Clinical population pharmacokinetics and toxicodynamics of linezolid

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxico-dynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs o

Cost-effectiveness of a post-splenectomy registry for prevention of sepsis in the asplenic

Background: Overwhelming, sometimes fatal infections represent a lifelong risk after surgical removal of the spleen, or in patients who develop hyposplenism as a consequence of illnesses. This risk may be reduced by all or a combination of vaccination, antibiotic prophylaxis and education. We aimed to determine if a registry approach to delivering these interventions would be cost effective using our own experience and published data.Method: The decision model compared a cohort of 1,000 people covered by a registry to a cohort of 1,000 people with no registry. The impact of the registry was assessed in terms of achieved rates of vaccination, chemoprophylaxis and education, consequent outcomes of overwhelming post-splenectomy infection (OPSI) and mortality (years of life lived). The cost-effectiveness of the registry compared with no registry was estimated in terms of additional cost per case of OPSI avoided and as additional cost per life year gained.Results: In the first two years, the additional cost of the registry was $152,611 per case of OPSI avoided or$205,931 per life year gained. After this initial registration period the costeffectiveness improves over time, such that over the cohort lifetime a post-splenectomy register is associated with an additional cost of $105,159 per case of OPSI avoided or$16,113 per life year gained.Conclusion: A registry-based approach is likely to prove cost effective in terms of mortality and rates of OPSI avoided.<br /

Mortality and length of stay associated with antimicrobial-susceptible and -resistant hospital-onset bloodstream infections at a tertiary referral hospital in Melbourne, Australia

Background and objectives: There are few Australian data regarding the burden of hospital-onset bloodstream infections (HO-BSIs). To quantify the impact of antimicrobial-susceptible and -resistant HO-BSIs on patient outcomes by augmenting laboratory-based surveillance data. Methods: We performed a retrospective cohort study at a tertiary referral hospital in Melbourne, Australia, from 2015 to 2020. We linked administrative data with bloodstream infection surveillance data from the Australian Group on Antimicrobial Resistance. We performed cause-specific Cox proportional hazards regression to quantify the impact of HO-BSI on inpatient mortality and discharge alive, with separate models for Enterobacterales, Staphylococcus aureus, Enterococcus species and the non-fermenting Gram-negative bacilli (NFGNB), Pseudomonas aeruginosa and Acinetobacter species, compared to admissions without HO-BSI. Excess length of stay (LOS) was estimated using multistate models. Results: The cohort of 278 984 admissions included 814 (0.3%) HO-BSIs. Enterobacterales were the most frequent pathogens, followed by enterococci, S. aureus and NFGNB (incidence 3.62, 2.34, 1.11 and 0.80 events per 10 000 patient-days, respectively). Both antimicrobial-resistant and -susceptible HO-BSI increased risk of death and LOS compared with admissions without HO-BSI. Antimicrobial-resistant and -susceptible HO-BSIs, respectively, increased LOS by 5.7 days (95% CI: 4.9–6.5) and 4.1 days (95% CI: 3.8–4.5) for Enterobacterales, 4.9 days (95% CI: 4.5–5.4) and 3.1 days (95% CI: 2.6–3.6) for enterococci, and 6.3 days (95% CI: 5.3–7.3) and 9.8 days (95% CI: 9.1–10.5) for S. aureus. Conclusions: Antimicrobial-susceptible and -resistant HO-BSIs have a substantial impact on patient outcomes. We demonstrated the feasibility of leveraging a national laboratory-based surveillance system to quantify the impact of HO-BSI

Evolution of carbapenem resistance in Acinetobacter baumannii during a prolonged infection.

Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenem resistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing. All isolates were multidrug resistant, carrying two genomic islands that harboured several antibiotic-resistance genes. Most isolates were genetically identical and represented a single founder genotype. We identified three novel non-synonymous substitutions associated with meropenem resistance: F136L and G288S in AdeB (part of the AdeABC efflux pump) associated with an increase in meropenem MIC to ≥8 µg ml-1; and A515V in FtsI (PBP3, a penicillin-binding protein) associated with a further increase in MIC to 32 µg ml-1. Structural modelling of AdeB and FtsI showed that these mutations affected their drug-binding sites and revealed mechanisms for meropenem resistance. Notably, one of the adeB mutations arose prior to meropenem therapy but following ciprofloxacin therapy, suggesting exposure to one drug whose resistance is mediated by the efflux pump can induce collateral resistance to other drugs to which the bacterium has not yet been exposed

Search and contain : impact of an integrated genomic and epidemiological surveillance and response program for control of carbapenemase-producing Enterobacterales

