Unravelling the complex interplay between antibiotic consumption and adaptive changes in methicillin-resistant Staphylococcus aureus.

OBJECTIVES: This study aims to elucidate the genomic dynamics driving the emergence of antimicrobial resistance (AMR), with a specific focus on the interplay between AMR and antimicrobial usage. METHODS: We conducted a comprehensive analysis using a ST239 methicillin-resistant Staphylococcus aureus (MRSA) dataset over a continuous 12-year period from a single hospital. Genomic analyses were performed tracking the changes in MRSA populations, particularly the emergence of reduced vancomycin susceptibility, and assessing the impact of glycopeptide use on these emergence events. RESULTS: Our findings reveal a significant correlation between hospital glycopeptide usage and the selection of MRSA strains with reduced vancomycin susceptibility. Genomic analyses provided insights into the molecular mechanisms driving resistance emergence, including the slowing of the molecular clock rate in response to heightened antimicrobial consumption. CONCLUSIONS: In conclusion, this study the highlights the complex dynamics between AMR and antimicrobial use at the hospital level. The observed correlation between antimicrobial consumption and the development of less susceptible MRSA strains underscores the importance of antimicrobial stewardship programmes and the establishment of optimal consumption thresholds for mitigating AMR effectively.

A multi-site, international laboratory study to assess the performance of penicillin susceptibility testing of Staphylococcus aureus.

OBJECTIVES: There is clinical uncertainty over the optimal treatment for penicillin-susceptible Staphylococcus aureus (PSSA) infections. Furthermore, there is concern that phenotypic penicillin susceptibility testing methods are not reliably able to detect some blaZ-positive S. aureus. METHODS: Nine S. aureus isolates, including six genetically diverse strains harbouring blaZ, were sent in triplicate to 34 participating laboratories from Australia (n = 14), New Zealand (n = 6), Canada (n = 12), Singapore (n = 1) and Israel (n = 1). We used blaZ PCR as the gold standard to assess susceptibility testing performance of CLSI (P10 disc) and EUCAST (P1 disc) methods. Very major errors (VMEs), major error (MEs) and categorical agreement were calculated. RESULTS: Twenty-two laboratories reported 593 results according to CLSI methodology (P10 disc). Nineteen laboratories reported 513 results according to the EUCAST (P1 disc) method. For CLSI laboratories, the categorical agreement and calculated VME and ME rates were 85% (508/593), 21% (84/396) and 1.5% (3/198), respectively. For EUCAST laboratories, the categorical agreement and calculated VME and ME rates were 93% (475/513), 11% (84/396) and 1% (3/198), respectively. Seven laboratories reported results for both methods, with VME rates of 24% for CLSI and 12% for EUCAST. CONCLUSIONS: The EUCAST method with a P1 disc resulted in a lower VME rate compared with the CLSI methods with a P10 disc. These results should be considered in the context that among collections of PSSA isolates, as determined by automated MIC testing, less than 10% harbour blaZ. Furthermore, the clinical relevance of phenotypically susceptible, but blaZ-positive S. aureus, remains unclear.

Validation of an HIV whole genome sequencing method for HIV drug resistance testing in an Australian clinical microbiology laboratory.

Detection of HIV drug resistance (HIVDR) is vital to successful anti-retroviral therapy (ART). HIVDR testing to determine drug-resistance mutations is routinely performed in Australia to guide ART choice in newly diagnosed people living with HIV or in cases of treatment failure. In 2022, our clinical microbiology laboratory sought to validate a next-generation sequencing (NGS)-based HIVDR assay to replace the previous Sanger-sequencing (SS)-based ViroSeq. NGS solutions for HIVDR offer higher throughput, lower costs and higher sensitivity for variant detection. We sought to validate the previously described low-cost probe-based NGS method (veSEQ-HIV) for whole-genome recovery and HIVDR-testing in a diagnostic setting. veSEQ-HIV displayed 100% and 98% accuracy in major and minor mutation detection, respectively, and 100% accuracy of subtyping (provided > 1000 mapped reads were obtained). Pairwise comparison exhibited low inter-and intrarun variability across the whole-genome (Jaccard index [J] = 0.993; J = 0.972) and the Pol gene (J = 0.999; J = 0.999), respectively. veSEQ-HIV met all our pre-set criteria based on WHO recommendations and successfully replaced ViroSeq in our laboratory. Scaling-down veSEQ-HIV to a limited batch size and sequencing on Illumina iSeq. 100, allowed easy implementation of the assay into the workflow of a small sequencing laboratory with minimal staff and equipment and the ability to meet clinically relevant test turn-around times. As HIVDR-testing moves from SS- to NGS-based methods and new ART drugs come to market (particularly those with targets outside the Pol region), whole-genome recovery using veSEQ-HIV provides a robust, cost-effective and "future-proof" NGS method for HIVDR-testing.

