Polymyxin B Pharmacodynamics in the Hollow-Fiber Infection Model: What You See May Not Be What You Get.

Dose range studies for polymyxin B (PMB) regimens of 0.75 to 12 mg/kg given every 12 h (q12h) were evaluated for bacterial killing and resistance prevention against an AmpC-overexpressing Pseudomonas aeruginosa and a blaKPC-3-harboring Klebsiella pneumoniae in 10-day in vitro hollow-fiber models. An exposure-response was observed. But all regimens failed due to regrowth. Lower-dose regimens amplified isolates that expressed transient, lower-level adaptive resistance to PMB (MICs ≤ 4 mg/liter). Higher PMB dosages amplified isolates that expressed this resistance mechanism, a higher-MIC "moderately stable" adaptive resistance, and a higher-MIC stable resistance to PMB. Failure of the highest dose regimens was solely due to subpopulations that expressed the two higher-level resistances. Total and bioactive PMB concentrations in broth declined below targeted PK profiles within hours of treatment initiation and prior to bacterial regrowth. With treatment failure, the total PMB measured in bacteria was substantially higher than in broth. But the bioactive PMB in broth and bacteria were low to nondetectable. Together, these findings suggest a sequence of events for treatment failure of the clinical regimen. First, PMB concentrations in broth are diluted as PMB binds to bacteria, resulting in total and bioactive PMB in broth that is lower than targeted. Bacterial regrowth and treatment failure follow, with emergence of subpopulations that express transient lower-level adaptive resistance to PMB and possibly higher-level adaptive and stable resistances. Higher-dose PMB regimens can prevent the emergence of transient lower-level adaptive resistance, but they do not prevent treatment failure due to isolates that express higher-level resistance mechanisms.

Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model.

Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log10(CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae (in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model.

Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log10 CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study.

Activity of Moxifloxacin against Mycobacterium tuberculosis in Acid Phase and Nonreplicative-Persister Phenotype Phase in a Hollow-Fiber Infection Model.

A major goal for improving tuberculosis therapy is to identify drug regimens with improved efficacy and shorter treatment durations. Shorter therapies improve patient adherence to the antibiotic regimens, which, in turn, decreases resistance emergence. Mycobacterium tuberculosis exists in multiple metabolic states. At the initiation of therapy, the bulk of the population is in log-phase growth. Consequently, it is logical to focus initial therapy on those organisms. Moxifloxacin has good early bactericidal activity against log-phase bacteria and is a logical component of initial therapy. It would be optimal if this agent also possessed activity against acid-phase and nonreplicative-persister (NRP) phenotype organisms. In our hollow-fiber infection model, we studied multiple exposures to moxifloxacin (equivalent to 200 mg to 800 mg daily) against strain H37Rv in the acid phase and against strain 18b in streptomycin starvation, which is a model for NRP-phase organisms. Moxifloxacin possesses good activity against acid-phase organisms, generating cell killing of 3.75 log10(CFU/ml) (200 mg daily) to 5.16 log10(CFU/ml) (800 mg daily) over the 28 days of the experiment. Moxifloxacin also has activity against streptomycin-starved strain 18b. The 400- to 800-mg daily regimens achieved extinction at day 28, while the no-treatment control still had 1.96 log10(CFU/ml) culturable. The lowest dose (200 mg daily) still had 0.7 log10(CFU/ml) measurable at day 28, a net kill of 1.26 log10(CFU/ml). Moxifloxacin is an attractive agent for early therapy, because it possesses activity against three metabolic states of M. tuberculosis.

Linezolid Kills Acid-Phase and Nonreplicative-Persister-Phase Mycobacterium tuberculosis in a Hollow-Fiber Infection Model.

The therapy for treatment of Mycobacterium tuberculosis infections is long and arduous. It has been hypothesized that the therapy duration is driven primarily by populations of organisms in different metabolic states that replicate slowly or not at all (acid-phase and nonreplicative-persister [NRP]-phase organisms). Linezolid is an oxazolidinone antimicrobial with substantial activity against Log-phase M. tuberculosis Here, we examined organisms in acid-phase growth and nonreplicative-persister-phenotype growth and determined the effect of differing clinically relevant exposures to linezolid in a hollow-fiber infection model (HFIM). The endpoints measured were bacterial kill over 29 days and whether organisms that were less susceptible to linezolid could be recovered during that period. In addition, we evaluated the effect of administration schedule on linezolid activity, contrasting daily administration with administration of twice the daily dose every other day. Linezolid demonstrated robust activity when administered daily against both acid-phase and NRP-phase organisms. We demonstrated a clear dose response, with 900 mg of linezolid daily generating ≥3 Log(CFU/ml) killing of acid-phase and NRP-phase M. tuberculosis over 29 days. Amplification of a population less susceptible to linezolid was not seen. Activity was reduced with every 48-h dosing, indicating that the minimum concentration (Cmin)/MIC ratio drove the microbiological effect. We conclude that once-daily linezolid dosing has substantial activity against M. tuberculosis in acid-phase and NRP-phase metabolic states. Other studies have shown activity against Log-phase M. tuberculosis Linezolid is a valuable addition to the therapeutic armamentarium for M. tuberculosis and has the potential for substantially shortening therapy duration.

