Impact of Rapid Identification of Staphylococcus Species in Positive Blood Culture Using GeneXpert Methicillin-Resistant Staphylococcus aureus / Staphylococcus aureus Blood Culture Assay Combined with Antibiotic Stewardship

Abstract

Staphylococcus aureus bacteremia is a life-threatening condition associated with a substantial financial burden on the health care system. The use of the GeneXpert^® methicillin-resistant S. aureus (MRSA)/S. aureus blood culture (BC) test for the identification of S. aureus may influence antibiotic stewardship and clinical outcomes. This study assessed the clinical and financial impact of utilizing GeneXpert MRSA/SA in combination with criterion-based testing. The outcomes between October 1, 2018, and June 30, 2019, were evaluated in 65 adult patients who had positive BCs with Gram-positive cocci in clusters. GeneXpert MRSA/SA significantly shortened the time to optimal antimicrobial therapy by 1.7 days (2.5 vs. 44 hr, p < 0.0001). The cost saved because of interventions based on GeneXpert testing results was $4,121. GeneXpert testing has shortened the time to optimal therapy and positively impacted cost, although it had no significant effect on length of hospital stay and mortality rate.

Introduction

Staphylococcus aureus is one of the most frequently isolated pathogens from blood cultures (BCs) in the inpatient setting.¹ According to the SENTRY Antimicrobial Surveillance Program, more than 81,000 pathogens were characterized between 1997 and 2002 in inpatient settings. Twenty-six percent of the nosocomial bloodstream infections are caused by S. aureus in North America.¹

S. aureus bacteremia (SAB) is associated with complex medical management, resulting in a substantial financial burden on the health care system. SAB is associated with a mortality rate ranging from 0% to 83%, and it is associated with a threefold incremental increase in mean length of hospital stay and hospital cost compared to those of patients without SAB (14.3 vs. 4.5 days, p < 0.001).² In addition, coagulase-negative staphylococci (CoNS)-contaminated BCs cause unnecessary antibiotic exposure and increase the length of hospital stay and costs.³

The choice of empiric therapy depends on the site of suspected or confirmed infection and clinical presentation. Antimicrobial therapy might be escalated or streamlined based on microbiology results (e.g., BCs) and the patient's clinical response to therapy. Identification of Gram-positive cocci in clusters (GPCCL) using Gram stain after initial growth in BC bottles provides incomplete information.⁴ Typically, it takes an additional 24–72 hr to obtain the final results regarding the organism identification and antibiotic sensitivities.⁴ Thus, the time to provide optimal antimicrobial therapy may be directly affected by the long turnaround time required to obtain results using the conventional methods.

This delay in appropriate antimicrobial therapy initiation is an independent risk factor for increased mortality in patients with SAB.⁵ More specifically, unfavorable outcomes are described for patients with methicillin-sensitive Staphylococcus aureus (MSSA) isolates, who have been treated with empiric vancomycin therapy. Vancomycin is inferior to both anti-staphylococcal penicillins and cefazolin in the treatment of MSSA bacteremia.⁶ In addition, unnecessary exposure to vancomycin increases the emergence of drug-resistant microorganisms.⁷ Shortening the turnaround time for pathogen identification may be achieved by utilizing rapid diagnostic tests.

This type of testing facilitates initiation time to optimal antimicrobial therapy, including antibiotic avoidance for CoNS contamination, thereby resulting in improved patient outcomes.⁸ Furthermore, CoNS-contaminated BCs cause unnecessary antibiotic exposure, increase the length of hospital stay by 5.4 days, and increase treatment cost by $7,502–$8,720 per patient.⁹

Universal implementation of rapid diagnostics drives hospital costs without clinical benefit¹⁰; therefore, diagnostic stewardship is essential for the cost-effective implementation of newer microbiology technologies. The GeneXpert^® methicillin-resistant S. aureus (MRSA)/SA BC assay is a real-time polymerase chain reaction (PCR)-based method that identifies S. aureus and methicillin resistance. The GeneXpert MRSA/SA BC assay has a turnaround time of 50 min and a sensitivity and specificity of 100% (95% confidence interval [CI]: 39.6–100) and 96.6% (95% CI: 89.7–99.1), respectively.^11,12

