The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal.

Pharmacokinetic/pharmacodynamic (PK/PD) modelling is the initial step in the semi-mechanistic approach for optimizing dosage regimens for systemically acting antimicrobial drugs (AMDs). Numerical values of PK/PD indices are used to predict dose and dosing interval on a rational basis followed by confirmation in clinical trials. The value of PK/PD indices lies in their universal applicability amongst animal species. Two PK/PD indices are routinely used in veterinary medicine, the ratio of the area under the curve of the free drug plasma concentration to the minimum inhibitory concentration (MIC) (fAUC/MIC) and the time that free plasma concentration exceeds the MIC over the dosing interval (fT > MIC). The basic concepts of PK/PD modelling of AMDs were established some 20 years ago. Earlier studies have been reviewed previously and are not reconsidered in this review. This review describes and provides a critical appraisal of more recent, advanced PK/PD approaches, with particular reference to their application in veterinary medicine. Also discussed are some hypotheses and new areas for future developments.First, a brief overview of PK/PD principles is presented as the basis for then reviewing more advanced mechanistic considerations on the precise nature of selected indices. Then, several new approaches to selecting PK/PD indices and establishing their numerical values are reviewed, including (a) the modelling of time-kill curves and (b) the use of population PK investigations. PK/PD indices can be used for dose determination, and they are required to establish clinical breakpoints for antimicrobial susceptibility testing. A particular consideration is given to the precise nature of MIC, because it is pivotal in establishing PK/PD indices, explaining that it is not a "pharmacodynamic parameter" in the usual sense of this term.

Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model.

The pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin.

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.

Assessing the public acceptability of proposed policy interventions to reduce the misuse of antibiotics in Australia: A report on two community juries.

OBJECTIVE: To elicit the views of well-informed community members on the acceptability of proposed policy interventions designed to improve community use of antibiotics in Australia. DESIGN: Two community juries held in 2016. SETTING AND PARTICIPANTS: Western Sydney and Dubbo communities in NSW, Australia. Twenty-nine participants of diverse social and cultural backgrounds, mixed genders and ages recruited via public advertising: one jury was drawn from a large metropolitan setting; the other from a regional/rural setting. MAIN OUTCOME MEASURE: Jury verdict and rationale in response to a prioritization task and structured questions. RESULTS: Both juries concluded that potential policy interventions to curb antibiotic misuse in the community should be directed towards: (i) ensuring that the public and prescribers were better educated about the dangers of antibiotic resistance; (ii) making community-based human and animal health-care practitioners accountable for their prescribing decisions. Patient-centred approaches such as delayed prescribing were seen as less acceptable than prescriber-centred approaches; both juries completely rejected any proposal to decrease consumer demand by increasing antibiotic prices. CONCLUSION: These informed citizens acknowledged the importance of raising public awareness of the risks, impacts and costs of antibiotic resistance and placed a high priority on increasing social and professional accountability through restrictive measures. Their overarching aim was that policy interventions should be directed towards creating collective actions and broad social support for changing antibiotic use through establishing and explaining the need for mechanisms to control and support better prescribing by practitioners, while not transferring the burdens, costs and risks of interventions to consumers.

Antimicrobial Use and Resistance in Australia (AURA) surveillance system: coordinating national data on antimicrobial use and resistance for Australia.

