daily clinical practice, severity of the acute illness is assessed on basis of history, comorbidity and on severity of local and vital signs. It has become clear that severity of illness can also be more objectively expressed in biomarkers, which individually are associated with complicated course of disease, such as bacteraemia, need for ICU admission, time to defervescence and length of hospital stay. Although PCT and proADM were correlated to these clinical outcome parameters in our patients, they did not help predict outcome of the otherwise standardized antibiotic treatment, irrespective of a treatment duration of 7 or 14 days. The most likely reason is that all patients were treated for at least 7 days after which treatment success was high already (i.e., 89%). Thus, the lack of predictive value for treatment guidance is likely explained by the fact that historically, empiric treatment duration is based on the anticipated time to clinical recovery, while taking into account the inter-individual variety in severity of acute illness at the start of treatment (i.e. practically, adding some days of treatment to average recovery time). Thus, in our patients, the median time to defervescence was 2.0 (IQR 1–3) days while randomization for short or prolonged treatment duration did not start until day 7. In other words, one could have predicted that our biomarker approach might have been successful in guiding treatments up to one or a few days after clinical recovery, but it lacked the ability to do so after the minimum 7 days of treatment, by which a strong margin surpasses the time for the biomarker signature to return to normal. Differences between patients in severity of illness at presentation and corresponding biomarker levels are likely to have normalized after 7 days of treatment, and definitely after 14 days. It should be noted, that antimicrobial resistance played no role in our study; patients with a ciprofloxacin resistant uropathogen were excluded from randomization and received effective therapy based on culture results.

In the original study we described that although 7 days of treatment was inferior to 14 days in male patients in terms of short term clinical cure, there was no difference in the requirement for antibiotic retreatment for UTI during longer follow up (90 days) in both women and men [1].

A retrospective analysis of a large database of male veterans also found that treatment duration longer than 7 days was not associated with a reduction of UTI recurrence [18]. In this study, UTI recurrence was independently associated with age and comorbidity. It is likely that a subgroup of patients can be treated with an even shorter course of antibiotics than 7 days. Hypothetically, within the current time frame of treatment, there is a moment when the patient has recovered from the acute illness and the biomarker levels have dropped below a certain cut-off, likely leaving room for further limitation of treatment duration. It stands to reason that the time to this recovery is defined by host related factors, and therefore differs between patient subgroups. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy, irrespective of patient characteristics. Unfortunately, as reasoned above, our study design did not allow for further discrimination.

The main strength of this trial is its pragmatic nature reflecting daily clinical practice. We randomized patients between the up until then standard treatment duration for fUTI of 14 days and half of that length (7 days), and included enough subjects to demonstrate non-inferiority. We enrolled consecutive patients with fUTI, irrespective of age, gender and underlying medical condition. Different biomarker concentrations were available at the day of presentation and after three days of treatment, each representing different aspects of the physiological condition of the acute illness.

Limitations of our study include the design in randomizing patients between 7 and 14 days, not allowing for analysis of biomarker value in shorter antibiotic treatment. This was unforeseen, because at the start of the trial 14 days of therapy were standard clinical practice, and reduction to 7 days was already a great improvement. Furthermore, our sample size may have been too small to exclude a type II error.

To our knowledge, only one study addressing biomarker-guided antibiotic therapy in community acquired urinary tract infection has been published [10]. In this study, Drozdov et al. randomized both patients with cystitis (N = 36) and febrile urinary tract infections (N = 84) between PCT-guided or standard treatment. Overall, antibiotic exposure was reduced whereas adverse outcomes (clinical recurrence and rehospitalization rate) were similar in both groups. In the subgroup analysis of patients with fUTI/pyelonephritis, PCT-guided duration of antibiotic therapy was significantly shorter than standard care (7.5 vs. 11.0 days). In bacteraemic patients, recurrence rate (56% vs. 16%) and persistent infection after treatment (13% vs. 6%) were higher in the PCT guided group, although the distribution of patients with bacteraemia was not well balanced between the groups (45% vs. 21%) and numbers were too small to reach significance. Although this study by Drozdov et al. is limited by the small sample size and heterogenicity of patients, it supports the potential use of PCT-based approach in patients with community acquired fUTI to safely reduce antibiotic consumption.

Future interventional studies should be conducted to examine if PCT-guided duration of antibiotic treatment can indeed aid in distinguishing a subgroup of patients with fUTI who can be treated with antibiotics for even shorter than 7 days, i.e. those with rapid normalization of elevated biomarkers, in order to further decrease antibiotic exposure and limit development of antimicrobial resistance.

In conclusion, although the biomarkers PCT and MR-proADM are correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection, who are treated for 7 or 14 days with ciprofloxacin. In our secondary analysis, CRP had no added value in the management of fUTI.