Epidemiology, clinical outcomes and risk factors of third-generation cephalosporin-resistant Escherichia coli hospitalized infections in remote Australia-a case-control study.

Background: Incidence of third-generation cephalosporin-resistant (3GCR) Escherichia coli infections has increased in remote Australia from 2012 to 2018. Objectives: To describe the epidemiology of 3GCR E. coli in Central Australia. Methods: A case-control study was conducted in the primary Central Australian hospital. Patient characteristics, antibiotic usage and clinical outcomes were compared between adult hospitalizations with 3GCR and susceptible E. coli isolates in 2018-19. Poisson regression was used to compare the incidence of 3GCR hospitalizations between Indigenous and non-Indigenous individuals. Patient characteristics and antibiotic usage were tested for associations with 3GCR isolates using univariate analysis. Results: A total of 889 E. coli isolates were identified, of which 187 (21%) were 3GCR. The incidence of 3GCR E. coli infection was 2.15 per 1000 person-years, with an incidence rate ratio of 6.8 (95% CI 4.6-10.1) between Indigenous and non-Indigenous individuals. When compared with the control group, 3GCR E. coli infections were associated with a higher Charlson comorbidity index (CCI ≥3 in 30.7% versus 15.0%, P < 0.001) and were more commonly healthcare associated (52.4% versus 26.7%, P < 0.001). A higher 1 year mortality was observed in the 3GCR group after adjustment for comorbidity (OR = 4.43, P = 0.002), but not at 30 days (2.4% versus 0.0%, P = 0.2). The 3GCR group used more antibiotics in the past 3 months (OR = 5.75, P < 0.001) and 12 months (OR = 3.65, P < 0.001). Conclusions: 3GCR E. coli infections in remote Australia disproportionally affect Indigenous peoples and are associated with a high burden of comorbidities and antibiotic use. Strategies to enhance antimicrobial stewardship should be considered in this remote setting.

Validating a novel three-times-weekly post-hemodialysis ceftriaxone regimen in infected Indigenous Australian patients-a population pharmacokinetic study.

OBJECTIVES: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis. METHODS: A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total)  ≥100 mg/L] were simulated for various dosing strategies. RESULTS: Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis. CONCLUSIONS: A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.

Prediction accuracy of commonly used pneumonia severity scores in Aboriginal patients with severe community-acquired pneumonia: a retrospective study.

BACKGROUND: Severe community-acquired pneumonia (SCAP) is highly prevalent in the Aboriginal population. Few pneumonia severity scores are validated in this population. AIMS: To assess the prediction accuracy of pneumonia severity scores in Aboriginal patients with SCAP and to identify risk factors for poor prognosis. METHODS: Retrospective cohort study examining Aboriginal patients admitted to the intensive care unit with confirmed SCAP between January 2011 and December 2014. Severity scores were calculated for SMARTCOP (systolic blood pressure, multi-lobar, albumin, respiratory rate, tachycardia, confusion, oxygenation and arterial pH), SMARTACOP (systolic blood pressure, multi-lobar, albumin, respiratory rate, tachycardia, Aboriginal status, confusion, oxygenation and arterial pH), CURB-65 (confusion, urea, respiratory rate, blood pressure and age ≥65 years), pneumonia severity index, Infectious Diseases Society of America and American Thoracic Society SCAP, and Acute Physiology and Chronic Health Evaluation (APACHE) II/III using medical records. Prediction accuracy of 30-day mortality and requirement for intensive respiratory and/or vasoactive support (IRVS) were assessed using logistic regression and the area under the receiver operating characteristic curve (AUROC). Multivariate analysis was used to test associations between poor prognosis and demographic/clinical variables. RESULTS: A total of 203 cases (49% women) was identified. Thirty-day mortality was 6.4% (n = 13), and 53% (n = 107) required IRVS. None of the tested pneumonia severity scores accurately predicted mortality. SMARTCOP and SMARTACOP predicted IRVS requirement with the highest diagnostic accuracy, but only achieved acceptable discrimination (P <0.001 and <0.001; AUROC = 0.74 and 0.75 respectively). APACHE II/III predicted both mortality (P = 0.003 and 0.001; AUROC = 0.74 and 0.73 respectively) and IRVS requirement (P <0.001 and <0.001; AUROC = 0.72 and 0.73 respectively). Multivariate analysis associated mortality with male gender, cirrhosis, immunosuppression and acidaemia, and IRVS requirement with multi-lobar pneumonia, hypotension and tachypnoea. Multivariate analysis for mortality and IRVS requirement achieved an AUROC of 0.93 and 0.87 respectively. CONCLUSION: None of the pneumonia severity scores accurately predicted mortality. We recommend SMARTACOP to predict IRVS requirement in Aboriginal patients with SCAP. Given Aboriginal patients are over-represented in Australian intensive care units, a new score is warranted for this understudied population.