Objective The aim of the present study was to describe the process of establishment and coordination of the national Antimicrobial Use and Resistance in Australia (AURA) surveillance system. Methods Existing surveillance programs conducted by health organisations at state or multi-jurisdictional levels were reviewed, and gaps and opportunities identified for the development of a national system. In view of the time frame available as part of the Australian Government Department of Health funding agreement, the strategy used by the Australian Commission on Safety and Quality in Health Care was to commence work with existing surveillance programs, expanding and enhancing them and developing new systems where gaps were identified. Using the specifications of the AURA national system, the data from each of these elements were then analysed and reported. The system provides coverage for the acute and community sectors for antimicrobial use and antimicrobial resistance. Results The AURA surveillance system integrates eight streams of surveillance activities, including passive and targeted surveillance of antimicrobial use and resistance from hospitals (public and private) and the community (general practitioners and aged care homes). A gap was identified in timely surveillance of critical antimicrobial resistances (CARs), which resulted in the development of the national CARAlert system. The first comprehensive analyses of data across the surveillance programs was published in June 2016, providing baseline data for future reports to build on. Conclusion The AURA surveillance system has established the framework and foundation systems for an integrated and comprehensive picture of both antimicrobial use and resistance in Australia over time. National coordination and support will improve data collection, standardisation and analysis, and will facilitate collaboration across the states and territories, the Australian Government and the private sector. AURA publications will inform policy development and clinical decision making and improve consumer awareness of antimicrobial use and resistance. The system will continue to develop as a comprehensive system, with additional data over time, and appropriate clinical and epidemiological review. What is known about this topic? Surveillance of antimicrobial use and resistance is critical to inform effective policy development and public health responses to the growing problem of antimicrobial resistance. Until now, surveillance of antimicrobial use and resistance in Australia has been fragmented, with state and territory and professional group differences in data collection, analysis and reporting. What does this paper add? This paper profiles the development of the AURA surveillance system, the first nationally coordinated surveillance system for antimicrobial use and resistance, and its use of a partnership approach with contributing programs in order to promote participation and to obtain data to inform strategies to prevent and contain antimicrobial resistance. This paper highlights the establishment phase, noting that the system continues to be improved with growing participation from all sectors. What are the implications for practitioners? National surveillance data from the AURA surveillance system provides evidence for action to guide improvements in infection control, antimicrobial prescribing and the prevention and control of antimicrobial resistance across all healthcare sectors. It will also enable trends to be identified and reported on, and have the capability of determining the effect of interventions to improve and rationalise antimicrobial prescribing.

Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved updated dose recommendations for intravenous colistin in patients with various degrees of renal function. We assessed the recommendations in relation to their ability to achieve clinically relevant plasma colistin concentrations. METHODS: Pharmacokinetic data from 162 adult critically ill patients (creatinine clearance range, 5.4-211 mL/min) were used to determine the average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose. Target attainment rates for FDA- and EMA-approved daily doses to achieve colistin Css,avg of ≥0.5, ≥1, ≥2, and ≥4 mg/L were determined for each creatinine clearance category (≥80 mL/min, 50 to <80 mL/min, 30 to <50 mL/min, and <30 mL/min). RESULTS: For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%-34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%-75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations. CONCLUSIONS: The study highlights important differences between the FDA- and EMA-approved dose recommendations and informs the setting of clinical breakpoints. CLINICAL TRIALS REGISTRATION: NCT00235690.

Phylogenetic diversity, antimicrobial susceptibility and virulence characteristics of phylogroup F Escherichia coli in Australia.

Unlike Escherichia coli strains belonging to phylogroup B2, the clinical significance of strains belonging to phylogroup F is not well understood. Here we report on a collection of phylogroup F strains recovered in Australia from faeces and extra-intestinal sites from humans, companion animals and native animals, as well as from poultry meat and water samples. The distribution of sequence types was clearly non-random with respect to isolate source. The antimicrobial resistance and virulence trait profiles also varied with the sequence type of the isolate. Phylogroup F strains tended to lack the virulence traits typically associated with phylogroup B2 strains responsible for extra-intestinal infection in humans. Resistance to fluoroquinolones and/or expanded-spectrum cephalosporins was common within ST648, ST354 and ST3711. Although ST354 and ST3711 are part of the same clonal complex, the ST3711 isolates were only recovered from native birds being cared for in a single wildlife rehabilitation centre, whereas the ST354 isolates were from faeces and extra-intestinal sites of dogs and humans, as well as from poultry meat. Although ST354 isolates from chicken meat in Western Australia were distinct from all other ST354 isolates, those from poultry meat samples collected in eastern Australia shared many similarities with other ST354 isolates from humans and companion animals.

Antimicrobial use in Australian hospitals: how much and how appropriate?

Antimicrobial agents play a central role in modern health care, especially in the hospital setting. This article describes the currently available information on the volumes of antimicrobial use in Australian hospitals, the appropriateness of that use, and the levels of compliance with nationally or locally endorsed prescribing guidelines. The data presented here come from the 2014 National Antimicrobial Utilisation Surveillance Program report and the 2013 and 2014 National Antimicrobial Prescribing Survey reports and are based on voluntary participation in the two programs. While the results can be considered indicative only, they show that Australia has high volumes of prescribing in hospitals, and that in certain circumstances and conditions these are inappropriate and/or not compliant with national or local prescribing guidelines. In 2014, the national aggregate use rate for antimicrobials was 936 defined daily doses per 1000 occupied bed days. In the same year, the overall rate of appropriate prescribing was 72%, and compliance with guidelines was 74% where this was assessable. The rate of surgical antimicrobial prophylaxis exceeding the benchmark of 24 hours was high (36%), as was the inappropriate prescribing for infective exacerbations of chronic obstructive pulmonary disease (38%). The findings indicate that there is room for improvement in antimicrobial prescribing in Australian hospitals, and provides insights into where the efforts for improvement might be directed.

