Prediction of Staphylococcus aureus bacteremia by molecular detection of S. aureus in urine: a proof of concept study

doi:10.21203/rs.3.rs-4976885/v1

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Prediction of Staphylococcus aureus bacteremia by molecular detection of S. aureus in urine: a proof of concept study

https://doi.org/10.21203/rs.3.rs-4976885/v1

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Journal Publication

published 31 Oct, 2024

Read the published version in European Journal of Clinical Microbiology & Infectious Diseases →

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Purpose

Staphylococcus aureus bacteremia (SAB) is associated with a 90-day mortality of 15–30%. Many SAB-patients (7.8–39%) have a secondary S. aureus bacteriuria (SABU) mainly without symptoms of a urinary tract infection. As early-targeted therapy of SAB can reduce mortality, there is an interest in rapid detection of S. aureus in blood or urine. Here, we compared a rapid nucleic acid amplification test (NAAT) with conventional culture to detect S. aureus in urine and to identify cases with SAB.

Methods

In a cross-sectional study, we assessed urine samples (mid-stream, clean catch and catheter urine) of patients with SAB and bacteremia other than SAB (non-SAB). Urine samples were collected ± 3 days to the collection of the positive blood culture and were cultured on a set of selective and non-selective agar plates. NAAT was performed using a commercial test (Xpert® SA Nasal Complete G3, Cepheid) from a sterile swab soaked in urine.

Results

We included samples from 100 patients (68% male, median age: 67.4 years) with SAB and 20 patients (75% male, median age: 65.84 years) with non-SAB. The sensitivity of detecting SAB from urine samples was 47% (specificity: 90%) for NAAT, when applying a Ct-value of ≤ 37.4 for positive results. Urine culture had a sensitivity of 25% and a specificity of 95%. Molecular and cultural methods showed a moderate agreement (80%, Cohens kappa: 0.55).

Conclusion

NAAT from urine has a higher sensitivity than culture for predicting SAB. Future studies should investigate whether this could translate to a clinical benefit through rapid detection.

Staphylococcus aureus

bacteremia

bacteriuria

nucleic acid amplification test

rapid assay

urine

Staphylococcus aureus bacteremia (SAB) is common with an annual incidence of 17–38/100,000 residents (1–4). Despite antibiotic therapy, SAB has a high 90-day mortality (28–34%) (5–7).

For the empirical therapy of an infection with unknown focus and/or without pathogen identification, cephalosporins or vancomycin are frequently chosen. Compared to the staphylococcal-specific beta-lactams (e.g. flucloxacillin, cefazolin), the empirical therapy with cephalosporins (e.g. cefuroxime, ceftriaxone/cefotaxime) or beta-lactam-beta-lactamase combinations is associated with a higher 30-day mortality of SAB (8). Several studies have described lower survival rates of SAB-patients with a methicillin-susceptible isolate under vancomycin therapy (9–11). In addition, secondary foci may occur in 16–34% of patients as a complication of SAB (7, 12). In patients with at least one risk factor for metastatic foci, treatment delay was strongly associated with the presence of metastatic foci, but not associated with mortality (13). Since early, specific therapy is critical for a favourable outcome of SAB, there is a clinical need for a rapid diagnosis of SAB.

True S. aureus urinary tract infections in our setting are uncommon (1.4–1.9 of all cases) (14). Worldwide, many SAB patients (7.8%-39%) have concomitant S. aureus bacteriuria (SABU) (15–25). The urinary tract as the primary source of SAB is infrequent (3.2%, n = 132/4181 SAB patients) (26) and is seen almost exclusively in the context of inserted foreign bodies (e.g. indwelling catheters) or urologic interventions (15, 26). SABU secondary to SAB is usually asymptomatic (e.g. absence of dysuria, flank or suprapubic pain, gross haematuria). The pathomechanisms of secondary SABU in patients with SAB are not fully understood and might include tissue destruction, micro-abscesses, transcytosis, paracytosis, or intracellular translocation in leukocytes and macrophages (25).

Urine is a readily available specimen, and we hypothesize that detecting secondary SABU with NAAT may enable a more rapid detection than urine culture.

In this study, we compared the test performance of a rapid NAAT with conventional urine culture to detect S. aureus in urine and to predict SAB.

Ethical consideration
Ethical approval was obtained from the institutional review board (IRB) of the University of Münster (Ethik-Kommission Westfalen-Lippe, 2020-615-f-S). The IRB granted a waiver to obtain a signed written informed consent from patients.