This method identifies S. aureus by detecting the staphylococcal protein A gene (spa) and infers methicillin resistance through concomitant detection of the methicillin resistance genes mecA/mecC and the junction between the staphylococcal cassette chromosome (SCCmec) and the genome (orfX).¹³ These three targets must be amplified and detected for the specimen to be identified as MRSA.¹³ The GeneXpert MRSA/SA BC assay has an advantage over other PCR-based assays, which target only the SCCmec junction, thereby resulting in false positives. The objective of this study was to evaluate the clinical and financial impact associated with implementing the use of GeneXpert MRSA/SA BC assay at our institution for selected patients with positive BCs compared to conventional culture-based technology combined with antimicrobial stewardship.

Methodology

Study design

The Piedmont Columbus Regional Health Care System (PCRH) is a community teaching hospital with a 600-bed capacity. A pre- and post-quasi-experimental, prospective observational cohort study were conducted after completion of GeneXpert validation at PCRH. A retrospective cohort study was conducted from January 1, 2018, to September 30, 2018, for adult patients with SAB to evaluate outcomes of interest, including time to optimal therapy, duration of antimicrobial therapy, and length of hospital stay before implementing GeneXpert (preintervention group). At that time, positive BCs were evaluated following the standard of care (conventional) protocol that included a Gram stain, plate culture, identification, and antimicrobial susceptibility testing using an automated system (Vitek-2). Of note, no positive BC was assessed by the infectious disease pharmacy service (ID pharmacist).

For the postintervention cohort, all adult patients admitted to the institution between October 1, 2018, and June 30, 2019, had positive BC with GPCCL and met the eligibility criteria for GeneXpert testing. Positive BCs were continuously worked up in accordance with the standard of care along with GeneXpert testing, if performed. Microbiology staff contacted the ID pharmacist by telephone for all positive BCs with GPCCL between 07:00 a.m. and 4:00 p.m. The concept of diagnostic stewardship was applied using the newly implemented GeneXpert testing to avoid over/unnecessary testing, especially for patients with probably contaminated BCs. Thus, selected patients would be eligible for testing after meeting the inclusion criteria.

Each case was assessed by an ID pharmacist to determine if the GeneXpert test results would impact the use of antimicrobial therapy. Patients eligible for testing included those ≥18 years of age, with no additional infectious disease that required continuation of empiric vancomycin other than bacteremia and whose antimicrobial therapy was determined to be possibly adjusted, including initiating optimal antimicrobial therapy for MRSA or MSSA bacteremia based on GeneXpert results, changing the vancomycin trough level goal (higher vs. lower trough level goal) if the patient was already receiving vancomycin as empiric therapy, placing contact precaution procedures for patients with MRSA, and recommending ID team consultation according to the GeneXpert result. Each case was investigated by an ID pharmacist to determine if GeneXpert was used as the inclusion criterion.

If the patient met the criteria, the ID pharmacist notified microbiology staff to run the GeneXpert test. Results were available for patient intervention, and the ID pharmacists were responsible for communicating ID service recommendations to the provider.

▪

Optimal antimicrobial therapy for MRSA bacteremia: starting vancomycin immediately after an organism is identified as MRSA.

▪

Optimal antimicrobial therapy for MSSA bacteremia: starting penicillinase-resistant penicillin (nafcillin) or cefazolin immediately after the organism is identified as MSSA.

▪

Time to optimal therapy: from the time of Gram stain (T₀) to the time of administering the first dose of optimal antimicrobial therapy (T_N). Patients who were administered optimal antimicrobial therapy, including targeting a higher trough level goal of vancomycin, or those who expired before receiving antimicrobial therapy were not included in the study.