Australian Group on Antimicrobial Resistance Australian Enterobacteriaceae Sepsis Outcome Programme annual report, 2014.

The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2014 survey was the second year to focus on blood stream infections. During 2014, 5,798 Enterobacteriaceae species isolates were tested using commercial automated methods (Vitek 2, BioMérieux; Phoenix, BD) and results were analysed using the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2015). Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 9.0%/9.0% of Escherichia coli (CLSI/EUCAST criteria) and 7.8%/7.8% of Klebsiella pneumoniae, and 8.0%/8.0% K. oxytoca. Non-susceptibility rates to ciprofloxacin were 10.4%/11.6% for E. coli, 5.0%/7.7% for K. pneumoniae, 0.4%/0.4% for K. oxytoca, and 3.5%/6.5% in Enterobacter cloacae. Resistance rates to piperacillin-tazobactam were 3.2%/6.8%, 4.8%/7.2%, 11.1%/11.5%, and 19.0%/24.7% for the same 4 species respectively. Fourteen isolates were shown to harbour a carbapenemase gene, 7 blaIMP-4, 3 blaKPC-2, 3 blaVIM-1, 1 blaNDM-4, and 1 blaOXA-181-lke.

Australian Group on Antimicrobial Resistance Australian Enterococcal Sepsis Outcome Programme annual report, 2014.

From 1 January to 31 December 2014, 27 institutions around Australia participated in the Australian Enterococcal Sepsis Outcome Programme (AESOP). The aim of AESOP 2014 was to determine the proportion of enterococcal bacteraemia isolates in Australia that were antimicrobial resistant, and to characterise the molecular epidemiology of the Enterococcus faecium isolates. Of the 952 unique episodes of bacteraemia investigated, 94.4% were caused by either E. faecalis (54.9%) or E. faecium (39.9%). Ampicillin resistance was detected in 0.6% of E. faecalis and in 89.4% of E. faecium. Vancomycin non-susceptibility was reported in 0.2% and 46.1% of E. faecalis and E. faecium respectively. Overall 51.1% of E. faecium harboured vanA or vanB genes. For the vanA/B positive E. faecium isolates, 81.5% harboured vanB genes and 18.5% vanA genes. The percentage of E. faecium bacteraemia isolates resistant to vancomycin in Australia is significantly higher than that seen in most European countries. E. faecium consisted of 113 pulsed-field gel electrophoresis pulsotypes of which 68.9% of isolates were classified into 14 major pulsotypes containing 5 or more isolates. Multilocus sequence typing grouped the 14 major pulsotypes into clonal cluster 17, a major hospital-adapted polyclonal E. faecium cluster. The geographical distribution of the 4 predominant sequence types (ST203, ST796, ST555 and ST17) varied with only ST203 identified across most regions of Australia. Overall 74.7% of isolates belonging to the four predominant STs harboured vanA or vanB genes. In conclusion, the AESOP 2014 has shown enterococcal bacteraemias in Australia are frequently caused by polyclonal ampicillin-resistant high-level gentamicin resistant vanA or vanB E. faecium, which have limited treatment options.

Australian Group on Antimicrobial Resistance Australian Staphylococcus aureus Sepsis Outcome Programme annual report, 2014.

