Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in sequence type 258 (ST258) -harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant isolates from a patient with pancreatitis. All susceptible ( = 3) and resistant ( = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G → T point mutation in (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤2 μg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type into a novel plasmid, an IS insertion upstream of , and disruption of the gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non- ST258 clonal backgrounds and alternative variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment.

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The most important geometric parameter in the friction stir welding (FSW) tool design is the shoulder diameter, which is currently estimated by trial and error. Here, we report a combined experimental and theoretical investigation on the influence of shoulder diameter on thermal cycles, peak temperatures, power requirements, and torque during FSW of AA7075-T6. An optimum tool shoulder diameter is identified using a three-dimensional, heat transfer and materials flow model. First, the predictive capability of the model is tested by comparing the computed values of peak temperature, spindle power, and torque requirements for various shoulder diameters against the corresponding experimental data. The change in the values of these variables with shoulder diameter is correctly predicted by the model. The model is then used to identify the optimum tool shoulder diameter that facilitates maximal use of the supplied torque in overcoming interfacial sticking. The tool with optimum shoulder diameter is shown to result in acceptable yield strength (YS) and ductility.

Experimental measurements of torque, traverse force and thermal cycles in friction stir welding (FSW) are challenging due to the simultaneous rotational and linear motions of the tool and the deformation of workpiece material around the tool pin. We propose here a methodology to measure the torque and the traverse force by monitoring the current and power transients of the electrical motors that drive the rotational and linear motions of the FSW tool respectively. The measured values of torque and traverse force in FSW of AA 7075-T6 and AA 2524-T351 at different combinations of tool rotational speed and tool shoulder diameter are validated with the corresponding computed results from a well tested numerical model. The proposed method alleviates the need to use expensive torque and force dynamometers, and provides an economical and robust route for indirect measurement of real time torque and traverse force in FSW.

In vivo induction of AmpC beta-lactamases produces high-level resistance to many beta-lactam antibiotics in Enterobacteriaceae, often resulting in the need to use carbapenems or cefepime (FEP). The clinical effectiveness of piperacillintazobactam (TZP), a weak inducer of AmpC beta-lactamases, is poorly understood. Here, we conducted a case-control study of adult inpatients with bloodstream infections (BSIs) due to Enterobacter, Serratia, or Citrobacter species from 2009 to 2015 to assess outcomes following treatment with TZP compared to FEP or meropenem (MEM). We collected clinical data and screened all isolates for the presence of ampC alleles by PCR. Primary study outcomes were 30-day mortality and persistent bacteremia at Ն72 h from the time of treatment initiation. Of 493 patients with bacteremia, 165 patients met the inclusion criteria, of which 88 were treated with TZP and 77 with FEP or MEM. To minimize differences between covariates, we carried out propensity score matching, which yielded 41 matched pairs. Groups only differed by age, with patients in the TZP group significantly older (P ϭ 0.012). There were no significant differences in 30-day mortality, persistent bacteremia, 7-day mortality, or treatment escalation between the two treatment groups, including in the propensity score-matched cohort. PCR amplification and sequencing of ampC genes revealed the presence of ampC in isolates with cefoxitin MICs below 16 g/ml, in particular in Serratia spp., and demonstrated that these alleles were highly genetically diverse. Taken together, TZP may be a valuable treatment option for BSIs due to AmpC betalactamase-producing Enterobacteriaceae, diminishing the need for broader-spectrum agents. Future studies are needed to validate these findings.

OBJECTIVE To assess antimicrobial prescriber knowledge, attitudes, and practices (KAP) regarding antimicrobial stewardship (AS) and associated barriers to optimal prescribing. DESIGN Cross-sectional survey. SETTING Online survey. PARTICIPANTS A convenience sample of 2,900 US antimicrobial prescribers at 5 acute-care hospitals within a hospital network. INTERVENTION The following characteristics were assessed with an anonymous, online survey in February 2015: attitudes and practices related to antimicrobial resistance, AS programs, and institutional AS resources; antimicrobial prescribing and AS knowledge; and practices and confidence related to antimicrobial prescribing. RESULTS In total, 402 respondents completed the survey. Knowledge gaps were identified through case-based questions. Some respondents sometimes selected overly broad therapy for the susceptibilities given (29%) and some "usually" or "always" preferred using the most broad-spectrum empiric antimicrobials possible (32%). Nearly all (99%) reported reviewing antimicrobial appropriateness at 48-72 hours, but only 55% reported "always" doing so. Furthermore, 45% of respondents felt that they had not received adequate training regarding antimicrobial prescribing. Some respondents lacked confidence selecting empiric therapy using antibiograms (30%), interpreting susceptibility results (24%), de-escalating therapy (18%), and determining duration of therapy (31%). Postprescription review and feedback (PPRF) was the most commonly cited AS intervention (79%) with potential to improve patient care. CONCLUSIONS Barriers to appropriate antimicrobial selection and de-escalation of antimicrobial therapy were identified among front-line prescribers in acute-care hospitals. Prescribers desired more AS-related education and identified PPRF as the most helpful AS intervention to improve patient care. Educational interventions should be preceded by and tailored to local assessment of educational needs. Infect Control Hosp Epidemiol 2018;39:316-322.

Background Understanding the changing epidemiology of Staphylococcus aureus bacteremia, as well as the variables associated with poor outcomes, can yield insight into potential interventions. Methods This study was a retrospective, observational cohort study of adult patients at an academic medical center in New York City who had S. aureus bloodstream infections between 1 January 2007 and 31 December 2015. Participants were divided into 3 periods: group 1 (2007–2009), group 2 (2010–2012), and group 3 (2013–2015) for trend analysis. All clinical strains were genotyped (spa.). The main outcome was 30-day all-cause mortality. Results There were 1264 episodes of methicillin-susceptible S. aureus (MSSA) and 875 episodes of methicillin-resistant S. aureus (MRSA) bacteremia, with a rising proportion due to MSSA (55% group 1; 59% group 2; 63% group 3; P = .03.) There were no significant changes in average age, gender, Charlson score, and distribution of strain genotypes. Mortality in MRSA infection was unchanged (25% group 1; 25% group 2; 26% group 3), while mortality in MSSA infection significantly declined (18% group 1; 18% group 2; 13% group 3). The average time to antistaphylococcal therapy (AST) in MSSA infection declined during the study (3.7 days group 1; 3.5 group 2; 2.2 group 3). In multivariate analysis, AST within 7 days of initial positive MSSA culture was associated with survival. Conclusions Mortality in MSSA bloodstream infection is declining, associated with a decrease in time to targeted therapy. These results emphasize the potential for rapid diagnostics and early optimization of treatment to impact outcomes in MSSA bacteremia.

Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter’s central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy.