Our laboratory processed 2822 positive blood culture bottles between January and June 2016. Of these, 1158 (41.0%, 95% CI 39.2-42.9%) demonstrated only GPCC on Gram stain and 231 samples were included in the study (19.9%, 95% CI 17.7-22.4%) due to convenience sampling. Selected variables were compared between the participants included in the study and all patients for whom blood cultures were submitted showing Gram positive cocci in clusters on Gram stain, between January and June 2016. No differences in age, gender or ward location per organism type at blood culture sampling were noted, with the exception of a larger proportion of coagulase-negative staphylococci from patients admitted to surgical wards (15.9% vs 9.2%, p 0.006) and high care units/ICU (15.9% vs 8.3%, p 0.002) in the study population. Contribution of the bottle types is outlined in Table 2.
A valid Xpert result was initially obtained from 225/231 bottles (97.4%, 95% CI 94.5-98.8%). Of the remaining 6 assays, 2 (2.6%, 95% CI 1.2-5.6%) were invalid (failure of internal control) and were not repeated. Four were resulted as “error” with signal loss after initial amplification; two provided a valid result after repeat testing. The conservative failure rate was 1.7% (95% CI 0.7-4.4%), with 227 bottles yielding an interpretable result.
MSSA was present in 42 samples (18.5%, 95% CI 14.0-24.1%) and MRSA in 15 (6.6%, 95% CI 4.1-10.6%). CoNS were present as the sole isolate in 169 patients, and were part of mixed cultures in an additional 4 cases. Three of these 4 mixed cultures contained MSSA together with CoNS, were detected as MSSA by the Xpert, and were included as MSSA in the analysis. The fourth culture contained Klebsiella pneumoniae (Gram negative bacilli missed on Gram stain) and a CoNS; the Xpert correctly assessed the CoNS.
There was 100% concordance between the systems for the identification of MSSA, MRSA and CoNS. The Xpert assay had an overall sensitivity of 100% (57/57; 95% CI 93.7-100%), and specificity of 100% (170/170, 95% CI 97.8-100%). The positive and negative predictive values of the assay were both 100% (95% CIs 93.7-100% and 97.8-100% respectively). Analysis by MSSA, MRSA and CoNS is summarised in Supplementary Table 1.
We performed a subanalysis of mecA and methicillin resistance in CoNS, for the 169 isolates in which cefoxitin susceptibility on culture was known. The gene target, mecA, was detected in 85 of 88 CoNS isolates that were cefoxitin-resistant on culture (96.6%; 95% CI 90.5%-98.8%) giving a positive predictive value of 86.7% (95% CI 78.6-92.1%). The specificity of detection of mecA in CoNS on Xpert was 84.0% (95% CI 74.5-90.4%) with a negative predictive value of 95.8% (95% CI 88.3-98.6%).
Potential impact of implementation
The median time between blood culture positivity and final result authorisation was 31.3h (interquartile range (IQR) 20.7-42.5h).
Of the 227 patients included, 50.7% (115/227, 95% CI 44.0-57.3%) were males. The median age of the adults included was 43.0 years (IQR 31.0-58.0); the median age of the paediatric population was 71.5 days (IQR 17.8-325.0). Twenty-five adults (25/151, 16.6%, 95% CI 11.2-23.7%) and 10 children (10/76, 13.2%, 95% CI 6.8-23.3%) were admitted to an ICU at the time of blood culture collection. Sepsis was CA in 51.1% (116/227, 95% CI 44.4-57.8%), HA in 38.3% (87/227, 95% CI 32.0-45.0%); and unknown in the remaining 10.6% (24/227, 95% CI 7.0-15.5%). Only 1/11 with MRSA BSI reportedly had CA onset of infection (9.1%, 95% CI 0.5-42.9%).
Adequate history regarding source of sepsis was obtained for 195 patients. Sixty-two patients (31.8%, 95% CI 25.4-38.9%) had an unclear source of sepsis. Respiratory tract infection was the most commonly identified suspected source overall (56/195, 28.7%, 95% CI 22.6-35.7%) and in CA-infection (33/101, 32.7%, 95% CI 23.9-42.8%). For HA-infection, 29 patients (36.3%, 95% CI 26.0-47.8%) had no clear source of sepsis; of those with known primary sources, the major foci were the respiratory tract and skin or skin structures (both 18/80 patients, 22.5%, 95% CI 14.2-33.5%).
