Multilaboratory Comparison of Omadacycline MIC Test Strip to Broth Microdilution MIC against Gram-Negative, Gram-Positive, and Fastidious Bacteria.

The performance of the Liofilchem omadacycline MIC Test Strip (MTS) was evaluated in a multisite study. Three testing sites collected/tested clinical isolates and one site tested challenge isolates that totaled 175 S. aureus, 70 S. lugdunensis, 121 E. faecalis, 100 E. faecium, 578 Enterobacterales, 142 Haemophilus spp., 181 S. pneumoniae, 45 S. anginosus group, 35 S. pyogenes,and 20 S. agalactiae. MIC testing was performed by CLSI broth microdilution (BMD) and MTS. Fastidious isolates testing included BMD and MTS testing with both CLSI and EUCAST Mueller-Hinton Fastidious (MH-F). In addition, each site performed reproducibility for nonfastidious and fastidious isolates and QC by MTS and BMD. All BMD and MTS results for the QC strains were within expected ranges, with exception of one MTS HTM result for H. influenzae ATCC 49247. Among reproducibility isolates, omadacycline MTS results were within one dilution of the modal MIC for 95.2% of nonfastidious Gram-positive, 100% of Gram-negative, 99.3% and 98.5% of fastidious isolates tested on CLSI and EUCAST media, respectively. MTS results for all study isolates were within one doubling dilution of the CLSI BMD MIC for 98.9% of S. aureus, 100% of S. lugdunensis, 98.3% of E. faecalis, 100% of E. faecium, and 99.6% of Enterobacterales. Essential agreement rates for CLSI and EUCAST MH-F agar compared to CLSI BMD were 98.2% and 98.2%, for H. influenzae, 91.1% and 73.6%, for S. pneumoniae and 100% and 85-91.7% for other streptococcus species, respectively. Based on CLSI media, all categorical errors were minor errors and categorical agreement rates were >90% with exception of C. freundii, S. lugdunensis, E. faecalis, S. anginosus and S. constellatus.

Multilab evaluation of delafloxacin MIC Test Strip against Gram-negative and Gram-positive organisms.

The performance of the delafloxacin MIC Test Strip (MTS) was evaluated. Three testing sites collected/tested clinical isolates, and 1 site tested challenge isolates that together total 224 S. aureus, 36 S. haemolyticus, 23 S. lugdunensis, 105 E. faecalis, 308 Enterobacteriales, and 140 P. aeruginosa. MIC testing was performed by broth microdilution (BMD) and MTS. Each site also tested 20 common isolates in triplicate on 3 days by MTS and 20 replicates of 4 QC strains by MTS and BMD. MTS results for consolidated clinical/challenge isolates were within 1 doubling dilution of the BMD MIC for 96.9% of S. aureus; 100% of S. haemolyticus, S. lugdunensis, and E. faecalis; 98.4% of Enterobacteriales; and 97.9% of P. aeruginosa. All reproducibility results were within 1 dilution of the modal MIC. All BMD and MTS results for the QC strains were within expected ranges. Overall, the delafloxacin MTS performed similar to BMD.

Scalable Molecular Dynamics with NAMD on the Summit System.

NAMD (NAnoscale Molecular Dynamics) is a parallel molecular dynamics application that has been used to make breakthroughs in understanding the structure and dynamics of large biomolecular complexes, such as viruses like HIV and various types of influenza. State-of-the-art biomolecular simulations often require integration of billions of timesteps, computing all interatomic forces for each femtosecond timestep. Molecular dynamics simulation of large biomolecular systems and long-timescale biological phenomena requires tremendous computing power. NAMD harnesses the power of thousands of heterogeneous processors to meet this demand. In this paper, we present algorithm improvements and performance optimizations that enable NAMD to achieve high performance on the IBM Newell platform (with POWER9 processors and NVIDIA Volta V100 GPUs) which underpins the Oak Ridge National Laboratory's Summit and Lawrence Livermore National Laboratory's Sierra supercomputers. The Top-500 supercomputers June 2018 list shows Summit at the number one spot with 187 Petaflop/s peak performance and Sierra third with 119 Petaflop/s. Optimizations for NAMD on Summit include: data layout changes for GPU acceleration and CPU vectorization, improving GPU offload efficiency, increasing performance with PAMI support in Charm++, improving efficiency of FFT calculations, improving load balancing, enabling better CPU vectorization and cache performance, and providing an alternative thermostat through stochastic velocity rescaling. We also present performance scaling results on early Newell systems.

Medication adherence among HIV+ adults: effects of cognitive dysfunction and regimen complexity.