Patients

This cross-sectional study was carried out at a tertiary care hospital in Germany (~ 1,300 beds) between February 2020 and May 2023. Patients were included consecutively if they had a culture-confirmed bacteremia and a urine culture ± 3 days to the collection of the positive blood culture. Patients with a likely contamination of the blood culture (e.g. coagulase negative staphylococci in one out of four blood culture bottles without signs of infection) were excluded. For each patient, age, sex and primary focus of infection were recorded.

Microbiological culture

Mid-stream, clean catch or catheter urine of patients with bacteremia was collected in a sterile tube (Urin-Monovette®, Sarstedt, Nümbrecht, Germany). Urine samples (10 µl per plate) were cultured on Columbia Blood agar with 5% Sheep Blood (BD, Heidelberg, Germany; ambient air), MacConkey agar (BD, ambient air) and a selective agar for Gram-positive bacteria (Columbia CNA Agar with 5% Sheep Blood, BD, 5% CO₂) for a maximum of 48 h at 35 ± 2°C. We defined SABU as detection of S. aureus in urine independent of the concentration (in CFU/ml) (27).

Pairs of aerobic and anaerobic blood culture bottles (BD) were incubated in a Bactec® FX device (BD) for five days (14 days in case of suspected endocarditis) and were subcultured on Columbia Blood agar (BD) and/or chocolate agar (BD, 5% CO₂) when the blood culture bottles were flagged positive (28). Species identification was done with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS, Biotyper® Sirius one, Bruker, Bremen, Germany) applying the Biotyper software IVD/Compass (version 4.2).

A screening test was used to detect substances that could inhibit the growth of bacteria in urine (e.g. antibiotics, cytostatic drugs). For that purpose, a blank cellulose disc (ThermoFisher scientific, Wesel, Germany) soaked with 10 µl urine was placed on a Mueller-Hinton II agar (BD, 35 ± 2°C, ambient air) inoculated with a highly susceptible bacterium (ATCC 6031 Bacillus subtilis). If an inhibition zone around the disc was seen after 24 hours (ambient air), the test was interpreted as positive. This screening was recommended in German guidelines until 2020 to aid the interpretation of negative urine cultures in patients with a high suspicion of urinary tract infection.

Nucleic acid amplification test for S. aureus

Urine samples were stored at -20°C until nucleic acid amplification test (NAAT) was done to guarantee equal bacterial cell counts for culture and NAAT. For NAAT, we used the Xpert® SA Nasal Complete G3 test cartridge (Cepheid, Krefeld, Germany) which was developed and validated for Methicillin-resistant S. aureus (MRSA)-Screening using nasal swabs and provides results within one hour. For the current study, we soaked a sterile swab (eSwab, Copan, Brescia, Italy) with urine, washed it in the buffer solution of the test cartridge and removed it afterwards. Then, we performed the test as recommended for nasal swabs. This procedure was chosen to use the test as recommended by the manufacturer with the only variation that urine instead of nasal swabs was sampled.

Analytical sensitivity

The limit of detection (LoD) is defined as the lowest number of colony forming units (CFU) per sample that can be distinguished from negative samples. We calculated the mean volume of urine that can be squeezed out of the swabs into the elution buffer of the cartridge test (= sample per test). Starting from a stock concentration of 2.45 x10⁸/ml of ATCC 29213 S. aureus, we prepared a dilution series in urine with negative inhibitory test to obtain a certain CFU per sample Then, the cartridge test was carried out. The final CFU per sample was calculated from the mean value of the CFU after plating the same volume from the dilution sample that was given into the cartridge test on Columbia Blood agar with 5% Sheep Blood (BD; ambient air).

Statistical analysis

A specific sample size calculation was not done in the absence of any data on the performance of the NAAT in urine samples. We considered a samples size of 100 SAB and 20 non-SAB cases as appropriate for our objective. Differences between groups in categorical variables were compared using Fisher´s exact test or Chi-squared test (RStudio version 4.3.1; (29)) with a significance level at p < 0.05.

To define the optimal Ct-threshold for the prediction of SAB, we performed a receiver operating characteristic (ROC) analysis using the Ct-value as the predictor and SAB as the outcome. For samples with undetermined Ct-values (i.e. no detection after 40 cycles), we imputed a Ct-value and set a maximum value of 40. The ROC curves and optimal cut-off values (Youden-Index) were computed with the R package “cutpointr” (30).

The test performance of NAAT and cultural detection to predict SAB was calculated (sensitivity, specificity, positive predictive value [PPV], negative predictive value, [NPV]) using the optimal Ct-cut-off value as determined by the ROC analysis. The concordance of molecular and cultural test was calculated using Cohen’s kappa coefficient.