Epidemiology and microbiology of severe community-acquired pneumonia in Central Australia: a retrospective study.

BACKGROUND: Severe community-acquired pneumonia (SCAP) has high mortality and morbidity. AIMS: To describe the epidemiology and microbiology of SCAP in Central Australia. METHODS: A retrospective epidemiological study describing the characteristics, incidence rates (IR) and microbiological aetiology of SCAP in Central Australia. Adult patients admitted to Alice Springs Hospital Intensive Care Unit (ICU) between 2011 and 2014 that fitted the Infectious Diseases Society of America and American Thoracic Society definition of SCAP were included. Medical records were reviewed and compared between indigenous and non-indigenous patients. Primary outcomes were incidence rate and microbiological aetiology of SCAP. Secondary outcomes were 30-day mortality, and ICU and hospital length of stay (LoS). RESULTS: A total of 185 patents were included (156 indigenous; 29 non-indigenous). The overall SCAP IR per 1000 person-years was 3.24 (3.75 indigenous; 1.87 non-indigenous) with an IR difference of 2.71 after adjustment (P < 0.001). Those aged ≥50 years had an IR 74.8% higher than those younger. Male IR was 50% higher than females. There was a significant difference between indigenous and non-indigenous groups for age (48 vs 64 years), but not for 30-day mortality (7.7% vs 10.3%), ICU LoS (4.8 vs 4.6 days) and hospital LoS (10.9 vs 15.1 days) respectively. Likely causative pathogen(s) were identified in 117 patients; Streptococcus pneumoniae was the most common pathogen (28.2%), followed by Haemophilus influenzae (19.7%), Influenza A/B (16.2%) and Staphylococcus aureus (14.5%). CONCLUSION: A high incidence of SCAP was observed in Central Australia, disproportionately affecting the indigenous population. Prevention strategies are imperative, as well as early identification of SCAP and appropriate empiric antibiotic regimens.

Antimicrobial stewardship in rural and remote primary health care: a narrative review.

