scholarly journals Combination of Mycobacterium tuberculosis RS ratio and CFU improves the ability of murine efficacy experiments to distinguish between drug treatments

2021 ◽  
Author(s):  
Christian Dide-Agossou ◽  
Allison A. Bauman ◽  
Michelle E Ramey ◽  
Karen Rossmassler ◽  
Reem Al Mubarak ◽  
...  
Keyword(s):  
Rank Order ◽  
Physiological State ◽  
Drug Efficacy ◽  
New Combination ◽  
Bacterial Burden ◽  
Biological Responses ◽  
Accelerate Development ◽  
Colony Forming Units ◽  
Single Marker ◽  
Pharmacodynamic Markers

Murine tuberculosis drug efficacy studies have historically monitored bacterial burden based on colony forming units of M. tuberculosis in lung homogenate. In an alternative approach, a recently described molecular pharmacodynamic marker called the RS ratio quantifies drug effect on a fundamental cellular process: ongoing ribosomal RNA synthesis. Here we evaluated the ability of different pharmacodynamic markers to distinguish between treatments in three BALB/c mouse experiments at two institutions. We confirmed that different pharmacodynamic markers measure distinct biological responses. We found that a combination of pharmacodynamic markers distinguishes between treatments better than any single marker. The combination of the RS ratio with colony forming units showed the greatest ability to recapitulate the rank order of regimen treatment-shortening activity, providing proof of concept that simultaneous assessment of pharmacodynamic markers measuring different properties will enhance insight gained from animal models and accelerate development of new combination regimens. These results suggest potential for a new era in which antimicrobial therapies are evaluated not only on culture-based measures of bacterial burden but also on molecular assays that indicate how drugs impact the physiological state of the pathogen.

scholarly journals No-Touch Automated Room Disinfection after Autopsies of Exhumed Corpses

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 648
Author(s):  
Patryk Tarka ◽  
Aleksandra Borowska-Solonynko ◽  
Małgorzata Brzozowska ◽  
Aneta Nitsch-Osuch ◽  
Krzysztof Kanecki ◽  
...  
Keyword(s):  
Forensic Pathology ◽  
Bacterial Burden ◽  
Fungal Burden ◽  
Colony Forming Units ◽  
Before And After ◽  
Life Threatening ◽  
Environmental Bacteria ◽  
The Mean

Autopsies of exhumed bodies pose a risk of infections with environmental bacteria or fungi, which may be life-threatening. Thus, it is important to use effective methods of disinfection in forensic pathology facilities. In this study, we investigated the effectiveness of no-touch automated disinfection (NTD) system after autopsies of exhumed bodies. Directly after 11 autopsies of exhumed bodies, we used an NTD system based on a peroxone vapor to disinfect the air and surfaces. We measured microbial burden in the air and on surfaces before and after NTD. The NTD system reduced the mean bacterial burden in the air from 171 colony forming units (CFU)/m3 to 3CFU/m3. The mean fungal burden in the air decreased from 221 CFU/m3 to 9CFU/m3. The mean all-surface microbial burden was 79 CFU/100 cm2 after all autopsies, and it decreased to 2 CFU/100 cm2 after NTD. In conclusion, the peroxone-based NTD system was effective for decontamination of the air and surfaces in a dissecting room after autopsies of exhumed bodies.

Kinetics of vasoconstrictor action of endothelins

1991 ◽  
Vol 261 (6) ◽  
pp. C986-C993 ◽  
Author(s):  
Robert Marsault ