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.

Activity of temafloxacin and other fluoroquinolones against typical and atypical community-acquired respiratory tract pathogens.

The microbiologic activities of temafloxacin, ciprofloxacin, and ofloxacin against community-acquired respiratory tract pathogens are reviewed. The 90% minimal inhibitory concentrations (MIC90s) of these fluoroquinolones for gram-negative pathogens were generally comparable, that is, less than 0.06 micrograms/mL. Overall, the agents were less active against gram-positive pathogens, although temafloxacin was two- to fourfold more active than the other agents against staphylococci and streptococci. For strains of Mycoplasma pneumoniae and Chlamydia pneumoniae, temafloxacin was generally inhibitory at concentrations of 0.5-2 micrograms/mL. This microbiologic activity, combined with its pharmacokinetic profile, should make temafloxacin a useful antimicrobial agent for treating community-acquired respiratory tract infections.

In vitro activity of temafloxacin against gram-negative bacteria: an overview.

The in vitro activities of temafloxacin, ciprofloxacin, and ofloxacin against gram-negative bacteria are compared. The 90% minimal inhibitory concentrations (MIC90s) of temafloxacin for respiratory pathogens such as Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Bordetella pertussis, and Legionella pneumophila are less than or equal to 0.06 micrograms/mL. Temafloxacin is also active against bacterial agents of sexually transmitted diseases, including Neisseria gonorrhoeae (MIC90 less than or equal to 0.015 micrograms/mL) and Chlamydia trachomatis (MIC90 0.25 micrograms/mL). For strains of Enterobacteriaceae, Campylobacter, Vibrio, Aeromonas, and Acinetobacter, temafloxacin is generally inhibitory at less than or equal to 0.5 micrograms/mL. The MIC90 of temafloxacin for Pseudomonas aeruginosa is higher than that of ciprofloxacin, approximately 4 micrograms/mL versus 0.5 micrograms/mL. This activity, combined with its pharmacokinetic characteristics, should make temafloxacin an effective antimicrobial agent against infections caused by gram-negative bacteria.

Synthesis and antibacterial activities of C-21 functionalized derivatives of (9R)-9-amino-9-deoxoerythromycins A and B.

Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin.

Synthesis, antibacterial activities, and pharmacological properties of enantiomers of temafloxacin hydrochloride.

Temafloxacin hydrochloride [(+/-)-7-(3-methylpiperazin-1-yl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro- 4-oxoquinoline-3-carboxylic acid hydrochloride] is a potent member of the 4-pyridone-3-carboxylic acid class of antibacterial agents and is currently under clinical development as a broad-spectrum antimicrobial agent. It is a racemate having a chiral center at the C3 of the 7-piperazin-1-yl group. The two enantiomers were synthesized and tested for their antibacterial activities. Although no difference in in vitro antibacterial activities was observed, a minor difference in in vivo antibacterial activities was observed. However, they both exhibited similar pharmacological profiles.

Preparation and in vitro and in vivo evaluation of quinolones with selective activity against gram-positive organisms.

A series of quinolones were prepared which contained oximes or substituted oximes as replacements for the amine substituents normally found on the pyrrolidine or piperidine fragments of quinolone antibacterial agents. These substituents led to compounds that had selective activity against Gram-positive organisms. These compounds showed in vivo activity against Staphylococcus aureus. Only compound 29 had in vivo activity against Streptococcus pneumoniae.

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.

Neonatal Trichosporon beigelii infection: report of a cluster of cases in a neonatal intensive care unit.

Trichosporon beigelii, a ubiquitous yeast found in soil, causes superficial dermatologic infections in normal hosts and rare cases of disseminated disease among immunocompromised patients. Neonatal cases are exceptionally rare. We report a cluster of cases of T. beigelii infections in a tertiary care hospital in Rochester, NY, during May to July, 1991. Three cases occurred in very low birth weight premature infants (23 to 25 weeks of gestation), two of whom died. The organism was isolated from urine alone in one case, skin and blood in one case and blood, tracheal aspirate and central venous catheter tip in one case. In a fourth, full term infant with respiratory distress syndrome T. beigelii was grown only from a femoral central venous catheter tip with no clinical evidence of infection. An epidemiologic investigation was performed and the mode of transmission in this outbreak was not identified, although cross-infection was suspected in the initial two cases. Our isolates were inhibited but not killed by usually achievable concentrations of amphotericin B. T. beigelii may cause outbreaks of serious infection in neonatal intensive care units, especially among premature infants.

Total parenteral nutrition-induced changes in gut mucosal function: atrophy alone is not the issue.

BACKGROUND: Total parenteral nutrition (TPN) has been implicated in gut atrophy and breakdown of barrier function leading to bacterial translocation (BT) in animals. BT during TPN, however, is not found consistently, and it has therefore been suggested that macromolecular permeability may occur independently of BT during TPN. METHODS: Male Sprague-Dawley rats were administered isocaloric standard TPN enterally, parenterally, or split equally between the two routes or allowed food ad lib. A second group of rats was administered isocaloric TPN with and without 4% lipids, and changes in gut barrier function were assessed by measuring lactulose permeability. RESULTS: Rats receiving TPN both enterally and parenterally maintained histologic intestinal structure to the same degree as rats fed enterally and those allowed food. Although parenteral feeding led to significant gut atrophy and cecal bacterial overgrowth, BT was not increased. Gut permeability to lactulose, however, was increased significantly in the TPN groups. Lipid content did not affect outcome. CONCLUSIONS: These results suggest that gut atrophy, BT, and permeability to macromolecules are not necessarily related. Gut-origin septic states during TPN or trauma may be caused by an increased escape of macromolecules from the gut, and BT may be an end result rather than a primary cause of such septic episodes.

Pathophysiology of primary meningococcal pericarditis associated with Neisseria meningitidis group C. A case report and review of the literature.

Pericarditis associated with Neisseria meningitidis in the absence of meningitis or meningococcemia is an extremely rare event. We report herein a case of a 59-yr-old woman with primary meningococcal pericarditis caused by Neisseria meningitidis group C. The patient responded to a course of penicillin therapy and recovery was uncomplicated. The pathophysiologic features underlying or contributing to the disease are discussed and the pertinent literature is reviewed.

Clarithromycin, a unique macrolide. A pharmacokinetic, microbiological, and clinical overview.

The in vitro and in vivo spectrum of antibacterial activity of clarithromycin is summarized and related to its human pharmacokinetics. In vitro studies by several investigators have documented clarithromycin's activity against bacterial agents of respiratory tract infections, skin and soft tissue infections, and sexually transmitted diseases. Clinical cure rates of 52%-83% (pneumonia), 79%-96% (bronchitis), 82%-96% (pharyngitis), 58% (sinusitis), and 78% (skin/skin-structure infections) have been reported in patients receiving clarithromycin in comparative trials. Respective bacteriologic eradication rates in clarithromycin recipients have been reported as 57%-89%, 79%-96%, 88%-100%, 89%, and 90%. In vitro and in vivo studies suggest that clarithromycin, when combined with its major human metabolite, 14-hydroxyclarithromycin, is also effective against Haemophilus influenzae. A New Drug Application claiming efficacy in the treatment of lower respiratory tract infection, sinusitis, pharyngitis, and skin and skin-structure infections caused by susceptible pathogens has been filed with the Food and Drug Administration (FDA). This review summarizes relevant pharmacokinetic, microbiological, and clinical data for clarithromycin.

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.

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.

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.

Phenelfamycins, a novel complex of elfamycin-type antibiotics. III. Activity in vitro and in a hamster colitis model.

Phenelfamycins A, B, C, E, F and unphenelfamycin make up a recently isolated group of elfamycin-type antibiotics. All of the phenelfamycins were active against Gram-positive anaerobes, including Clostridium difficile. Phenelfamycin A was also active in vitro against Neisseria gonorrhoeae and Streptococci. Phenelfamycin A was found to be effective in prolonging the survival of hamsters in an animal model of C. difficile enterocolitis. After oral administration of phenelfamycin A to hamsters, antibiotic was detected in the caecal contents but not in the blood.

Altromycins, novel pluramycin-like antibiotics. I. Taxonomy of the producing organism, fermentation and antibacterial activity.

The altromycins are novel anthraquinone-derived antibiotics related to the pluramycins. They are produced by an actinomycete, AB 1246E-26, which was isolated from a South African bushveld soil. The altromycins have Gram-positive antibacterial activity with MICs of 0.2 to 3.12 micrograms/ml against Streptococci and Staphylococci.

Pacidamycins, a novel series of antibiotics with anti-Pseudomonas aeruginosa activity. III. Microbiologic profile.

Pacidamycins are nucleosidyl-peptide antibiotics which have activity only against Pseudomonas aeruginosa. Their MICs for other organisms such as Enterobacteriaceae, Staphylococcus aureus, most Streptococci and other Pseudomonas species are greater than 100 micrograms/ml. These compounds had no activity against erythromycin-susceptible Streptococci. The MICs for Streptococcus pyogenes with constitutive- and inducible-type of macrolide-lincosamide-streptogramin resistance were 12.5 and 25 micrograms/ml, respectively. The MICs against P. aeruginosa ranged from 8 to 64 micrograms/ml. The activity of these compounds was 1 to 2-fold less in serum than broth. Time-kill curves were performed using 4 and 8 times the MIC of pacidamycin 1. It was bactericidal against P. aeruginosa (3 log10 decrease in 4 to 6 hours). At 24 hours, resistant mutants were found in the cultures. The MICs of piperacillin and gentamicin for these mutants were the same as for the parent strain. The frequency of resistance to these compounds was less than 3.5 x 10(-6). The resistant mutants were stable after 10 transfers in antibiotic-free medium. The pacidamycins were inactive against P. aeruginosa in mouse protection test. After a single subcutaneous injection of 25 mg/kg of pacidamycin 1, the Cmax was approximately 50 micrograms/ml and the serum half-life was 0.5 hour.