We included 100 patients (68% male, median age: 67.4 years [range 0.6–93.2]) with SAB and 20 patients (75% male, median age: 65.8 years [range 30.3–83.3]) with positive blood cultures other than S. aureus (non-SAB). The most common infective focus in patients with SAB was the central venous catheter (20%, 20/100), skin and soft tissue infections (16%, 16/100), pneumonia (10%, 10/100), endocarditis (6%, 6/100) or unknown (24%, 24/100).

We calculated an optimal cut-off Ct-value of 37.4 (Youden-index = 0.37) for our sample set when maximizing the sum of sensitivity and specificity. The area under the curve (AUC) of the respective ROC curve was 0.69 (Fig. 1).

In 25% (25/100) of SAB patients, we detected S. aureus by urine culture and in 47% (47/100) of patients (p = 0.002) by NAAT applying a Ct-value of ≤ 37.4 (Table 1).

Table 1

Results of *Staphylococcus aureus* detection in urine culture and NAAT from urine, in SAB and non-SAB
		Bacteremia
S. aureus detection in urine		SAB	Non-SAB	Total
culture	Positive	25 (25%)	1 (5%)	26
	Negative	75 (75%)	19 (95%)	94
	Total	100	20	120
NAAT^a	Positive	47 (47%)	2 (10%)	49
	Negative	53 (53%)	18 (90%)	71
	Total	100	20	120
^aCt values ≤ 37.4 were interpreted as positive.

The detection of SAB by urine culture had a sensitivity of 25% and a specificity of 95% (Table 2). The detection of SAB by NAAT had a sensitivity of 47% and a specificity of 90% (Table 2). The PPV was 95.9% and NPV 25.4%.

Table 2

Concordance between NAAT and culture for the detection of *Staphylococcus aureus* in urine
		NAAT^a
		Positive	Negative	Total
Urine culture	Positive	25	1	26
	Negative	23	71	94
	Total	48	72	120
^aCt values ≤ 37.4 were interpreted as positive.

Molecular and cultural methods for the detection of S. aureus in urine showed a moderate agreement (80%, Cohens kappa: 0.55, Table 3).

Of 32 samples that were tested culture negative, but NAAT-positive (Ct-value ≤ 37.4), 19 (59%) had a positive urine inhibitory test.

Median Ct-values for the detection of S. aureus in urine were higher in culture negative than in culture positive urine samples (34.6 vs 23.9, Fig. 2). One patient with MRSA-bacteremia and MRSA-positive screening of the nose, throat and axilla had no detection of S. aureus in urine by NAAT. One patient with the detection of penicillin-susceptible S. aureus in blood and urine had a positive NAAT result for MRSA.

In the non-SAB group, 11 different species were detected. Bacteremia in non-SAB cases was mostly caused by Escherichia coli (n = 9) followed by Staphylococcus epidermidis (n = 2) and others (n = 9). Four non-SAB patients had a S. aureus detected in urine by NAAT and one of them was also culture positive for S. aureus. Three of them had nasal colonisation with S. aureus, the fourth patient had no nasal screening performed. The rate of NAAT detection of S. aureus in urine was lower in the non-SAB compared to the SAB group (5% [2/20] vs. 47% [47/100], p = 0.002).

Under the conditions of the study, the robustness /reproducibility of the test was 100% for positive and negative samples (Table S1). The LoD of the NAAT to detect SA in urine was 23 CFU/sample (Table S2). This corresponds to 354 CFU/ml of urine.

We compared the test performance of culture and a NAAT for the detection of S. aureus in urine to predict cases of SAB. Main findings were a moderate sensitivity (47%) and high specificity (90%) of the urine NAAT to identify patients with SAB.

The test cartridges were used to analyse the urine samples with a rapid and easy-to-handle method. For the rapid diagnosis of invasive Legionella pneumophila and pneumococcal infections, antigen-based immunochromatographic tests from urine are integrated into routine diagnostics since many years. These tests have a good sensitivity (95–97%) and specificity (95–99%) according to the manufacturer to diagnose invasive infections (e.g. pneumonia). In contrast, the test performance of NAAT from urine to detect SAB has a much lower sensitivity in our study. When performing the NAAT, we followed the proposed method for MRSA screening from nasal swabs. We calculated a mean volume of 65µl [49.7–83.4µl] that can be squeezed out of the swabs and was therefore transferred into the elution buffer of the cartridge test. We speculate that by using a higher volume of urine, e.g. by direct inoculation of urine (e.g. 100 µl) in the test cartridge, a higher sensitivity could be achieved. The target gene in Xpert® SA Nasal Complete Assay for the detection of S. aureus is spa, which can vary in size between different S. aureus spa types and is located as a single copy in the genome. Other (multi-copy) genes or antigens with high expression levels might therefore be alternative targets to detect S. aureus in urine of patients with SAB. Such a urine antigen test could be used as a Point-of-Care-Testing (POCT) that would lead to a straightforward diagnostic work up for patients with SAB (e.g. transesophageal echocardiography) and the additional therapy with staphylococcal-specific antibiotics.

