Genomic interrogation of the burden and transmission of multidrug-resistant pathogens within and across hospital networks

Sherry, Norelle L; Lee, Robyn; Gorrie, Claire L.; Kwong, Jason C; Stuart, Rhonda L.; Korman, Tony M.; Marshall, Caroline; Higgs, Charlie; Chan, Hiu Tat; Graham, Maryza; Johnson, Paul D R; Leroi, Marcel; Reed, Caroline M.; Richards, Michael J.; Slavin, Monica; Worth, Leon J.; Howden, Benjamin P; Grayson, Lindsay

doi:10.1101/764787

Cited by 6 publications

(15 citation statements)

References 28 publications

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“…To broaden the exploration of low-level oxacillin adaptation, we investigated a collection of 490 previously described mec -negative S. aureus clinical isolates obtained from two cohort studies of S. aureus bacteremia ( 4 , 32 ) and a genomic study of multidrug-resistant microorganisms ( 33 ). The majority of the isolates had a low MIC (median, 0.38 mg/liter; interquartile range [IQR], 0.19 to 0.38 mg/liter); however, 40 of them (∼8%) had reduced oxacillin susceptibility (MIC of ≥1 mg/liter) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We selected 490 mec -negative isolates from a combined collection of S. aureus bacteremia isolates ( 4 , 32 ), supplemented with high-oxacillin-MIC isolates (MIC of ≥1 mg/liter) from a prospective genomic study of multidrug-resistant microorganisms ( 33 ). Whole-genome sequencing, quality control, resistome, and multilocus sequence type analysis were performed as described above.…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in Staphylococcus aureus

Giulieri

Guérillot

Kwong

et al. 2020

mBio

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Antistaphylococcal penicillins such as oxacillin are the key antibiotics in the treatment of invasive methicillin-susceptible Staphylococcus aureus (MSSA) infections; however, mec gene-independent resistance adaptation can cause treatment failure. Despite its clinical relevance, the basis of this phenomenon remains poorly understood. Here, we investigated the genomic adaptation to oxacillin at an unprecedented scale using a large collection of 503 clinical mec-negative isolates and 30 in vitro-adapted isolates from independent oxacillin exposures. By combining comparative genomics, evolutionary convergence, and genome-wide association analysis, we found 21 genetic loci associated with low-level oxacillin resistance, underscoring the polygenic nature of this phenotype. Evidence of adaptation was particularly strong for the c-di-AMP signal transduction pathways (gdpP and dacA) and in the clpXP chaperone-protease complex. The role of mutations in gdpP in conferring low-level oxacillin resistance was confirmed by allele-swapping experiments. We found that resistance to oxacillin emerges at high frequency in vitro (median, 2.9 × 10−6; interquartile range [IQR], 1.9 × 10−6 to 3.9 × 10−6), which is consistent with a recurrent minimum inhibitory concentration (MIC) increase across the global phylogeny of clinical isolates. Nevertheless, adaptation in clinical isolates appears sporadically, with no stably adapted lineages, suggesting a high fitness cost of resistance, confirmed by growth assessment of mutants in rich media. Our data provide a broader understanding of the emergence and dynamics of oxacillin resistance adaptation in S. aureus and a framework for future surveillance of this clinically important phenomenon. IMPORTANCE The majority of Staphylococcus aureus strains causing human disease are methicillin-susceptible (MSSA) and can be treated with antistaphylococcal penicillins (such as oxacillin). While acquisition of the mec gene represents the main resistance mechanism to oxacillin, S. aureus can acquire low-level resistance through adaptive mutations in other genes. In this study, we used genomic approaches to understand the basis of S. aureus adaption to oxacillin and its dynamic at the population level. By combining a genome analysis of clinical isolates from persistent MSSA infections, in vitro selection of oxacillin resistance, and genome-wide association analysis on a large collection of isolates, we identified 21 genes linked to secondary oxacillin resistance. Adaptive mutations in these genes were easy to select when S. aureus was exposed to oxacillin, but they also came at a substantial cost in terms of bacterial fitness, suggesting that this phenotype emerges preferentially in the setting of sustained antibiotic exposure.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in Staphylococcus aureus

Giulieri

Guérillot

Kwong

et al. 2020

mBio

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“…We defined probable strain transmission events on the basis of chromosomal SNVs (see Methods, Figure 3b-c ). Using a threshold of ≤20 SNVs for transmission of 3GCR-GN (based on recent studies [10,13,14,28]) we identified six putative 3GCR-GN transmission clusters each involving 2-3 patients (maximum 8 SNVs, Table 2 ). With a single exception, all patients within clusters were epidemiologically linked (overlapping ICU stays or ≤14 days between stays).…”