From 1 January to 31 December 2014, 27 institutions around Australia participated in the Australian Staphylococcal Sepsis Outcome Programme (ASSOP). The aim of ASSOP 2014 was to determine the proportion of Staphylococcus aureus bacteraemia (SAB) isolates in Australia that are antimicrobial resistant, with particular emphasis on susceptibility to methicillin and to characterise the molecular epidemiology of the isolates. Overall, 18.8% of the 2,206 SAB episodes were methicillin resistant, which was significantly higher than that reported in most European countries. The 30-day all-cause mortality associated with methicillin-resistant SAB was 23.4%, which was significantly higher than the 14.4% mortality associated with methicillin-sensitive SAB (P <0.0001). With the exception of the beta-lactams and erythromycin, antimicrobial resistance in methicillin-sensitive S. aureus remains rare. However in addition to the beta-lactams, approximately 50‰ of methicillin-resistant S. aureus (MRSA) were resistant to erythromycin and ciprofloxacin and approximately 15% were resistant to co-trimoxazole, tetracycline and gentamicin. When applying the European Committee on Antimicrobial Susceptibility Testing breakpoints, teicoplanin resistance was detected in 2 S. aureus isolates. Resistance was not detected for vancomycin or linezolid. Resistance to non-beta-lactam antimicrobials was largely attributable to 2 healthcare-associated MRSA clones; ST22-IV [2B] (EMRSA-15) and ST239-III [3A] (Aus-2/3 EMRSA). ST22-IV [2B] (EMRSA-15) has become the predominant healthcare associated clone in Australia. Sixty per cent of methicillin-resistant SAB were due to community-associated (CA) clones. Although polyclonal, almost 44% of community-associated clones were characterised as ST93-IV [2B] (Queensland CA-MRSA) and ST1-IV [2B] (WA1). CA-MRSA, in particular the ST45-V [5C2&5] (WA84) clone, has acquired multiple antimicrobial resistance determinants including ciprofloxacin, erythromycin, clindamycin, gentamicin and tetracycline. As CA-MRSA is well established in the Australian community it is important that antimicrobial resistance patterns in community and healthcare-associated SAB is monitored as this information will guide therapeutic practices in treating S. aureus sepsis.

Prolonged growth of a clinical Staphylococcus aureus strain selects for a stable small-colony-variant cell type.

An undetermined feature of Staphylococcus aureus pathogenesis is its persistence and then relapse of disease. This has been explained by its switch to alternative lifestyles, mainly as biofilm or small-colony variants (SCVs). Studying the native characteristics of SCVs has been problematic due to their reversion to the parental lifestyle. We have observed that for a number of S. aureus strains as they switch to an SCV lifestyle, there is the formation of an extracellular matrix. We focused our analysis on one strain, WCH-SK2. For bacterial survival in the host, the combination of low nutrients and the prolonged time frame forms a stress that selects for a specific cell type from the population. In this context, we used steady-state growth conditions with low nutrients and a controlled low growth rate for a prolonged time and with methylglyoxal. These conditions induced S. aureus WCH-SK2 into a stable SCV cell type; the cells did not revert after subculturing. Analysis revealed these cells possessed a metabolic and surface profile that was different from those of previously described SCVs or biofilm cells. The extracellular matrix was protein and extracellular DNA but not polysaccharide. The SCV cells induced expression of certain surface proteins (such as Ebh) and synthesis of lantibiotics while downregulating factors that stimulate the immune response (leucocidin, capsule, and carotenoid). Our data reveal cell heterogeneity within an S. aureus population and under conditions that resemble long-term survival in the host have identified a previously unnoticed S. aureus cell type with a distinctive metabolic and molecular profile.

Use of in vitro vancomycin testing results to predict susceptibility to oritavancin, a new long-acting lipoglycopeptide.

Oritavancin is a recently approved lipoglycopeptide antimicrobial agent with activity against Gram-positive pathogens. Its extended serum elimination half-life and concentration-dependent killing enable single-dose treatment of acute bacterial skin and skin structure infections. At the time of regulatory approval, new agents, including oritavancin, are not offered in the most widely used susceptibility testing devices and therefore may require application of surrogate testing using a related antimicrobial to infer susceptibility. To evaluate vancomycin as a predictive susceptibility marker for oritavancin, 26,993 recent Gram-positive organisms from U.S. and European hospitals were tested using reference MIC methods. Organisms included Staphylococcus aureus, coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci (BHS), viridans group streptococci (VGS), and enterococci (ENT). These five major pathogen groups were analyzed by comparing results with FDA-approved susceptible breakpoints for both drugs, as well as those suggested by epidemiological cutoff values and supported by pharmacokinetic/pharmacodynamic analyses. Vancomycin susceptibility was highly accurate (98.1 to 100.0%) as a surrogate for oritavancin susceptibility among the indicated pathogen species. Furthermore, direct MIC comparisons showed high oritavancin potencies, with vancomycin/oritavancin MIC90 results of 1/0.06, 2/0.06, 0.5/0.12,1/0.06, and >16/0.06 µg/ml for S. aureus, CoNS, BHS, VGS, and ENT, respectively. In conclusion, vancomycin demonstrated acceptable accuracy as a surrogate marker for predicting oritavancin susceptibility when tested against the indicated pathogens. In contrast, 93.3% of vancomycin-nonsusceptible enterococci had oritavancin MIC values of ≤0.12 µg/ml, indicating a poor predictive value of vancomycin for oritavancin resistance against these organisms. Until commercial oritavancin susceptibility testing devices are readily available, isolates that when tested show vancomycin susceptibility can be inferred to be susceptible to oritavancin by using FDA-approved breakpoints.

