The objectivity of Subjective Bayesianism

Abstract

Subjective Bayesianism is a major school of uncertain reasoning and statistical inference. It is often criticized for a lack of objectivity: (i) it opens the door to the influence of values and biases, (ii) evidence judgments can vary substantially between scientists, (iii) it is not suited for informing policy decisions. My paper rebuts these concerns by connecting the debates on scientific objectivity and statistical method. First, I show that the above concerns arise equally for standard frequentist inference with null hypothesis significance tests (NHST). Second, the criticisms are based on specific senses of objectivity with unclear epistemic value. Third, I show that Subjective Bayesianism promotes other, epistemically relevant senses of scientific objectivity—most notably by increasing the transparency of scientific reasoning.

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Influence of reactive oxygen species on de novo acquisition of resistance to bactericidal antibiotics [PublishAheadOfPrint]

The radical-based theory proposes that three major classes of bactericidal antibiotics, beta-lactams, quinolones, and aminoglycosides, have in common the downstream formation of lethal levels of reactive oxygen species (ROS) as part of the killing mechanism. If bactericidal antibiotics exhibit a common mechanism, it is to be expected that the acquisition of resistance against these drugs has some shared traits as well. Indeed, cells made resistant to one bactericidal antibiotic became more rapidly resistant to another. This effect was absent after induced resistance to a bacteriostatic drug. De novo acquisition of resistance to one bactericidal antibiotic provided partial protection to killing by bactericidals from a different class. This protective effect was observed in short-term experiments. No protective effect was detected during 24 hour exposures, suggesting that cross-resistance did not occur. In the wild-type, exposure to bactericidal antibiotics increased intracellular ROS levels. This increase in ROS levels was not observed when strains resistant to these drugs were exposed to the same concentrations. These results indicate that de novo acquisition of resistance against the bactericidal drugs tested involves a common cellular response that provides protection against ROS accumulation upon exposure to this type of antibiotics. Possibly a central mechanism or at least a few common elements within the separate mechanisms play a role during acquisition of antibiotic resistance.

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Novel Ciprofloxacin-Modifying Enzyme (CrpP) Encoded by the Pseudomonas aeruginosa pUM505 Plasmid [PublishAheadOfPrint]

The pUM505 plasmid, isolated from a clinical Pseudomonas aeruginosa isolate, confers resistance to ciprofloxacin (CIP) when transferred into the standard P. aeruginosa PAO1 strain. CIP is an antibiotic of the quinolone family that is used to treat P. aeruginosa infections. In silico analysis, performed to identify CIP-resistance genes, revealed that the 65-amino acid product encoded by the orf131 gene in pUM505 displays 40% amino acid identity to the Mycobacterium smegmatis aminoglycoside phosphotransferase (an enzyme that phosphorylates and inactivates aminoglycoside antibiotics). We cloned orf131 (renamed as crpP for ciprofloxacin-resistance protein plasmid-encoded) into the pUCP20 shuttle vector. The resulting recombinant plasmid, pUC-crpP, conferred resistance to CIP in the Escherichia coli J53-3 strain, suggesting that the product of this gene encodes a protein involved in CIP resistance. Using a coupled enzymatic analysis, we determined that the activity of CrpP on CIP is ATP-dependent, while little activity was detected towards norfloxacin, suggesting that CIP may undergo phosphorylation. Using a recombinant His-tagged CrpP protein and liquid chromatography--tandem mass spectrometry, we also showed that CIP was phosphorylated prior to its degradation. Thus, our findings demonstrate that CrpP, encoded on the pUM505 plasmid, represents a new mechanism of CIP-resistance in P. aeruginosa, which involves phosphorylation of the antibiotic.

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PHARMACOKINETICS OF INTRAVENOUS POSACONAZOLE IN CRITICALLY ILL PATIENTS [PublishAheadOfPrint]

To date, there is no information on the IV posaconazole pharmacokinetics in ICU patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of IV posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if aged ≥ 18 years, central venous access was available, were not pregnant, and didn't receive prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 minutes. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by non-compartmental methods. Eight patients (7 male) were enrolled; median (interquartile range, IQR) age 46 years (40-51), weight 68 kg (65-82) and albumin concentration 20 g/L (18-24). Median (IQR) pharmacokinetic parameter estimates were Cmax, 1,702 ng/mL (1,352-2,141); AUC_0-, 17,932 ng*h/mL (13,823 — 27, 905); CL, 16.8 L/h (11.1-21.7); and Vd, 529.1 L (352.2 — 720.6). The Vd and CL were greater than two fold and AUC_0- was 39% of values reported for heathy volunteers. The AUC_0- was only 52% of the steady-state AUC_0-24 reported for hematology patients. The median of estimated average steady-steady state concentrations was 747 ng/mL (IQR, 576 -1,163), which is within but close to the lower end of previously recommended therapeutic range of 500 to 2,500 ng/mL. In conclusion, we observed different pharmacokinetics of intravenous posaconazole in this cohort of critically ill patients compared to healthy volunteers and hematology patients.

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Determination of the dynamically-linked indices of fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model (HFIM) [PublishAheadOfPrint]

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 the 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 Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened study duration to 24 hours but sampled the system more intensively. Doses and schedules of 12 and 18 g/day and daily, 8 hourly administration and continuous infusion were studied at each daily dose. We measured fosfomycin concentrations (by LC/MS/MS), total bacterial burden and less-susceptible burden. We applied a mathematical model to all the data simultaneously. There was rapid emergence of resistance in all doses and schedules. Prior to the resistance emergence, an initial kill of 2-3 Log₁₀(CFU/ml) was observed. The model demonstrated that AUC/MIC Ratio was linked to total bacterial kill, while Time > MIC (equivalently C_min/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 high bacterial burden infections, 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 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.

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Dextromethorphan Attenuates NADPH Oxidase-regulated GSK-3{beta} and NF-{kappa}B Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection [PublishAheadOfPrint]

Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through a NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47^phox and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression, NO, TNF-α and IL-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-B nuclear translocation, which were also markedly inhibited by treatment with DM and NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to down-regulation of the GSK-3β/NF-B/NO signaling pathway.

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Survival in Patients with Candida glabrata Bloodstream Infections is Associated with Fluconazole Dose [PublishAheadOfPrint]

Robust pharmacodynamic indices that align fluconazole dose or exposure with outcome in invasive candidiasis due to C. glabrata remain elusive. The purpose of this retrospective, multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole using adjusted analyses to identify risk factors for 28-day mortality. No significant correlations were found between fluconazole AUC, AUC:MIC, or MIC and survival. However, on multivariable logistic regression, higher average fluconazole dose (odds ratio (OR) 1.006, 95% confidence interval (CI), 1.001-1.010, p=0.008), average fluconazole dose ≥ 400 mg (OR 3.965, 95% CI 1.509-10.418, p=0.005), and higher fluconazole dose on day 1 of therapy (OR 1.007, 95% CI 1.002-1.011, p=0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for mortality. In conclusion, we found fluconazole dose to be an independent predictor for 28-day survival in patients with C. glabrata fungemia, with doses ≥ 400mg/day associated with 28-day survival approaching 90%. These data inform the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears necessary when using fluconazole for the treatment of C. glabrata fungemia, irrespective of MIC.

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