Funding: This work was supported by the National Health and Medical Research Council through a partnership grant (grant number GNT1149991) and individual supporting grants (grant numbers GNT1142613 [to J. C. K.], GNT1123854 [to D. A. W.], GNT1105905 [to B. P. H.], GNT1141398 to [A. J. S]); N. L. S. and C. R. L. are supported by Australian Government Research Training Program scholarships and the Microbiological Diagnostic Unit Public Health Laboratory is funded by the Victorian Government.Background Multiresistant organisms (MROs) pose a critical threat to public health. Population-based programs for control of MROs such as carbapenemase-producing Enterobacterales (CPE) have emerged and evaluation is needed. We assessed the feasibility and impact of a statewide CPE surveillance and response program deployed across Victoria, Australia (population 6.5 million). Methods A prospective multimodal intervention including active screening, carrier isolation, centralized case investigation, and comparative pathogen genomics was implemented. We analyzed trends in CPE incidence and clinical presentation, risk factors, and local transmission over the program’s first 3 years (2016–2018). Results CPE case ascertainment increased over the study period to 1.42 cases/100 000 population, linked to increased screening without a concomitant rise in active clinical infections (0.45–0.60 infections/100 000 population, P = .640). KPC-2 infection decreased from 0.29 infections/100 000 population prior to intervention to 0.03 infections/100 000 population in 2018 (P = .003). Comprehensive case investigation identified instances of overseas community acquisition. Median time between isolate referral and genomic and epidemiological assessment for local transmission was 11 days (IQR, 9–14). Prospective surveillance identified numerous small transmission networks (median, 2; range, 1–19 cases), predominantly IMP and KPC, with median pairwise distance of 8 (IQR, 4–13) single nucleotide polymorphisms; low diversity between clusters of the same sequence type suggested genomic cluster definitions alone are insufficient for targeted response. Conclusions We demonstrate the value of centralized CPE control programs to increase case ascertainment, resolve risk factors, and identify local transmission through prospective genomic and epidemiological surveillance; methodologies are transferable to low-prevalence settings and MROs globally.Peer reviewe

Gastrointestinal Carriage Is a Major Reservoir of Klebsiella pneumoniae Infection in Intensive Care Patients.

BACKGROUND: Klebsiella pneumoniae is an opportunistic pathogen and leading cause of hospital-associated infections. Intensive care unit (ICU) patients are particularly at risk. Klebsiella pneumoniae is part of the healthy human microbiome, providing a potential reservoir for infection. However, the frequency of gut colonization and its contribution to infections are not well characterized. METHODS: We conducted a 1-year prospective cohort study in which 498 ICU patients were screened for rectal and throat carriage of K. pneumoniae shortly after admission. Klebsiella pneumoniae isolated from screening swabs and clinical diagnostic samples were characterized using whole genome sequencing and combined with epidemiological data to identify likely transmission events. RESULTS: Klebsiella pneumoniae carriage frequencies were estimated at 6% (95% confidence interval [CI], 3%-8%) among ICU patients admitted direct from the community, and 19% (95% CI, 14%-51%) among those with recent healthcare contact. Gut colonization on admission was significantly associated with subsequent infection (infection risk 16% vs 3%, odds ratio [OR] = 6.9, P < .001), and genome data indicated matching carriage and infection isolates in 80% of isolate pairs. Five likely transmission chains were identified, responsible for 12% of K. pneumoniae infections in ICU. In sum, 49% of K. pneumoniae infections were caused by the patients' own unique strain, and 48% of screened patients with infections were positive for prior colonization. CONCLUSIONS: These data confirm K. pneumoniae colonization is a significant risk factor for infection in ICU, and indicate ~50% of K. pneumoniae infections result from patients' own microbiota. Screening for colonization on admission could limit risk of infection in the colonized patient and others

Antimicrobial resistant <i>Klebsiella pneumoniae</i> carriage and infection in specialized geriatric care wards linked to acquisition in the referring hospital

AbstractBackgroundKlebsiella pneumoniae is a leading cause of extended-spectrum beta-lactamase (ESBL) producing hospital-associated infections, for which elderly patients are at increased risk.MethodsWe conducted a 1-year prospective cohort study, in which a third of patients admitted to two geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole genome sequencing and antimicrobial susceptibility testing.ResultsK. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8% and ESBL carriage 1.7%. K. pneumoniae infection incidence was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15and belonged to clones associated with hospital-acquired ESBL infections in other countries (ST29, ST323, ST340).One also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital.ConclusionsThe data suggest the major source of K. pneumoniae was the patient’s own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection control. Rectal screening for ESBL organisms upon admission to geriatric wards could help inform patient management and infection control in such facilities.SummaryPatients’ own gut microbiota were the major source of K. pneumoniae, but extended-spectrum beta-lactamase strains were acquired in the referring hospital. This highlights the potential for rectal screening, and the importance of the wider hospital network, for local risk management.</jats:sec

Case-case-control study on factors associated with vanB vancomycin-resistant and vancomycin-susceptible enterococcal bacteraemia

BACKGROUND: Enterococci are a major cause of healthcare-associated infection. In Australia, vanB vancomycin-resistant enterococci (VRE) is the predominant genotype. There are limited data on the factors linked to vanB VRE bacteraemia. This study aimed to identify factors associated with vanB VRE bacteraemia, and compare them with those for vancomycin-susceptible enterococci (VSE) bacteraemia. METHODS: A case-case-control study was performed in two tertiary public hospitals in Victoria, Australia. VRE and VSE bacteraemia cases were compared with controls without evidence of enterococcal bacteraemia, but may have had infections due to other pathogens. RESULTS: All VRE isolates had vanB genotype. Factors associated with vanB VRE bacteraemia were urinary catheter use within the last 30 days (OR 2.86, 95% CI 1.09-7.53), an increase in duration of metronidazole therapy (OR 1.65, 95% CI 1.17-2.33), and a higher Chronic Disease Score specific for VRE (OR 1.70, 95% CI 1.05-2.77). Factors linked to VSE bacteraemia were a history of gastrointestinal disease (OR 2.29, 95% CI 1.05-4.99) and an increase in duration of metronidazole therapy (OR 1.23, 95% CI 1.02-1.48). Admission into the haematology/oncology unit was associated with lower odds of VSE bacteraemia (OR 0.08, 95% CI 0.01-0.74). CONCLUSIONS: This is the largest case-case-control study involving vanB VRE bacteraemia. Factors associated with the development of vanB VRE bacteraemia were different to those of VSE bacteraemia