Protracted COVID-19 pneumonitis early post-ABO incompatible kidney transplantation: Management considerations and the role of whole genome sequencing.

We present the case of a recent ABO incompatible kidney transplant recipient with persistent SARS-CoV-2 infection and pneumonitis. Serial whole genome sequencing confirmed intra-host viral evolution, which was used as a surrogate to confirm active viral replication and support re-treatment with antivirals, late in the course of infection. A prolonged course of remdesivir combined with immunosuppression modulation resulted in successful clearance of virus and clinical improvement. The diagnostic process undertaken in this case provides a useful guide for other clinicians when approaching similar patients.

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

A vanA vancomycin-resistant Enterococcus faecium ST80 outbreak resulting from a single importation event.

BACKGROUND: A marked genotype shift among vancomycin-resistant Enterococcus faecium (VREfm) from vanB to vanA in Australia between 2011 and 2015 is a well-known phenomenon. It is hypothesized that this was caused by multiple independent clones emerging simultaneously in different settings and/or regions. OBJECTIVES: To gain insights into the circumstances surrounding the shift from vanB to vanA VREfm in one Australian hospital. METHODS: The genomes of 69 vanA VREfm isolates from St George Hospital collected between 2009 and 2018 were studied. An expansion of ST80 vanA VREfm was noted following a single introduction. ST80 isolates were thus further characterized using hybrid sequencing and contextualized through comparisons with other published Australian ST80 isolates. Phylogenies were constructed with plasmid sequences compared with the index isolate. RESULTS: The 2011 expansion of ST80 vanA VREfm isolates in our institution originated from the 2009 index isolate, from a patient transferred from overseas. Phylogenetic analysis with other Australian ST80 vanA VREfm isolates showed that the 2011 expansion event was unique, with limited spread to adjacent local health districts. Plasmid analysis showed multiple variants, which can also be traced back to the 2009 isolate, consistent with ongoing plasmid adaptation over time. CONCLUSIONS: These findings confirm an expansion event following a VREfm introduction event leading to a sustained clonal and plasmid outbreak over several years. Moreover, it demonstrates the complexity of countrywide replacement events. This study also highlights the use of hybrid sequencing in establishing an epidemiological relationship to the index isolate that was initially inapparent.

Bayesian Forecasting for Intravenous Tobramycin Dosing in Adults With Cystic Fibrosis Using One Versus Two Serum Concentrations in a Dosing Interval.

BACKGROUND: Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration-time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice. METHODS: Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively. RESULTS: A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L-1 and rRMSE of <15% for sequential c1 and c2 conditions. CONCLUSIONS: Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2-6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

A multicentre outbreak of ST45 MRSA containing deletions in the spa gene in New South Wales, Australia.

BACKGROUND: Early identification of MRSA by diagnostic medical microbiology laboratories enables improved antimicrobial choice and outcomes. The Cepheid Xpert® MRSA/SA BC test rapidly identifies Staphylococcus aureus bloodstream infections through spa gene detection and methicillin resistance via mecA gene detection. Recent emergence of S. aureus with deletions in the spa gene has resulted in false-negative results for this test, leading to misidentification of infections with this organism, particularly MRSA ST45. OBJECTIVES: To investigate the emergence and prevalence of ST45 MRSA in New South Wales (NSW), Australia. METHODS: WGS read data from six NSW hospitals were collected for 131 ST45 MRSA isolates and analysed. RESULTS: Of the 131 ST45 MRSA investigated, 88.5% (116/131) contained a deletion in the spa gene that appeared to have arisen once in approximately 2010 followed by clonal expansion. Given the successful establishment of this 'spa-deletion' MRSA clone, the Cepheid Xpert® MRSA/SA BC test became unreliable for confirming S. aureus bacteraemia in NSW. Subsequently, the algorithm used by this test has been updated and evaluated to take into account the presence of S. aureus with either a spa deletion or SCCmec target variations. CONCLUSIONS: This study highlighted the applied use of WGS for assessing diagnostic assays and informing necessary changes to ensure the viability of the Cepheid Xpert® MRSA/SA BC test in the context of the new 'spa-deletion' MRSA clone. It demonstrated how continued surveillance through WGS can reveal evolutionary events that may impact diagnostic assays, allowing corrective modifications to be made in real time.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Clinical experience with new formulation SUBA®-itraconazole for prophylaxis in patients undergoing stem cell transplantation or treatment for haematological malignancies.