Information on the suspected source of sepsis was obtained in 46 patients with S. aureus BSI. The most commonly identified suspected source of sepsis (in isolation or as part of two potential sources) was skin or skin structure infection (n=16, 34.8%), followed by suspected respiratory tract infection (n=11, 23.9%). Source was undetermined at the time of clinician interview in 8 patients with S. aureus BSI (17.4%).
Characteristics of the included patients can be found in Supplementary Table 2.
Impact on antibiotic administration
Adequate antibiotic history was obtained in 181 patients, including 34 with MSSA and 11 with MRSA BSI. Three patients were unclassified due to discordance between culture result, clinical history and antibiotic therapy; these were excluded from the analysis (additional notes in Supplementary Table 3). Empiric antibiotic therapy choices for the remaining 178 patients (including one with significant CoNS BSI resulting from a central line infection) are outlined in Figure 1.
The antibiotic changes over time are summarised in Figure 2 (whole cohort) and Table 3 (subgroup with S. aureus BSI). The impact of the Xpert could be discerned by proxy if culture result availability approximated availability of the Gram stain result (i.e. final result available about an hour after Gram stain availability, in place of the overnight incubation required by reference methods). Analysis by organism category (MRSA, MSSA or CoNS) can be found in Supplementary Table 4.
Most patients with MRSA BSI did not receive an MRSA-active agent until release of the final culture result (Table 3). Cessation of an additional antimicrobial agent occurred in 7 patients on final culture result (63.6%, 95% CI 31.6-87.6%); this could have occurred at least one day sooner with Xpert.
For the 34 patients who had MSSA BSI, notable aspects of the antibiotic regimen include:
- Empiric cover: Empiric vancomycin was prescribed unnecessarily in 3/34 (8.8%, 95% CI 2.3-24.8%); this could have been avoided if Xpert was used.
- In response to Gram stain availability: 2/34 (5.9%, 95% CI 1.0-21.1) received modifications to their antibiotic regimens in response to Gram stain result availability. In one case, vancomycin was started when the Gram stain became available. In the second, a non MSSA-active beta-lactam agent (ampicillin) was changed to an MSSA-active agent (cefotaxime).
- In response to final culture result availability: Overall, there was a change in antibiotic therapy on final result in 25 patients (73.5%, 95% CI 55.4-86.5%). These could have occurred at least one day earlier had the Xpert assay been used.
- De-escalation to a semisynthetic penicillin in 18/25 (72.0%, 95% CI 50.4-87.1%)
- Modification to a more effective agent in the remaining 7/25 (28.0%, 95% CI 12.9-49.6%)
Antibiotics were stopped in 13/133 patients on release of the final result indicating CoNS (9.8%, 95% CI 5.5-16.5%).
Antimicrobial stewardship impact
Overall, 31/45 patients with S. aureus BSI and known antibiotic history could have received more appropriate antistaphylococcal therapy one day sooner, with adoption of the Xpert assay (68.9%, 95% CI 53.2-81.4%). Eleven of the 45 patients (24.4%, 95% CI 13.4-39.9%) were not receiving an agent with activity against their pathogen following Gram stain result availability (6 patients with MRSA and 5 with MSSA BSI).
Days of therapy potentially saved
In the 178 patients with known antibiotic history, at least 32 days of exposure to a broad spectrum beta-lactam (beta-lactam-beta-lactamase inhibitor combination, extended-spectrum cephalosporin or carbapenem) could have been spared with earlier knowledge of the final result, equating to a reduction in broad spectrum beta-lactam use in 18.0% of the patients in this study (32/178, 95% CI 12.8-24.6%).
A further 5 days of vancomycin use could have been avoided, and 17 days of antibiotic therapy could have been spared for the other agents (Supplementary Table 5). This equates to a reduction of 0.3 antibiotic days per patient (95% CI, 0.2-0.4).
In total, at least 54 days of antibiotic therapy could have been spared in the 178 patients with GPCC on blood culture in this study.