▪

Cost saving associated with interventions made after GeneXpert implementation: this included all cost savings resulting from interventions made as per GeneXpert testing results, including discontinuing antimicrobial therapy, avoiding unnecessary vancomycin exposure, avoiding calling patients after hospital discharge who had BC drawn during an emergency department (ED) visit (ED call back), and avoiding to withhold hospital discharge or any therapeutic procedure. The cost was calculated as follows:

Cost saving by antimicrobial therapy discontinuation: this was calculated by multiplying the cost of total daily doses of discontinued antimicrobial therapy (based on dose and frequency) by 5 days. A duration of 5 days was used as an observation period during data evaluation from our retrospective cohort that the treating team tended to continue broad-spectrum antimicrobial therapy for 5–7 days for patients with SAB, considering that ID consultation was not mandatory for SAB at our institution.

Cost saving by avoiding ED callback: this was calculated by multiplying the number of patients by the approximated cost of ED call back, $1,284.

Cost per prevention of withholding hospital discharge or therapeutic procedure: this was calculated by multiplying the cost of hospital stay per day (varied based on admission floor/area) by the number of days that were anticipated to be necessary for BC result finalization.

Baseline characteristics were collected from patients' electronic medical records, including demographic data (age, weight, body mass index, and race), medical history-comorbidities (coronary artery disease; myocardial infarction; chronic kidney disease [CKD]; diabetes mellitus [DM]; hypertension [HTN]; heart failure; and chronic obstructive pulmonary disease [COPD]), infection source (respiratory, gastrointestinal, urinary tract, and skin/soft tissues), current antimicrobial therapy received before testing, time to optimize antimicrobial therapy, de-escalation of antimicrobial therapy, cost associated with antimicrobial therapy de-escalation, length of hospital stay, and hospital mortality rate.

The impact of implementing GeneXpert testing was analyzed on the time to optimize antimicrobial therapy as the primary outcome. Secondary outcomes including length of hospital stay, 30-day mortality rate, and relapse were also evaluated. In addition, the cost savings per category was evaluated after GeneXpert implementation.

Categorical variables are expressed as percentages, and they were compared between groups using the Chi-square test, and Fisher's exact test based on the distribution of the data. Continuous variables are presented as the median and range. The Student's t-test and Mann–Whitney U test were used to compare between groups for parametric and nonparametrically distributed data, respectively.

Results

The retrospective cohort review (preintervention) identified 25 patients with SAB (13 with MRSA and 12 with MSSA). A total of 65 patients were identified during the study period (postintervention period), in which 35 underwent GeneXpert testing. Patients were divided into two groups based on the diagnostic stewardship undertaken (GeneXpert with antibiotic stewardship group, n = 35, vs. the culture-based method, n = 30, which were excluded), as shown in Figure 1.

FIG. 1.

Patient recruitment flow chart.

In the GeneXpert group, patients with SAB accounted for 14/35 (40%), of which seven had MSSA bacteremia and seven had MRSA bacteremia. The rest had CoNS isolated from one BC bottle, which was considered a contaminant (n = 15), and six had CoNS isolated from two BC bottles from immunocompromised patients with foreign devices in place, such as a central line, and treated as CoNS bacteremia. For more descriptive details, see Table 1.

Table 1.