Section: Resultsmentioning

confidence: 99%

“…Interpretation of VRE pairwise SNVs is more complex because several healthcare-associated lineages are known to be circulating in Melbourne and the regional hospital network. Consequently, it is not uncommon to find near-identical isolates in patients from different wards, hospitals or cities without epidemiological links [7,8,13]. We therefore used a more conservative threshold of ≤3 SNVs to define putative recent VRE transmissions (based on empirical distribution, see Figure S3 ), which identified four clusters of 2-7 patients each ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Asymptomatic gut colonisation is considered a key risk factor for enterococcal, Enterobacteriaceae and other GN infections [9–12]. A number of hospitals have implemented rectal screening programs to identify patients colonised with VRE and/or carbapenemase-producing Enterobacteriaceae in high-risk wards such as intensive care units (ICUs), oncology and hematology wards [7,8,13,14]. However, few facilities conduct routine screening for ESBL- Enterobacteriaceae or other high-risk carbapenem-susceptible GNs in part due to a lack of evidence to inform the interpretation of these results and to appropriately target infection control measures.…”

Section: Introductionmentioning

confidence: 99%

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Genomic surveillance of antimicrobial resistant bacterial colonisation and infection in intensive care patients

Wyres

Hawkey

Mirčeta

et al. 2020

Preprint

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Background Third-generation cephalosporin-resistant Gram-negatives (3GCR-GN) and vancomycin-resistant Enterococci (VRE) are common causes of multi-drug resistant healthcare-associated infections, for which gut colonisation is considered a prerequisite. However, there remains a key knowledge gap about colonisation and infection dynamics in high-risk settings such as the intensive care unit (ICU), thus hampering infection prevention efforts. Methods We performed a three-month prospective genomic survey of infection and gut-colonisation with 3GCR-GN and VRE among patients admitted to an Australian ICU. Results Among 287 patients screened on admission, 17.4% and 8.4% were colonised by 3GCR-GN and VRE, respectively. Escherichia coli was the most common species (n=36 episodes, 58.1%) and the most common cause of 3GCR-GN infection. Only two VRE infections were identified. The rate of infection among patients colonised with E. coli was low, but higher than those who were not colonised on admission (6% vs 2% E. coli, p=0.3). While few patients were colonised with 3GCR- Klebsiella pneumoniae or Pseudomonas aeruginosa on admission (n=4), all such patients developed infections with the colonising strain. Genomic analyses revealed 10 putative nosocomial transmission clusters: four VRE, six 3GCR-GN, with epidemiologically linked clusters accounting for 21% and 6% of episodes, respectively (OR 4.3, p=0.02). Conclusions 3GCR-E. coli and VRE were the most common gut colonisers. E. coli was the most common cause of 3GCR-GN infection, but other 3GCR-GN species showed greater risk for infection in colonised patients. Larger studies are warranted to elucidate the relative risks of different colonisers and guide the use of screening in ICU infection control.

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Emergence and clonal expansion of a qacA-harbouring sequence type 45 lineage of methicillin-resistant Staphylococcus aureus

Nong,

Steinig,

Pollock

et al. 2024

Commun Biol

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The past decade has seen an increase in the prevalence of sequence type (ST) 45 methicillin-resistant Staphylococcus aureus (MRSA), yet the underlying drivers for its emergence and spread remain unclear. To better understand the worldwide dissemination of ST45 S. aureus, we performed phylogenetic analyses of Australian isolates, supplemented with a global population of ST45 S. aureus genomes. Our analyses revealed a distinct lineage of multidrug-resistant ST45 MRSA harbouring qacA, predominantly found in Australia and Singapore. Bayesian inference predicted that the acquisition of qacA occurred in the late 1990s. qacA was integrated into a structurally variable region of the chromosome containing Tn552 (carrying blaZ) and Tn4001 (carrying aac(6’)-aph(2”)) transposable elements. Using mutagenesis and in vitro assays, we provide phenotypic evidence that qacA confers tolerance to chlorhexidine. These findings collectively suggest both antimicrobial resistance and the carriage of qacA may play a role in the successful establishment of ST45 MRSA.

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Genomic interrogation of the burden and transmission of multidrug-resistant pathogens within and across hospital networks

Cited by 6 publications

References 28 publications

Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in Staphylococcus aureus

Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in Staphylococcus aureus

Genomic surveillance of antimicrobial resistant bacterial colonisation and infection in intensive care patients

Emergence and clonal expansion of a qacA-harbouring sequence type 45 lineage of methicillin-resistant Staphylococcus aureus

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