Topology and Morphology Design of Spherically Reconfigurable Homogeneous Modular Soft Robots.

Imagine a swarm of terrestrial robots that can explore an environment, and, on completion of this task, reconfigure into a spherical ball and roll out. This dimensional change alters the dynamics of locomotion and can assist them in maneuvering variable terrains. The sphere-plane reconfiguration is equivalent to projecting a spherical shell onto a plane, an operation that is not possible without distortions. Fortunately, soft materials have the potential to adapt to this disparity of the Gaussian curvatures. Modular Soft Robots (MSoRos) have promise of achieving dimensional change by exploiting their continuum and deformable nature. However, the design of such soft robots has remained unexplored thus far. Here, for the first time, we present the topology and morphology design of MSoRos that are capable of reconfiguring between spherical and planar configurations. Our approach is based in geometry, where a platonic solid determines the number of modules required for plane-to-sphere reconfiguration and the radius of the resulting sphere, for example, four "tetrahedron-based" or six "cube-based" MSoRos are required for spherical reconfiguration. The methodology involves: (1) inverse orthographic projection of a "module-topology curve" onto the circumscribing sphere to generate the spherical topology; (2) azimuthal projection of the spherical topology onto a tangent plane at the center of the module resulting in the planar topology; and (3) adjusting the limb stiffness and curling ability by manipulating the geometry of cavities to realize a physical finite-width, Motor-Tendon Actuated MSoRo that can actuate between the sphere-plane configurations. The topology design is shown to be scale invariant, that is, the scaling of base platonic solid is reflected linearly in spherical and planar topologies. The module-topology curve is optimized for the reconfiguration and locomotion ability using an intramodular distortion metric that quantifies sphere-to-plane distortion. The geometry of the cavity optimizes for the limb stiffness and curling ability without compromising the actuator's structural integrity.

Return to Sport After Bone-Patellar Tendon-Bone Autograft ACL Reconstruction in High School-Aged Athletes.

BACKGROUND: Anterior cruciate ligament (ACL) injuries are occurring with increasing frequency in the adolescent population. Outcomes after ACL reconstruction (ACLR) are inconsistently reported in homogeneous patient populations. PURPOSE/HYPOTHESIS: To evaluate outcomes after bone-patellar tendon-bone (BTB) autograft ACLR in competitive high school-aged athletes by examining return to sport (RTS), patient satisfaction, and reinjury rates. Our hypothesis was that RTS rates and satisfaction will be high and reinjury rates will be low. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: An institutional ACL registry was utilized to identify competitive high school-aged athletes (14-18 years old) who underwent primary ACLR using BTB autograft with a minimum 2-year follow-up. A postoperative questionnaire was administered to determine rates and types of RTS, quality of sports performance, reinjury, and satisfaction. Uni- and multivariable analyses were used to identify demographic, sport-specific, and clinical factors related to RTS. RESULTS: A total of 53 patients were included (mean ± SD age at the time of surgery, 16.6 ± 1.34 years). Mean follow-up was 3.78 ± 0.70 years (range, 2.60-4.94 years). The overall ipsilateral ACL retear rate was 7.5% (n = 4). There were 10 subsequent ACL tears to the contralateral knee (19%). Forty-four (83%) patients successfully returned to at least their prior level of sport at a mean 10.5 ± 8.7 months (range, 3-48 months). Overall satisfaction was high, with 91% of patients very satisfied with the outcome. Higher confidence levels regarding performance of the reconstructed knee were associated with increased probability of RTS on multivariate analysis. CONCLUSION: BTB autograft ACLR results in high rates of RTS and satisfaction and low rates of subsequent ipsilateral ACL injuries in competitive high school-aged athletes. Patients with higher confidence in performance of the reconstructed knee are more likely to return to at least their prior level of sport.