Baseline Characteristics for Patients with Staphylococcus aureus Bacteremia

Population parameters	GeneXpert with antibiotics stewardship N = 14	Conventional culture-based method N = 25	p-Value
Age in years, median (min.–max.)	61 (38–85)	67 (26–82)	0.159^a
Weight in kg, median (min.–max.)	73.5 (26–193)	70 (52–158)	0.629^a
Sex (male), n (%)	7 (50)	21 (84)	0.017^b
Race, n (%)
Caucasian	7 (50)	11 (44)	0.718^c
African American	7 (50)	14 (56)	0. 625^c
Baseline comorbidities, n (%)
Congestive heart failure	6 (43)	2 (8)	0.016^b
Hypertension	12 (86)	16 (64)	0.141^b
Diabetes mellitus	9 (64)	13 (52)	0.458^c
Chronic kidney disease	8 (57)	8 (32)	0.126^c
On hemodialysis or peritonial dialysis	6 (43)	4 (16)	0.074^b
Chronic liver disease	3 (21)	1 (4)	0.123^b
Chronic respiratory diseases
COPD/asthma	3 (21)	5 (20)	0.611^b
Immunocompromised host
HIV/active malignancy	1 (7)	0 (0)	0.359^b
Baseline laboratory parameters
WBCs, mean ± SD	12.44 ± 4.33	12.601 ± 4.99	0.923^d
Lactic acid, median (min.–max.)	1.8 (1–7.7)	2 (0.7–12.4)	0.861^a
Infection primary source, n (%)
Respiratory	4 (29)	6 (24)	0.520^b
Urine	0	3 (12)	0.252^b
Catheter related	2 (14)	2 (8)	0.455^b
Skin/soft tissue	2 (14)	2 (8)	0.455^b
GI	1 (7)	2 (8)	0.711^b
CNS	0	1 (4)	0.641^b
Surgical wound	3 (21)	6 (24)	0.592^b
VP-shunt	1 (7)	NA	—
No source identified	2 (14)	5 (20)	0.507^b
Baseline clinical characteristics, n (%)
On mechanical ventilation	1 (14)	3 (12)	0.545^b
Receiving TPN	0	1 (4)	0.641^b
Central line	6 (43)	8 (32)	0.498^c
Foley catheter	2 (14)	3 (12)	0.600^b
ICU admission	3 (21)	4 (16)	0.493^b
Empiric antibiotics received before GeneXpert test, n (%)
Aztreonam	0	2 (8)	0.405^b
Piperacillin/tazobactam	6 (43)	9 (36)	0.673^c
Cefazolin	0	0	—
Ceftriaxone	0	6 (24)	0.054^b
Cefepime	1 (7)	0	0.359^b
Meropenem	1 (7)	1 (4)	0.595^b
Levofloxacin	3 (21)	2 (8)	0.237^b
Azithromycin	0	0	—
Clindamycin	0	0	—
Vancomycin	9 (64)	20 (80)	0.241^b
NA	1 (7)	2 (8)	0.711^b
Antibiotics modification post GeneXpert testing results, n (%)
Initiate/switch to vancomycin administration	3 (21)	2 (8)	0.237^b
Initiate/switch to cefazolin/nafcillin administration	7 (50)	12 (48)	0.905^c
Discontinuing vancomycin administration	5 (36)	12 (48)	0.95^c

Mann–Whitney U test.

Fisher's exact test.

Chi-square test.

Student's t-test.

COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; WBC, white blood cell; SD, standard deviation; GI, gastrointestinal; CNS, central nervous system; VP, ventriculoperitoneal; TPN, total parenteral nutrition; ICU, intensive care unit; NA, not available.

Baseline characteristics of patients with SAB in the GeneXpert group (postintervention)

A total of 14 patients with an average age of 61 years were included in the GeneXpert group; 50% were male and Caucasian. The most frequently encountered comorbidities were HTN, DM, and CKD. Three patients had a central line for dialysis and two were admitted to the intensive care unit. Baseline laboratory parameters were consistent with those of bacterial infection. In the MRSA bacteremia subgroup, three patients received levofloxacin as empiric therapy for COPD exacerbation. However, the rest were on vancomycin with a low goal trough target. In contrast, the MSSA bacteremia group had one patient who had not received an empiric antimicrobial therapy since infection was not suspected. The rest received vancomycin (Table 1).

Baseline characteristics of patients with SAB in the conventional culture-based method group (preintervention)

A total of 25 patients were included in the conventional culture-based method group (preintervention) with an average age of 67 years; majority of patients were male and African American. The most frequently encountered comorbidities were HTN, DM, and CKD. Two patients did not receive any empiric antimicrobial therapy as they had no signs or symptoms of systemic infection at the time of admission (Table 1).

Outcomes for patients with SAB

Outcomes for patients with SAB in the GeneXpert group

The median time to optimal therapy was 2.5 hr. Patients on inappropriate antimicrobial therapy were administered vancomycin or switched to cefazolin depending on the GeneXpert results within hours from the results of the Gram stain. In addition, a higher trough concentration of vancomycin for MRSA bacteremia was simultaneously targeted for all patients. The median length of hospital stay was 13.5 days. Two cases in the MRSA-B group had prolonged hospital stay because of MRSA sternal osteomyelitis and MRSA infective endocarditis. Antimicrobial therapy was de-escalated after identification of MRSA or MSSA on BC using GeneXpert for twelve patients. The relapse and 30-day mortality rates were 14% (Table 2).