BACKGROUND: SUper BioAvailability-itraconazole (SUBA®-itraconazole) was introduced into Australia in April 2014 as a substitute for standard itraconazole on the basis of improved bioavailability, tolerance and interpatient variability. Shortly after its introduction, our centre converted to the novel formulation for mould prophylaxis in patients undergoing allogeneic HSCT, autologous HSCT or treatment for haematological malignancies with an intermediate/high risk of invasive fungal infection (IFI). METHODS: A single-institution, investigator-initiated retrospective cohort study was conducted between June 2016 and April 2018 to assess therapeutic drug concentrations, safety and tolerability of a standard prophylactic dose of SUBA®-itraconazole. RESULTS: A total of 74 patients were assessed across 98 admissions with 178 measured itraconazole trough concentrations. The median duration of prophylaxis was 15.5 (1-59) days. No significant correlation was identified between trough concentrations and patient demographics including gender and weight. Drug concentrations were reduced by gastric acid suppression and diarrhoea. Therapeutic itraconazole trough concentrations (≥0.5 mg/L) were achieved at a median of 7 (95% CI = 6-8) days, with 87% of patients achieving therapeutic concentrations at day 14 (expected steady-state). One (1%) proven/probable IFI and 5 (5%) possible breakthrough IFIs were identified. Although adverse events were experienced by 42% of the cohort, only a single event was directly attributable to SUBA®-itraconazole, resulting in change of prophylactic agent. CONCLUSIONS: SUBA®-itraconazole achieved rapid therapeutic trough concentrations, was associated with low rates of IFI and was well tolerated in the study population. This formulation should be considered a realistic and safe first-line agent for the prevention of IFIs in those undergoing HSCT and intermediate/high-risk therapy for haematological malignancies.

Identification of multiple species and subpopulations among Australian clinical Sporothrix isolates using whole genome sequencing.

Whole genome sequencing (WGS) was used to demonstrate the wide genetic variability within Sporothrix schenckii sensu lato and establish that there are two main species of Sporothrix within Australian clinical isolates-S. schenckii sensu stricto and Sporothrix globosa. We also demonstrated southwest Western Australia contained genetically similar S. schenckii ss strains that are distinct from strains isolated in the eastern and northern states of Australia. Some genetic clustering by region was also noted for northern NSW, Queensland, and Northern Territory. Phylogenetic analysis of WGS data provided greater phylogenetic resolution compared to analysis of the calmodulin gene alone.

Cronobacter sakazakii Infection from Expressed Breast Milk, Australia.

Cronobacter sakazakii neonatal infections are often epidemiologically linked to the consumption of contaminated powdered infant formula. We describe a case resulting from consumption of contaminated expressed breast milk, as confirmed by whole-genome sequencing. This case highlights potential risks associated with storage and acquisition of expressed breast milk.

Recommendations To Address the Difficulties Encountered When Determining Linezolid Resistance from Whole-Genome Sequencing Data.

Mutations associated with linezolid resistance within the V domain of 23S rRNA are annotated using an Escherichia coli numbering system. The 23S rRNA gene varies in length, nucleotide sequence, and copy number among bacterial species. Consequently, this numbering system is not intuitive and can lead to confusion when mutation sites are being located using whole-genome sequencing data. Using the mutation G2576T as an example, we demonstrate the difficulties associated with using the E. coli numbering system.

Relentless spread and adaptation of non-typeable vanA vancomycin-resistant Enterococcus faecium: a genome-wide investigation.

Background: VRE are prevalent among patients in ICUs. Non-typeable vanA VRE, due to loss of one of the genes used for MLST (pstS), have increased in Australia, suggestive of a new, hospital-acquired lineage. Objectives: To understand the significance of this lineage and its transmission using WGS of strains isolated from patients in ICUs across New South Wales, Australia. Methods: A total of 240 Enterococcus faecium isolates collected between February and May 2016, and identified by conventional PCR as vanA positive, were sequenced. Isolates originated from 12 ICUs in New South Wales, grouped according to six local health districts, and represented both rectal screening swab (n = 229) and clinical (n = 11) isolates. Results: ST analysis revealed the absence of the pstS gene in 84.2% (202 of 240) of vanA isolates. Two different non-typeable STs were present based on different allelic backbone patterns. Loss of the pstS gene appeared to be the result of multiple recombination events across this region. Evidence for pstS-negative lineage spread across all six local health districts was observed suggestive of inter-hospital transmission. In addition, multiple outbreaks were detected, some of which were protracted and lasted for the duration of the study. Conclusions: These findings confirmed the evolution, emergence and dissemination of non-typeable vanA E. faecium. This study has highlighted the utility of WGS when attempting to describe accurately the hospital-based pathogen epidemiology, which in turn will continue to inform optimal infection control measures necessary to halt the spread of this important nosocomial organism.