BACKGROUND: Although the use of highly active antiretroviral therapy in the treatment of HIV infection has led to considerable improvement in morbidity and mortality, unless patients are adherent to their drug regimen (i.e., at least 90 to 95% of doses taken), viral replication may ensue and drug-resistant strains of the virus may emerge. METHODS: The authors studied the extent to which neuropsychological compromise and medication regimen complexity are predictive of poor adherence in a convenience sample of 137 HIV-infected adults. Medication adherence was tracked through the use of electronic monitoring technology (MEMS caps). RESULTS: Two-way analysis of variance revealed that neurocognitive compromise as well as complex medication regimens were associated with significantly lower adherence rates. Cognitively compromised participants on more complex regimens had the greatest difficulty with adherence. Deficits in executive function, memory, and attention were associated with poor adherence. Logistic regression analysis demonstrated that neuropsychological compromise was associated with a 2.3 times greater risk of adherence failure. Older age (>50 years) was also found to be associated with significantly better adherence. CONCLUSIONS: HIV-infected adults with significant neurocognitive compromise are at risk for poor medication adherence, particularly if they have been prescribed a complex dosing regimen. As such, simpler dosing schedules for more cognitively impaired patients might improve adherence.

Methylphenidate improves HIV-1-associated cognitive slowing.

Sixteen HIV-1 seropositive individuals participated in a single-blind, placebo-controlled, crossover-design study of the effectiveness of 30 mg/ day of methylphenidate (MPH) in the treatment of HIV-associated cognitive slowing. Regression analyses revealed that participants who entered the study with a greater degree of either depressive symptomatology or cognitive slowing tended to demonstrate a better response to MPH on computerized measures of choice and dual-task reaction time. Participants without evidence of cognitive slowing at study entry did not show greater improvement on MPH than on placebo. Contrary to expectation, symptoms of depression did not respond better to MPH than to placebo, regardless of initial symptomatology. Information processing slowing in HIV-1 infection therefore appears amenable to pharmacologic intervention with the dopamine agonist MPH. However, results suggest clinicians should consider reserving the use of MPH for patients with more pronounced cognitive and affective deficits.

Dual task performance in HIV-1 infection.

Fifty HIV-infected individuals and 20 uninfected controls participated in an investigation of dual task performance in HIV-1 infection. Participants first engaged in a simple auditory reaction time (RT) task followed by a visual choice RT task (single task condition), and then they simultaneously engaged in both tasks (dual task condition). Under single task conditions, the HIV+ participants did not significantly differ from controls on either simple or choice RT (though a trend was evident on single task choice RT). In contrast, under dual task conditions the HIV+ group's performance decrement, relative to controls, was significantly greater on both simple and choice RT. This dual task decrement was also significantly associated with slower performance on the interference condition of the Stroop. Patients with AIDS tended to have greater dual task decrements than did the pre-AIDS group, though this fell short of statistical significance. These results suggest that HIV-1 infection leads to deficits in divided attention and the simultaneous processing of competing stimuli, deficits which have been linked to disruption of the anterior attentional system.

Microbial resistance: novel screens for a contemporary problem.

Historically, natural products have been the source of a large variety of antibacterial agents. In the 1980s, no additional useful antibacterial agents were discovered, leading to the belief that most useful chemotypes from natural product sources had already been discovered. At this time, advances in biotechnology made it feasible to produce sufficient enzyme to set up cell-free screens. Chemical compound libraries and combinatorial synthesis became the source of chemical diversity for the screens. In spite of these efforts, very few new antibacterial agents have been discovered in the last decade. At Small Molecule Therapeutics, Inc., we have developed phenotype-based screens that take advantage of the natural physiology and biochemistry of the target enzymes. We have developed a screen to identify bacterial DNA gyrase and topoisomerase IV poisons. The "hits" identified in this screen are being characterized further. A second screen has also been developed against bacterial topoisomerase 1 in which compounds that cause DNA damage through their interaction with bacterial topoisomerase 1 have been identified. Three of the compounds identified in the screen inhibit DNA relaxation mediated by bacterial topoisomerase 1, induce DNA cleavage, are noncytotoxic at >10 microM, and have MICs of 4.0 microg/mL against Staphylococcus aureus.

Computerized and traditional stroop task dysfunction in HIV-1 infection.

Controlled processing, response inhibition, and set adoption were examined in 51 HIV-1 infected participants and 21 uninfected controls who were administered a vocal reaction time (RT) version of the Stroop task (Stroop-RT; J. R. Stroop, 1935) as well as the traditional 100 item paper-and-pencil version. Response set expectancies on the Stroop-RT were manipulated by presenting 50% of trials in homogenous blocks and randomly varying the stimulus type during the remaining trials. As hypothesized, HIV seropositive (HIV+) participants were significantly slower than HIV seronegative controls on both versions of the Stroop. Significant interference effects were apparent on the paper-and-pencil version of the Stroop, but were not as prominent on the Stroop-RT. The HIV+ participants did profit from the blocking manipulation on the Stroop-RT, suggesting that set adoption is retained in HIV infection. These data suggest that HIV infection may result in deficient response inhibition, possibly secondary to frontostriatal dysfunction and dopaminergic alterations.