We saw that culture negative, but NAAT-positive urine samples had a positive inhibitory test in more than one-half of the cases. We conclude that antibacterial substances in urine samples (i.e. antibiotics) are frequent and might inhibit cultural growth of S. aureus.

We had one false-positive MRSA detection in NAAT, which was not confirmed by culture of blood and/or urine. The manufacturer of the NAAT reports a specificity of 97.9% for the detection of MRSA. This minor error would lead to a less effective initial therapy (e.g. vancomycin) for susceptible isolates.

According to the manufacturer the LoD for S. aureus was 93.7 (95% CI 75.5 -137.8 CFU) CFU/sample. The analytical LoD for S. aureus is conservatively given as 138 CFU/sample. We estimated a lower LoD (23 CFU/sample) for the assay from urine as described for nasal swabs. One reason for this difference is most likely the difference in calculating the LoD. We did not choose the calculated CFU/sample of the dilution series as the reference value for the PCR, but the CFU/sample actually grown on culture. In addition, we have evaluated Ct-values below 37.4 as positive in contrast to the manufacturer's specifications (Ct-threshold 35.0).

Our study has limitations. First, urine samples positive for S. aureus by NAAT in patients with and without SAB might be due to perineal colonisation or contamination of the urine vial during the collection of the specimen. Second, since the study design is cross sectional, we cannot state if SAB was secondary to a urinary tract infection or vice versa. We rate the risk as low, as true S. aureus urinary tract infections in our setting are uncommon (1.4–1.9 of all cases) (14). In addition, the urinary tract as the primary source of SAB is infrequent (3.2%, n = 132/4181 SAB patients) (26). Third, the Xpert® SA Nasal Complete detects S. aureus by the amplification of spa. False negative results are possible due to deletions in spa (31). Fourth, due to high costs of the test cartridges, the approach of this study might not be suitable for all cases in routine diagnostics.

The NAAT detection of S. aureus in urine can identify patients with SAB with a moderate sensitivity (47%) and a high specificity (90%) and a good positive predictive value. This warrants further evaluation of urine rapid test for the detection of SAB.

CFU/ml	Colony forming units per ml
LoD	limit of detection
MRSA	Methicillin-resistant Staphylococcus aureus
NAAT	Nucleic acid amplification testing
POCT	Point-of-Care-Testing
ROC	receiver operating characteristic
SAB	Staphylococcus aureus bacteremia
SABU	Staphylococcus aureus bacteriuria

Funding

Financial support was received from Deutsche Forschungsgemeinschaft (Project number: 518834831).

Competing interests

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Authors’ contribution statements

All authors contributed to the conception and design of the study. Franziska Schuler screened patients for eligibility and took responsibility of the lab work. Franziska Schuler and Frieder Schaumburg performed the statistical analysis. All authors interpreted the findings. Franziska Schuler wrote the first draft of the manuscript and all authors reviewed subsequent versions and approved the final version. All authors had full access to all data of the study.

Data Availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at University Hospital Münster.

Ethics approval/Consent

Ethical approval was obtained from the institutional review board (IRB) of the University of Münster (Ethik-Kommission Westfalen-Lippe, 2020-615-f-S). The IRB granted a waiver to obtain signed a written informed consent from patients.

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No competing interests reported.

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You are reading this latest preprint version

Prediction of Staphylococcus aureus bacteremia by molecular detection of S. aureus in urine: a proof of concept study

Status:

Journal Publication

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Ethical consideration
Ethical approval was obtained from the institutional review board (IRB) of the University of Münster (Ethik-Kommission Westfalen-Lippe, 2020-615-f-S). The IRB granted a waiver to obtain a signed written informed consent from patients.

Patients

Microbiological culture

Statistical analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1

Prediction of Staphylococcus aureus bacteremia by molecular detection of S. aureus in urine: a proof of concept study

Status:

Journal Publication

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Ethical consideration Ethical approval was obtained from the institutional review board (IRB) of the University of Münster (Ethik-Kommission Westfalen-Lippe, 2020-615-f-S). The IRB granted a waiver to obtain a signed written informed consent from patients.

Patients

Microbiological culture

Statistical analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1

Ethical consideration
Ethical approval was obtained from the institutional review board (IRB) of the University of Münster (Ethik-Kommission Westfalen-Lippe, 2020-615-f-S). The IRB granted a waiver to obtain a signed written informed consent from patients.