New pharmacokinetic/pharmacodynamic studies of systemically administered colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection.

OBJECTIVES: This study investigated the exposure-response relationships between unbound colistin in plasma and antibacterial activity in mouse thigh and lung infections. METHODS: Dose fractionation studies (subcutaneous colistin sulphate at 1.25-160 mg/kg/day) were conducted in neutropenic mice in which infection (three strains of Pseudomonas aeruginosa and three strains of Acinetobacter baumannii) had been produced by intramuscular thigh injection or aerosol lung delivery. Bacterial burden was measured at 24 h after initiation of colistin treatment. Plasma protein binding was measured by rapid equilibrium dialysis and ultracentrifugation. The inhibitory sigmoid dose-effect model and non-linear least squares regression were employed to determine the relationship between exposure to unbound colistin and efficacy. RESULTS: Plasma binding of colistin was constant over the concentration range ∼2-50 mg/L. The average ±â€ŠSD percentage bound for all concentrations was 92.9 ±â€Š3.3% by ultracentrifugation and 90.4 ±â€Š1.1% by equilibrium dialysis. In the thigh model, across all six strains the antibacterial effect of colistin was well correlated with fAUC/MIC (R(2) = 0.82-0.94 for P. aeruginosa and R(2) = 0.84-0.95 for A. baumannii). Target values of fAUC/MIC for 2 log10 kill were 7.4-13.7 for P. aeruginosa and 7.4-17.6 for A. baumannii. In the lung model, for only two strains of P. aeruginosa and one strain of A. baumannii was it possible to achieve 2 log10 kill (fAUC/MIC target values 36.8-105), even at the highest colistin dose tolerated by mice. This dose was not able to achieve bacteriostasis for the other two strains of A. baumannii. CONCLUSIONS: Colistin was substantially less effective in lung infection. The pharmacokinetic/pharmacodynamic target values will assist in the design of optimized dosage regimens.

Reviving old antibiotics.

In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

Molecular epidemiology of enterococcal bacteremia in Australia.

Enterococci are a major cause of health care-associated infections and account for approximately 10% of all bacteremias globally. The aim of this study was to determine the proportion of enterococcal bacteremia isolates in Australia that are antimicrobial resistant, with particular emphasis on susceptibility to ampicillin and the glycopeptides, and to characterize the molecular epidemiology of the Enterococcus faecalis and Enterococcus faecium isolates. From 1 January to 31 December 2011, 1,079 unique episodes of bacteremia were investigated, of which 95.8% were caused by either E. faecalis (61.0%) or E. faecium (34.8%). The majority of bacteremias were health care associated, and approximately one-third were polymicrobial. Ampicillin resistance was detected in 90.4% of E. faecium isolates but was not detected in E. faecalis isolates. Vancomycin nonsusceptibility was reported in 0.6% and 36.5% of E. faecalis and E. faecium isolates, respectively. Unlike Europe and the United States, where vancomycin resistance in E. faecium is predominately due to the acquisition of the vanA operon, 98.4% of E. faecium isolates harboring van genes carried the vanB operon, and 16.1% of the vanB E. faecium isolates had vancomycin MICs at or below the susceptible breakpoint of the CLSI. Although molecular typing identified 126 E. faecalis pulsed-field gel electrophoresis pulsotypes, >50% belonged to two pulsotypes that were isolated across Australia. E. faecium consisted of 73 pulsotypes from which 43 multilocus sequence types were identified. Almost 90% of the E. faecium isolates were identified as CC17 clones, of which approximately half were characterized as ST203, which was isolated Australia-wide. In conclusion, the Australian Enterococcal Sepsis Outcome Programme (AESOP) study has shown that although they are polyclonal, enterococcal bacteremias in Australia are frequently caused by ampicillin-resistant vanB E. faecium.

Genetic and molecular predictors of high vancomycin MIC in Staphylococcus aureus bacteremia isolates.