Methods of measuring susceptibility of anaerobic bacteria to trovafloxacin, including quality control parameters.

Three methods approved by the National Committee for Clinical Laboratory Standards for testing the susceptibility of anaerobic bacteria were used to evaluate the fluoroquinolone, trovafloxacin. The methods gave essentially comparable results with 126 anaerobes and with three quality control strains. A collaborative study defined the quality control range for trovafloxacin MICs. Trovafloxacin had good in vitro activity against the more common anaerobes (MIC 90 < = or 2.0 micrograms/ml).

Low-dose enteral feeding is beneficial during total parenteral nutrition.

BACKGROUND: Enteral support is the preferred feeding route for stressed patients due in part to the provision of gut-specific fuels. In those patients who must be maintained parenterally, small amounts of enteral stimulation might blunt gut atrophy and lead to improvement in host defense mechanisms decreasing macromolecular and/or bacterial translocation (BT). METHODS: Forty-eight rats were infused with TPN for 9 days, and were randomized to receive 0%, 6%, 12%, or 25% of their calories as partial enteral nutrition (PEN) in an isocaloric, isonitrogenous fashion. Twenty-four hours before harvest animals were gavaged with lactulose and urinary excretion quantified. At harvest, mesenteric lymph nodes were cultured to assess BT and intestinal histology determined. RESULTS: Provision of as little as 25% of total calories PEN improved nitrogen balance and reduced BT, in a dose dependent fashion. It did not alter TPN-associated increased macromolecular lactulose permeability (4.4% +/- 1.0%). CONCLUSION: Concurrent small amounts of PEN, aimed to support the gut's metabolic needs, are beneficial during periods of prolonged TPN.

Neisseria elongata subsp. elongata, a case of human endocarditis complicated by pseudoaneurysm.

We report an unusual case of endocarditis caused by Neisseria elongata subsp. elongata. The illness was complicated by a ruptured mycotic aneurysm of the right brachial artery, with compression of the brachial plexus. A cure was achieved after aneurysm resection and treatment with intravenous ceftriaxone and gentamicin.

Selective utilization of DNA probes for identification of Mycobacterium species on the basis of cord formation in primary BACTEC 12B cultures.

Primary BACTEC 12B cultures with serpentine cords observed in Kinyoun-stained smears were tested with a probe for Mycobacterium tuberculosis complex, while cultures without cords were tested with a probe for M. avium complex. The sensitivity, specificity, and positive and negative predictive values of cording for the presumptive identification of M. tuberculosis were 95, 95, 90, and 98%, respectively. With experience, the selection of a probe for testing of primary BACTEC 12B cultures on the basis of cord formation and history of tuberculosis can provide a rapid and reliable approach to the laboratory diagnosis of tuberculosis.

Liver abscess in Crohn's disease.

Liver abscess is a rare but serious complication of Crohn's disease. Intra-abdominal abscesses, fistulous disease, and metronidazole or steroid therapy have all been reported to be important predisposing factors in the pathogenesis of the disease, and the mortality has been reported to be high. We report six patients who developed a liver abscess as a complication of Crohn's disease. Three patients presented with a liver abscess as the first manifestation of Crohn's disease and two others had quiescent disease at presentation. The diagnosis was delayed by 1-8 wk after the onset of fever because of the paucity of signs indicating a hepatic infection. None of the patients had intra-abdominal abscesses, active fistulas, or metronidazole therapy before the onset of symptoms. The only predisposing conditions identified were two minor skin infections in patients developing staphylococcal liver abscesses. Nonoperative catheter drainage was successful in four of the six patients. One patient required surgical placement of drains, and the patient with the longest delay before diagnosis required hepatic lobectomy because of extensive necrosis. Shaking chills, fever with leukocytosis, and an elevated alkaline phosphatase are suggestive of a liver abscess and should prompt an ultrasound examination. Catheter drainage with antibiotic therapy is effective if the liver abscess is diagnosed before extensive necrosis has occurred. Minor skin infections may predispose to staphylococcal liver abscess in some cases.

In-vitro activity of five beta-lactam/beta-lactamase inhibitor combinations against consecutive isolates of the Enterobacteriaceae and Pseudomonas aeruginosa.

Susceptibility tests were performed on 2402 of consecutive isolates of Enterobacteriaceae and 254 strains of Pseudomonas aeruginosa in five separate medical centres. Five beta-lactams were evaluated with and without a beta-lactamase inhibitor. The effect of different inhibitors was species specific and the rank order of decreasing efficacy against all enteric bacilli was: cefoperazone-sulbactam > piperacillin-tazobactam > cefoperazone > ticarcillin-clavulanic acid > piperacillin > co-amoxiclav > ampicillin-sulbactam > ticarcillin > ampicillin > amoxycillin.