Table 2.

Outcomes Associated with Implementation of GeneXpert

Primary outcome
Time to optimal therapy in hours, median (min.–max.)	2.5 (1–5)	44 (0–72)	<0.0001^a
Switch to targeted therapy, n (%)	10 (71)	14 (56)	0.342^b
Targeting higher vancomycin trough goal for MRSA bacteremia, n (%)	7 (50)	13 (52)	0.905^b
Secondary outcomes in days, median (min.–max.)
Duration of inpatient antibiotic therapy	13.5 (2–27)	7 (4–16)	0.076^a
Length of hospital stay	13.5 (2–27)	7 (4–16)	0.076^a
Other outcomes, n (%)
30-Day mortality rate	2 (14)	4 (16)	0.635^c
30-Day relapse rate	2 (14)	2 (8)	0.455^c

Mann–Whitney U test.

Chi-square test.

Fisher's exact test.

MRSA, methicillin-resistant S. aureus.

The GeneXpert testing cost was $910 ($65 per patient). Cost savings associated with the de-escalation of antibiotics was $1,120.1. More details are listed in Table 3. The total cost saving was $210.1.

Table 3.

Detailed Cost Savings Information Associated with Discontinuing Broad-Spectrum Antimicrobial Therapy After GeneXpert Testing Results

Patient group	Discontinued antimicrobial therapy	Cost/day ($)	Duration (days)	Cost saved ($)
MRSA-B	Levofloxacin 750 mg IV q 24 hr	2.7	5	13.5
MRSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MRSA-B	Levofloxacin 750 mg IV q 24 hr	2.7	5	13.5
MRSA-B	Levofloxacin 750 mg IV q 24 hr	2.7	5	13.5
MRSA-B	Meropenem 1 g q 8 hr	18.54	5	92.7
MRSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Vancomycin 1 g q 12 hr	11	5	55
MSSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Vancomycin 1 g q 12 hr	11	5	55
MSSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Vancomycin 1 g q 12 hr	11	5	55
MSSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Vancomycin 1 g q 12 hr	11	5	55
MSSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Pip/taz 3.375 g q 8 hr	20.34	5	101.7
MSSA-B	Vancomycin 1 g q 12 hr	11	5	55
Savings associated with antimicrobial therapy streamlining for patients with SAB				1,120.1

MRSA-B, methicillin-resistant S. aureus bacteremia; MSSA-B, methicillin-susceptible Staphylococcus aureus bacteremia; Pip/taz, piperacillin/tazobactam.

Outcomes for patients with SAB in the conventional culture-based method group

The median time to optimal therapy was 44 hr. Appropriate antimicrobial therapy was started within 1.7 days from the results of the Gram stain. The median length of hospital stay was 7 days. The relapse and 30-day mortality rates were 8% and 16%, respectively (Table 2).

Subgroup analysis

Patients with a CoNS contaminant in the GeneXpert group

All patients in this group had GPCCL isolated from one BC bottle. All had signs and symptoms of infection related to the respiratory system. Therefore, CoNS was deemed to be a contaminant, and the average length of hospital stay was 3 days. The cost associated with GeneXpert testing was $975 ($65 per patient).

Cost savings associated with GeneXpert testing for these patients were estimated to be $4,886, including avoiding vancomycin therapy ($396), avoiding canceling fecal microbiota transplantation and endoscopy ($600), ED call back ($1,284), and avoiding to withhold hospital discharge ($1,303). More details are provided in Table 4. The net cost savings were $3,911.

Table 4.