BACKGROUND: Antimicrobial resistance is an emerging problem worldwide and poses a significant threat to human health. Antimicrobial stewardship programmes are being implemented in health systems globally, primarily in hospitals, to address the growing threat of antimicrobial resistance. Despite the significance of primary health care services in providing health care to communities, antimicrobial stewardship programmes are not well established in this sector, especially in rural and remote settings. This narrative review aims to identify in rural and remote primary health care settings the (1) correlation of antimicrobial resistance with antibiotic prescribing and volume of antibiotic use, (2) appropriateness of antimicrobial prescribing, (3) risk factors associated with inappropriate use/prescribing of antibiotics, and (4) effective antimicrobial stewardship strategies. METHODS: The international literature was searched for English only articles between 2000 and 2020 using specified keywords. Seven electronic databases were searched: Scopus, Cochrane, Embase, CINAHL, PubMed, Ovid Medline and Ovid Emcare. Publication screening and analysis were conducted using Joanna Briggs Institute systematic review tools. RESULTS: Fifty-one eligible articles were identified. Inappropriate and excessive antimicrobial prescribing and use directly led to increases in antimicrobial resistance. Increasing rurality of practice is associated with disproportionally higher rates of inappropriate prescribing compared to those in metropolitan areas. Physician knowledge, attitude and behaviour play important roles in mediating antimicrobial prescribing, with strong intrinsic and extrinsic influences including patient factors. Antimicrobial stewardship strategies in rural and remote primary health care settings focus on health care provider and patient education, clinician support systems, utility of antimicrobial resistance surveillance, and policy changes. Results of these interventions were generally positive with decreased antimicrobial resistance rates and improved appropriateness of antimicrobial prescribing. CONCLUSIONS: Inappropriate prescribing and excessive use of antimicrobials are an important contributor to the increasing resistance towards antimicrobial agents particularly in rural and remote primary health care. Antimicrobial stewardship programmes in the form of education, clinical support, surveillance, and policies have been mostly successful in reducing prescribing rates and inappropriate prescriptions. The narrative review highlighted the need for longer interventions to assess changes in antimicrobial resistance rates. The review also identified a lack of differentiation between rural and remote contexts and Indigenous health was inadequately addressed. Future research should have a greater focus on effective interventional components and patient perspectives.

The impact of infectious diseases consultation on the management and outcomes of Pseudomonas aeruginosa bacteraemia in adults: a retrospective cohort study.

BACKGROUND: Pseudomonas aeruginosa bacteraemia (PAB) is associated with high mortality. The benefits of infectious diseases consultation (IDC) has been demonstrated in Staphylococcal aureus bacteraemia and other complex infections. Impact of IDC in PAB is unclear. This study aimed to evaluate the impact of IDC on the management and outcomes in patients with PAB. METHODS: This is a retrospective cohort single-centre study from 1 November 2006 to 29 May 2019, in all adult patients admitted with first episode of PAB. Data collected included demographics, clinical management and outcomes for PAB and whether IDC occurred. In addition, 29 Pseudomonas aeruginosa (PA) stored isolates were available for Illumina whole genome sequencing to investigate if pathogen factors contributed to the mortality. RESULTS: A total of 128 cases of PAB were identified, 71% received IDC. Patients who received IDC were less likely to receive inappropriate duration of antibiotic therapy (4.4%; vs 67.6%; p < 0.01), more likely to be de-escalated to oral antibiotic in a timely manner (87.9% vs 40.5%; p < 0.01), undergo removal of infected catheter (27.5% vs 13.5%; p = 0.049) and undergo surgical intervention (20.9% vs 5.4%, p = 0.023) for source control. The overall 30-day all-cause mortality rate was 24.2% and was significantly higher in the no IDC group in both unadjusted (56.8% vs 11.0%, odds ratio [OR] = 10.63, p < 0.001) and adjusted analysis (adjusted OR = 7.84; 95% confidence interval, 2.95-20.86). The genotypic analysis did not reveal any PA genetic features associated with increased mortality between IDC versus no IDC groups. CONCLUSION: Patients who received IDC for PAB had lower 30-day mortality, better source control and management was more compliant with guidelines. Further prospective studies are necessary to determine if these results can be validated in other settings.

Evaluating antimicrobial prescribing practice in Australian remote primary healthcare clinics.