Application of Machine Learning Algorithms to Predict Clinically Meaningful Improvement After Arthroscopic Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Understanding specific risk profiles for each patient and their propensity to experience clinically meaningful improvement after anterior cruciate ligament reconstruction (ACLR) is important for preoperative patient counseling and management of expectations. PURPOSE: To develop machine learning algorithms to predict achievement of the minimal clinically important difference (MCID) on the International Knee Documentation Committee (IKDC) score at a minimum 2-year follow-up after ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: An ACLR registry of patients from 27 fellowship-trained sports medicine surgeons at a large academic institution was retrospectively analyzed. Thirty-six variables were tested for predictive value. The study population was randomly partitioned into training and independent testing sets using a 70:30 split. Six machine learning algorithms (stochastic gradient boosting, random forest, neural network, support vector machine, adaptive gradient boosting, and elastic-net penalized logistic regression [ENPLR]) were trained using 10-fold cross-validation 3 times and internally validated on the independent set of patients. Algorithm performance was assessed using discrimination, calibration, Brier score, and decision-curve analysis. RESULTS: A total of 442 patients, of whom 39 (8.8%) did not achieve the MCID, were included. The 5 most predictive features of achieving the MCID were body mass index ≤27.4, grade 0 medial collateral ligament examination (compared with other grades), intratunnel femoral tunnel fixation (compared with suspensory), no history of previous contralateral knee surgery, and achieving full knee extension preoperatively. The ENPLR algorithm had the best relative performance (C-statistic, 0.82; calibration intercept, 0.10; calibration slope, 1.15; Brier score, 0.068), demonstrating excellent predictive ability in the study's data set. CONCLUSION: Machine learning, specifically the ENPLR algorithm, demonstrated good performance for predicting a patient's propensity to achieve the MCID for the IKDC score after ACLR based on preoperative and intraoperative factors. The femoral tunnel fixation method was the only significant intraoperative variable. Range of motion and medial collateral ligament integrity were found to be important physical examination parameters. Increased body mass index and prior contralateral surgery were also significantly predictive of outcome.

Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation.

INTRODUCTION: There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance. METHODS: Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment. Doses that achieved maximum bacterial kill while suppressing the emergence of drug resistance were determined. Through Monte Carlo simulations the quantitative output of this in vitro study was bridged to the human patient population to inform optimal dosage regimens while accounting for clinical minimum inhibitory concentration (MIC) distributions. RESULTS AND DISCUSSION: Moxifloxacin activity was significantly decreased in an acidified environment. The loss of activity was compensated by accumulation of the drug in TB lung lesions; therefore, moderate efficacy can be expected. Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. Linezolid demonstrated very good activity even at a reduced pH. Linezolid 900 mg once-daily (QD) is likely to achieve a maximum killing effect and prevent the emergence of drug resistance; 600 mg QD in a robust drug regimen may have similar potential.

Emotional intelligence and perceived employability for internship curriculum.

Emotional Intelligence dimensions of motivation as well as social and communication skills were associated with perceived entry-level employability. Feedback from internship hosts was the measure of association for 77 college juniors or seniors between the ages of 18 and 22 (49 women, 28 men), enrolled in a one-semester communications internship. Chi squared supported the hypothesis that interns scoring high on emotional intelligence are more likely to be considered for employment by the internship host than those scoring low. Given replication of this work applications for an internship curriculum can be identified.

A comprehensive faculty, staff, and student training program enhances student perceptions of a course-based research experience at a two-year institution.

Early research experiences must be made available to all undergraduate students, including those at 2-yr institutions who account for nearly half of America's college students. We report on barriers unique to 2-yr institutions that preclude the success of an early course-based undergraduate research experience (CURE). Using a randomized study design, we evaluated a CURE in equivalent introductory biology courses at a 4-yr institution and a 2-yr institution within the same geographic region. We found that these student populations developed dramatically different impressions of the experience. Students at the 4-yr institution enjoyed the CURE significantly more than the traditional labs. However, students at the 2-yr institution enjoyed the traditional labs significantly more, even though the CURE successfully produced targeted learning gains. On the basis of course evaluations, we enhanced instructor, student, and support staff training and reevaluated this CURE at a different campus of the same 2-yr institution. This time, the students reported that they enjoyed the research experience significantly more than the traditional labs. We conclude that early research experiences can succeed at 2-yr institutions, provided that a comprehensive implementation strategy targeting instructor, student, and support staff training is in place.