Detailed Cost Savings Information Associated with Interventions Made After GeneXpert Testing Results

Number of patients	Intervention per category	Cost/day ($)	Duration (days)	Cost saved ($)
Twelve patients	Avoided initiating vancomycin therapy	11	3	396
One patient	ED call back	1,284	NA	1,284
One Patient	Avoid withholding hospital discharge	1,303	2	2,606
One patient	Avoid canceling therapeutic procedure—FMT and endoscopy	600	NA	600
Cost savings associated with interventions made after GeneXpert testing result				4,886

ED, emergency department; FMT, fecal microbiota transplant.

Discussion

GeneXpert has shortened time to optimal antimicrobial therapy by 1.7 days (2.5 hr vs. 44 hr). Furthermore, 100% of MRSA and MSSA bacteremia subgroups had optimal antimicrobial coverage, including first-line antibiotic therapy and/or targeting higher trough levels for MRSA. These results are consistent with those of Bauer et al. for which time to optimal therapy was 2 hr in the MSSA group and 4.5 hr in the MRSA group who had a GeneXpert MRSA/SA BC test.¹⁴ Data from a previous study shows a significant increase in the rate of appropriate antimicrobial therapy in the first 24 hr for patients who underwent the GeneXpert test (54% vs. 80.6%).¹⁵

In this study, hospital stay was longer for the GeneXpert group compared with the conventional method group (13.5 days vs. 7 days, p = 0.076). Data on the impact of PCR-based diagnostic tests (such as Gram-positive 12 multiplex PCR, GeneXpert, and Verigene) on length of hospital stay are inconclusive, and the majority of data on the length of hospital stay range between 2 and 6 days.^8,14,15

The 30-day mortality rate is 2% lower in the GeneXpert group, which is similar to that of the study conducted by Zboromyrska et al.¹² Theoretically, these differences were anticipated since PCR testing ensured starting appropriate antibiotic therapy earlier, thereby decreasing the mortality rate. Not surprisingly, the mortality rate difference was not statistically different and needs to be explored using a well-designed randomized controlled trial.

This study demonstrated the impact of interventions after GeneXpert testing. Interventions, such as de-escalation of antimicrobial therapy, prevention of hospital discharge delay, calling back for hospital admission, and canceling scheduled procedures were found to be associated with a cost savings of $4,121 for different interventions in 25 patients (11 in the SAB group and 15 in the CoNS contaminant group). There was no doubt that antimicrobial therapy de-escalation was associated with many advantages, including reducing risk of collateral damage such as Clostridioides difficile infection and acute kidney injury with vancomycin.

This work is the first to explore and highlight the impact of GeneXpert MRSA/SA BC testing on de-escalation of antimicrobial therapy in patients with positive BCs for Staphylococcus spp., particularly in patients with CoNS. It also provides a road map to implement diagnostic testing, such as GeneXpert, and the method to combine it with effective antibiotic stewardship.

The retrospective nature of this cohort study has limitations because of selection and sampling bias. The very small number of participants had an impact on the ability to identify statistical differences when comparing outcomes between groups. In addition, conducting GeneXpert testing during working hours (07:00 a.m. to 4:00 p.m.) would potentially underestimate the impact of interventions carried out after GeneXpert testing when compared to performing the test over 24 hr.

Cost saving data were calculated per intervention instead of total cost savings, which would be more comprehensive and ideal to present. This was secondary to prolonged length of hospitalization in the GeneXpert group, which was mainly due to two cases (MRSA sternal osteomyelitis and MRSA infective endocarditis). Theoretically, the cost of hospital stay would be higher in the GeneXpert group, thereby reducing the total cost savings compared to the conventional method. Therefore, considering cost savings per intervention would be more reflective of potential cost savings associated with GeneXpert testing.

Conclusion

In this study, GeneXpert testing has shortened time to optimal therapy to 2.5 hr compared to 44 hr in the conventional culture-based method. The length of hospital stay was prolonged in the GeneXpert group owing to the complexity of two cases and small sample size in the GeneXpert group (14 vs. 25). It was demonstrated that the interventions made after GeneXpert testing had potential cost saving benefits. Randomized controlled trials with larger sample sizes are recommended to evaluate the clinical outcomes of GeneXpert testing.

Compliance with Ethical Standards

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the Institutional Review Board of the Piedmont Columbus Regional Health Care System. Open access of this article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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