BACKGROUND: Inappropriate antimicrobial prescribing contributes to the emergence of antimicrobial resistance. Gaps exist in the understanding of antimicrobial prescribing in the remote setting. We aimed to assess adherence to guidelines and appropriateness of antimicrobial prescribing in Central Australia. METHODS: A retrospective study assessing antimicrobial prescriptions in ten Aboriginal clinics (three in remote communities and seven in regional centre) using a validated evaluation tool. Antimicrobials prescribed between 1 January-31 December 2018 were randomly selected for inclusion into the study. The main outcome measures were the rates of guideline adherence and inappropriate prescribing. RESULTS: A total of 180 prescriptions were included (96.1% Aboriginal, 32.2% male). Ninety-nine (55.0%) prescriptions were written by general practitioners (GPs), 57 (31.7%) by nurses and 24 (13.3%) by others. Forty-three (25.7%) assessable prescriptions were deemed inappropriate and 75 (44.4%) did not adhere to guidelines. Prescriptions written by GPs were less likely to adhere to guidelines, particularly GPs located in remote communities. The most common reasons for inappropriate prescribing were incorrect dosage/frequency and antimicrobial not indicated. Skin and soft-tissue infection was the commonest indication, with 29 of 41 (70.7%) prescriptions deemed appropriate. Prescriptions for lower respiratory-tract infection had the lowest rate of appropriateness, with one of seven prescriptions deemed appropriate (14.3%). Antimicrobials with the lowest rate of appropriateness were ciprofloxacin, amoxicillin-clavulanate and cefalexin, at 50%, 56%, and 62%, respectively. CONCLUSION: A quarter of antimicrobial prescriptions written in select remote central Australian Aboriginal primary healthcare clinics were deemed inappropriate. The implementation of a comprehensive antimicrobial stewardship program is recommended.

Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis.

Currently there are no pharmacokinetic (PK) data to guide antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis. This study aimed to determine whether the population pharmacokinetics of meropenem were different between critically ill Australian Indigenous and critically ill Caucasian patients. Serial plasma and urine samples as well as clinical and demographic data were collected over two dosing intervals from critically ill Australian Indigenous patients. Plasma meropenem concentrations were assayed by validated chromatography. Concentration-time data were analysed with data from a previous PK study in critically ill Caucasian patients using Pmetrics. The population PK model was subsequently used for Monte Carlo dosing simulations to describe optimal doses for these patients. Six Indigenous and five Caucasian subjects were included. A two-compartment model described the data adequately, with meropenem clearance and volume of distribution of the central compartment described by creatinine clearance (CLCr) and patient weight, respectively. Patient ethnicity was not supported as a covariate in the final model. Significant differences were observed for meropenem clearance between the Indigenous and Caucasian groups [median 11.0 (range 3.0-14.1) L/h vs. 17.4 (4.3-30.3) L/h, respectively; P <0.01]. Standard dosing regimens (1 g intravenous every 8 h as a 30-min infusion) consistently achieved target exposures at the minimum inhibitory concentration breakpoint in the absence of augmented renal clearance. No significant interethnic differences in meropenem pharmacokinetics between the Indigenous and Caucasian groups were detected and CLCr was found to be the strongest determinant of appropriate dosing regimens.

Total and unbound ceftriaxone pharmacokinetics in critically ill Australian Indigenous patients with severe sepsis.

In the absence of specific data to guide optimal dosing, this study aimed to describe the pharmacokinetics of ceftriaxone in severely septic Australian Indigenous patients and to assess achievement of the pharmacodynamic target of the regimens prescribed. A pharmacokinetic study was conducted in a remote hospital intensive care unit in patients receiving ceftriaxone dosing of 1 g every 12 h (q12h). Serial blood and urine samples were collected over one dosing interval on two consecutive days. Samples were assayed using a validated chromatography method for total and unbound concentrations. Concentration-time data collected were analysed with a non-compartmental approach. A total of 100 plasma samples were collected from five subjects. Ceftriaxone clearance, volume of distribution at steady-state, elimination half-life and elimination rate constant estimates were 0.9 (0.6-1.5) L/h, 11.2 (7.6-13.4) L, 9.5 (3.2-10.2) h and 0.07 (0.07-0.21) h-1, respectively. The unbound fraction of ceftriaxone ranged between 14% and 43%, with a higher unbound fraction present at higher total concentrations. The unbound concentrations at 720 min from the initiation of infusion for the first and second dosing intervals were 7.2 (4.8-10.7) mg/L and 7.8 (4.7-12.1) mg/L respectively, which exceeds the minimum inhibitory concentration of all typical target pathogens. In conclusion, the regimen of ceftriaxone 1 g q12h is adequate for critically ill Australian Indigenous patients with severe sepsis caused by non-resistant pathogens.

Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis.

There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment (Vc), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ± 3.2 liters/h, 14.5 ± 6.6 liters, 1.5 ± 0.4 h-1, and 1.8 ± 0.9 h-1, respectively, where CL and Vc were found to be described by creatinine clearance (CLCR) and total body weight, respectively. In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CLCR was found to be the most important determinant of piperacillin pharmacokinetics.

Pharmacokinetic/pharmacodynamic considerations for the optimization of antimicrobial delivery in the critically ill.

PURPOSE OF REVIEW: Antimicrobials are very commonly used drugs in the intensive care setting. Extensive research has been conducted in recent years to describe their pharmacokinetics/pharmacodynamics in order to maximize the pharmacological benefit and patient outcome. Translating these new findings into clinical practice is encouraged. RECENT FINDINGS: This article will discuss mechanistic data on factors causing changes in antimicrobial pharmacokinetics in critically ill patients, such as the phenomena of augmented renal clearance as well as the effects of hypoalbuminemia, renal replacement therapy, and extracorporeal membrane oxygenation. Failure to achieve clinical cure has been correlated with pharmacokinetics/pharmacodynamics target nonattainment, and a recent meta-analysis suggests an association between dosing strategies aimed at optimizing antimicrobial pharmacokinetics/pharmacodynamics with improvement in clinical cure and survival. Novel dosing strategies including therapeutic drug monitoring are also now being tested to address challenges in the optimization of antimicrobial pharmacokinetics/pharmacodynamics. SUMMARY: Optimization of antimicrobial dosing in accordance with pharmacokinetics/pharmacodynamics targets can improve survival and clinical cure. Dosing regimens for critically ill patients should aim for pharmacokinetics/pharmacodynamics target attainment by utilizing altered dosing strategies including adaptive feedback using therapeutic drug monitoring.

Interethnic differences in pharmacokinetics of antibacterials.

BACKGROUND: Optimal antibacterial dosing is imperative for maximising clinical outcome. Many factors can contribute to changes in the pharmacokinetics of antibacterials to the extent where dose adjustment may be needed. In acute illness, substantial changes in important pharmacokinetic parameters such as volume of distribution and clearance can occur for certain antibacterials. The possibility of interethnic pharmacokinetic differences can further complicate attempts to design an appropriate dosing regimen. Factors of ethnicity, such as genetics, body size and fat distribution, contribute to differences in absorption, distribution, metabolism and elimination of drugs. Despite extensive previous work on the altered pharmacokinetics of antibacterials in some patient groups such as the critically ill, knowledge of interethnic pharmacokinetic differences for antibacterials is limited. OBJECTIVES: This systematic review aims to describe any pharmacokinetic differences in antibacterials between different ethnic groups, and discuss their probable mechanisms as well as any clinical implications. METHODS: We performed a structured literature review to identify and describe available data of the interethnic differences in the pharmacokinetics of antibacterials. RESULTS: We found 50 articles that met our inclusion criteria and only six of these compared antibacterial pharmacokinetics between different ethnicities within the same study. Overall, there was limited evidence available. We found that interethnic pharmacokinetic differences are negligible for carbapenems, most ß-lactams, aminoglycosides, glycopeptides, most fluoroquinolones, linezolid and daptomycin, whereas significant difference is likely for ciprofloxacin, macrolides, clindamycin, tinidazole and some cephalosporins. In general, subjects of Asian ethnicity achieve drug exposures up to two to threefold greater than Caucasian counterparts for these antibacterials. This difference is caused by a comparatively lower volume of distribution and/or drug clearance. CONCLUSION: Interethnic pharmacokinetic differences of antibacterials are likely; however, the clinical relevance of these differences is unknown and warrants further research.