Extent and spectrum of the antimicrobial activity of clarithromycin.

Clarithromycin, a new semisynthetic macrolide, is lipophilic and achieves concentrations in tissue that are generally 10 times greater than concentrations achieved in serum. Its binding to serum proteins is low and reversible. Clarithromycin has in vitro and in vivo activity against a variety of Gram-positive and Gram-negative bacteria, Mycoplasma, Chlamydia and mycobacteria. 14-Hydroxyclarithromycin, the major metabolite of clarithromycin in humans, is generally as active as clarithromycin against these organisms but is more active in vitro and in vivo than clarithromycin against Haemophilus influenzae. Organisms resistant to erythromycin by plasmid or transposon-encoded methylase, macrolide-lincosamide-streptogramin resistance, are also resistant to clarithromycin. Unlike older macrolides, however, clarithromycin has in vitro and in vivo activity against atypical mycobacteria. The antimicrobial activities of clarithromycin and 14-hydroxyclarithromycin are reviewed in this article.

Tentative criteria for confirming the in vitro susceptibilities of Haemophilus influenzae and Neisseria gonorrhoeae to two fluoroquinolones (sparfloxacin and levofloxacin), including quality control parameters.

Sparfloxacin and levofloxacin were evaluated against 150 Haemophilus influenzae isolates and 149 Neisseria gonorrhoeae isolates in order to define susceptibility testing parameters. Sparfloxacin-susceptible H. influenzae strains were defined as those for which the MICs were < or = 0.25 microgram/ml and the zones were > or = 30 mm, and N. gonorrhoeae susceptible strains were those for which the MICs were < or = 0.03 microgram/ml and the zones were > or = 39 mm (5-micrograms disks). Levofloxacin-susceptible strains of H. influenzae included those for which the MICs were < or = 0.12 microgram/ml and the zones were > or = 32 mm and N. gonorrhoeae susceptible strains were those for which the MICs were < or = 0.12 microgram/ml and the zones were > or = 37 mm (5-micrograms disks). Criteria for a resistant category cannot yet be defined for either quinolone. In multilaboratory studies with different lots of Haemophilus Test Medium, replicate tests with the standard control strain of H. influenzae (ATCC 49247) were evaluated. For sparfloxacin disk tests, the proposed zone size limits were 33 to 42 mm and broth microdilution MIC limits were 0.004 to 0.016 microgram/ml, whereas for levofloxacin tests, zone size limits were 32 to 41 mm and broth microdilution MIC limits were 0.008 to 0.03 microgram/ml. Other multilaboratory studies evaluated tests with supplemented GC agar and N. gonorrhoeae ATCC 49226; for both drugs, zone size limits were 44 to 52 mm and agar dilution MIC limits were 0.004 to 0.016 microgram/ml.

In vitro activity of ampicillin, amoxicillin, ampicillin-sulbactam, and amoxicillin-clavulanic acid against consecutive clinical isolates of Enterobacteriaceae.

Ampicillin was generally twice as active as amoxicillin against 2440 consecutive isolates of Enterobacteriaceae from five medical centers. When beta-lactamase inhibitors were added to the penicillins, there was a significant increase in susceptibility. The magnitude of the increased susceptibility to ampicillin-sulbactam (A-S) and amoxicillin-clavulanic (A-C) acid varied with the species and types of beta-lactamases elaborated. Although cross-susceptibility and cross-resistance between ampicillin and amoxicillin was nearly complete, major differences were documented between A-S and A-C with 6.7% of our consecutive isolates of Enterobacteriaceae. The clinical significance of these findings remains uncertain, but they may help explain some of the discrepancies occasionally observed by clinical microbiologists with the combination drugs.

Interpretive criteria and quality control parameters for determining bacterial susceptibility to fosfomycin tromethamine.

Studies with fosfomycin tromethamine disks containing 200 micrograms of fosfomycin and 50 micrograms of glucose-6-phosphate confirmed the following zone diameter criteria for the NCCLS method: < or = 12 mm for resistant (MIC > or = 256 micrograms/ml), 13-15 mm for intermediate (MIC 128 micrograms/ml) and > or = 16 mm for susceptible (MIC < or = 64 micrograms/ml). Additional studies defined acceptable MIC and zone diameter ranges for the following quality control strains: Escherichia coli ATCC 25922, MIC 0.5 to 4.0 micrograms/ml, zone diameter 23 to 29 mm; Staphylococcus aureus ATCC 25923, zone diameter 26 to 32 mm; Pseudomonas aeruginosa ATCC 27813, MIC 2.0 to 8.0 micrograms/ml; and Enterococcus faecalis, ATCC 29212, MIC 16 to 64 micrograms/ml.