An elevated vancomycin MIC is associated with poor outcomes in Staphylococcus aureus bacteremia (SAB) and is reported in patients with methicillin-susceptible S. aureus (MSSA) bacteremia in the absence of vancomycin treatment. Here, using DNA microarray and phenotype analysis, we investigated the genetic predictors and accessory gene regulator (agr) function and their relationship with elevated vancomycin MIC using blood culture isolates from a multicenter binational cohort of patients with SAB. Specific clonal complexes were associated with elevated (clonal complex 8 [CC8] [P < 0.001]) or low (CC22 [P < 0.001], CC88 [P < 0.001], and CC188 [P = 0.002]) vancomycin MIC. agr dysfunction (P = 0.014) or agr genotype II (P = 0.043) were also associated with an elevated vancomycin MIC. Specific resistance and virulence genes were also linked to an elevated vancomycin MIC, including blaZ (P = 0.002), sea (P < 0.001), clfA (P < 0.001), splA (P = 0.001), and the arginine catabolic mobile element (ACME) locus (P = 0.02). These data suggest that inherent organism characteristics may explain the link between elevated vancomycin MICs and poor outcomes in patients with SAB, regardless of the antibiotic treatment received. A consideration of clonal specificity should be included in future research when attempting to ascertain treatment effects or clinical outcomes.

Hospital-onset Gram-negative Surveillance Program annual report, 2011.

The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2011 survey focussed on hospital-onset infections, examining isolates from all specimens presumed to be causing disease. In 2011, 1,827 Escherichia coli, 537 Klebsiella species and 269 Enterobacter species were tested using a commercial automated method (Vitek 2, BioMérieux) and results were analysed using Clinical and Laboratory Standards Institute breakpoints from January 2012. Of the key resistances, non-susceptibilty to the third-generation cephalosporin, ceftriaxone, was found in 9.6% of E. coli and 9.5%-12.1% of Klebsiella spp. Non-susceptibility rates to ciprofloxacin were 10.6% for E. coli, 0.0%-8.3% for Klebsiella spp. and 0.0%-5.0% in Enterobacter spp. Resistance rates to gentamicin were 8.6%, 2.9%-10.9%, and 0.0%-15.6% for the same 3 groups respectively. Eight strains, 5 Klebsiella spp. and 3 Enterobacter spp. were shown to harbour a carbapenemase (IMP-4).

Community-onset Gram-negative Surveillance Program annual report, 2012.

The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2012 survey focussed on community-onset infections, examining isolates from urinary tract infections from patients presenting to outpatient clinics, emergency departments or to community practitioners. In 2012, 2,025 Escherichia coli, 538 Klebsiella species and 239 Enterobacter species were tested using a commercial automated method (Vitek 2, BioMérieux) and results were analysed using Clinical and Laboratory Standards Institute breakpoints from January 2012. Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 4.2% of E. coli and 4.6%-6.9% of Klebsiella spp. Non-susceptibility rates to ciprofloxacin were 6.9% for E. coli, 0.0%-3.5% for Klebsiella spp. and 0.8%-1.9% in Enterobacter spp, and resistance rates to piperacillin-tazobactam were 1.7%, 0.7%-9.2%, and 8.8%-11.4% for the same 3 groups respectively. Only 1 Enterobacter cloacae was shown to harbour a carbapenemase (IMP-4).

Enterobacteriaceae Sepsis Outcome Programme annual report, 2013.

The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2013 survey focussed for the first time on blood stream infections. Four thousand nine hundred and fifty-eight Enterobacteriaceae species were tested using commercial automated methods (Vitek® 2, BioMérieux; Phoenix™, BD). The results were analysed using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (January 2014). Of the key resistances, non-susceptibility to the third-generation cephalosporin, ceftriaxone, was found in 7.5%/7.5% (CLSI/EUCAST criteria respectively) of Escherichia coli; 6.3%/6.3% of Klebsiella pneumoniae, and 7.4%/7.4% of K. oxytoca. Non-susceptibility rates to ciprofloxacin were 10.3%/11.3% for E. coli, 4.6%/7.5% for K. pneumoniae, 0.6%/0.6% for K. oxytoca, and 3.6%/6.1% in Enterobacter cloacae. Resistance rates to piperacillin-tazobactam were 3.1%/6.2%, 4.2%/7.0%, 11.9% /12.6%, and 17.3% /22.2% for the same 4 species respectively. Fourteen isolates were shown to harbour a carbapenemase gene, 9 blaIMP, 3 blaKPC, and 2 blaNDM.