Morbidity from in-hospital complications is greater than treatment failure in patients with Staphylococcus aureus bacteraemia.

BACKGROUND: Various studies have identified numerous factors associated with poor clinical outcomes in patients with Staphylococcus aureus bacteraemia (SAB). A new study was created to provide deeper insight into in-hospital complications and risk factors for treatment failure. METHODS: Adult patients hospitalised with Staphylococcus aureus bacteraemia (SAB) were recruited prospectively into a multi-centre cohort. The primary outcome was treatment failure at 30 days (composite of all-cause mortality, persistent bacteraemia, or recurrent bacteraemia), and secondary measures included in-hospital complications and mortality at 6- and 12-months. Data were available for 222 patients recruited from February 2011 to December 2012. RESULTS: Treatment failure at 30-days was recorded in 14.4% of patients (30-day mortality 9.5%). Multivariable analysis predictors of treatment failure included age > 70 years, Pitt bacteraemia score ≥ 2, CRP at onset of SAB > 250 mg/L, and persistent fevers after SAB onset; serum albumin at onset of SAB, receipt of appropriate empiric treatment, recent healthcare attendance, and performing echocardiography were protective. 6-month and 12-month mortality were 19.1% and 24.2% respectively. 45% experienced at least one in-hospital complication, including nephrotoxicity in 19.5%. CONCLUSIONS: This study demonstrates significant improvements in 30-day outcomes in SAB in Australia. However, we have identified important areas to improve outcomes from SAB, particularly reducing renal dysfunction and in-hospital treatment-related complications.

Invasive Fungal Sinusitis Presenting as Acute Posterior Ischemic Optic Neuropathy.

Invasive fungal sinusitis causes painful orbital apex syndrome with ophthalmoplegia and visual loss; the mechanism is unclear. We report an immunocompromised patient with invasive fungal sinusitis in whom the visual loss was due to posterior ischaemic optic neuropathy, shown on diffusion-weighted MRI, presumably from fungal invasion of small meningeal-based arteries at the orbital apex. After intensive antifungal drugs, orbital exenteration and immune reconstitution, the patient survived, but we were uncertain if the exenteration helped. We suggest that evidence of acute posterior ischaemic optic neuropathy should be a contra-indication to the need for orbital exenteration in invasive fungal sinusitis.

Polyclonal emergence of vanA vancomycin-resistant Enterococcus faecium in Australia.

Objectives: To investigate the genetic context associated with the emergence of vanA VRE in Australia. Methods: The whole genomes of 18 randomly selected vanA -positive Enterococcus faecium patient isolates, collected between 2011 and 2013 from hospitals in four Australian capitals, were sequenced and analysed. Results: In silico typing and transposon/plasmid assembly revealed that the sequenced isolates represented (in most cases) different hospital-adapted STs and were associated with a variety of different Tn 1546 variants and plasmid backbone structures. Conclusions: The recent emergence of vanA VRE in Australia was polyclonal and not associated with the dissemination of a single 'dominant' ST or vanA -encoding plasmid. Interestingly, the factors contributing to this epidemiological change are not known and future studies may need to consider investigation of potential community sources.

Combination of Vancomycin and ß-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial.

BACKGROUND: In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal ß-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking. METHODS: In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days. RESULTS: We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity. CONCLUSIONS: Combining an antistaphylococcal ß-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).

When sepsis persists: a review of MRSA bacteraemia salvage therapy.

MRSA bacteraemia (MRSAB), including infective endocarditis, carries a high mortality rate, with up to 50% of patients failing initial therapy with vancomycin and requiring salvage therapy. Persistent MRSAB can be difficult to successfully eliminate, especially when source control is not possible due to an irremovable focus or the bacteraemia still persists despite surgical intervention. Although vancomycin and daptomycin are the only two antibiotics approved by the US FDA for the treatment of patients with MRSAB as monotherapy, the employment of novel strategies is required to effectively treat patients with persistent MRSAB and these may frequently involve combination drug therapy. Treatment strategies that are reviewed in this manuscript include vancomycin combined with a ß-lactam, daptomycin-based therapy, ceftaroline-based therapy, linezolid-based therapy, quinupristin/dalfopristin, telavancin, trimethoprim/sulfamethoxazole-based therapy and fosfomycin-based therapy. We recommend that combination antibiotic therapy be considered for use in MRSAB salvage treatment.