The Xpert MRSA/SA BC system reliably differentiated S. aureus from CoNS. The assay showed a high sensitivity and specificity, was easy to use and is potentially implementable in a South African setting, where Xpert modules are widely available as part of the national programme for diagnosis of tuberculosis.
Methicillin resistance was detected with 100% accuracy; the small MRSA sample size precludes firm conclusions. Methicillin resistance in S. aureus is chiefly mediated by mecA at present, although mecC-mediated resistance has been reported in 0.004% of human isolates (6). The assay also performed well for MSSA BSI, showing 100% concordance with culture-based testing. The error rate of 1.7% is similar to previous reports (3, 7) and is acceptable.
We recommend conventional culture to be performed at least limitedly in parallel, for mixed cultures, as a backup in case of an unsuccessful Xpert result and for further antimicrobial susceptibility testing or surveillance. Genotype-phenotype mismatch, with the Xpert assay incorrectly reporting a susceptible methicillin result due to insertions in the SCCmec-orfX junction region, has been reported in 3 isolates from the United States (8), and misclassification of S. aureus as CoNS in 2 isolates from Australia (9). Studies investigating the prevalence of mutations that may affect the targets of this assay in a South African setting are needed to define the role of this assay more accurately.
Potential impact of implementation
To our knowledge, this is the largest study assessing the potential impact of this assay to date. The median time saving to final result with use of this assay was approximately 30 hours if the Xpert assay was performed immediately after microscopy, in line with previous estimates of a time saving of 24–48 hours (2, 10). This crude estimate can be influenced by factors such as workflow. Antibiotic therapy was optimised on availability of final result in 68.9% with S. aureus BSI. This impact was most clearly demonstrated in patients with MRSA BSI, where more than 50% received anti-MRSA therapy only in response to the final culture result. A more modest impact could be seen for patients with MSSA BSI (approximately 21%); however, it must be noted that this is a conservative estimate as all beta-lactam agents were considered to have activity against MSSA in this analysis, although they may not be equally suitable for the treatment of MSSA BSI and some are associated with a higher odds of death (11).
More rapid administration of appropriate therapy can significantly impact mortality. In one study, the mean mortality rate was 59% for patients with MRSA BSI who were initially started on a semisynthetic penicillin, as opposed to 23–36% for patients initially started on vancomycin (12). The mean mortality rate was as low as 12% in patients empirically placed on a semisynthetic penicillin, who cultured MSSA (12). Future studies should specifically assess the clinical impact of Xpert on more appropriate S. aureus therapy.
We estimated a reduction in broad spectrum beta-lactam antibiotic use in 17.5% of the cohort where antibiotic history was available, with 53 days of antibiotic therapy saved. This translates to a modest reduction in antibiotic days of therapy of 0.3 days per patient. When combined with the benefits shown in optimising therapy for S. aureus BSI infection, this may still be regarded as advantageous, particularly when considered with the consequences of unnecessary antibiotic prescription.
We initially expected this assay to be of most use in reducing antibiotic therapy in patients with CoNS, as has been reported previously (13), but this finding was not replicated. The clinicians in our setting favoured continuing antibiotic therapy if sepsis was the initial diagnostic consideration and CoNS was cultured, in the majority of patients. We attributed this finding at least in part, to the high rate of BC contamination in our setting (14), which may be regarded as having masked the presence of a true pathogen. Decisions regarding antibiotics are also governed by other factors not measured here, such as the clinical response to antibiotic therapy and additional test results.
The potential benefits described must be weighed against the expense of the assay, including additional labour, infrastructure and consumable costs. The total cost of the test may be prohibitive in a resource-constrained setting such as our own.
Limitations to this study include that the S. aureus BSI rate was only 25.1% of all blood cultures with Gram positive cocci in clusters, and that methicillin resistance was detected in 26.3% of all S. aureus-containing blood cultures (similar to a contemporaneous study in our setting (27.1%) (15)); this resulted in modest absolute numbers of MSSA and MRSA BSI. This may confer a more moderate impact of test performance than would be seen in higher prevalence settings. CA-MRSA is also not common in our setting currently (16). Secondly, complete clinical records were not available for all patients, prohibiting case-by-case assessment of whether antibiotic changes occurred as a result of the microbiological results or the evolving clinical picture. Furthermore, clinician recall bias may have influenced these results. Thirdly, other patient comorbidities, such as renal failure, and severity of illness may have contributed to the choice of agents used and the decision to modify antibiotic therapy; this could not be easily assessed. Fourthly, as mentioned previously, most beta-lactam agents were considered to have anti-MSSA activity for the purposes of this study, which may result in an underestimate of the clinical benefit of the assay for MSSA BSI.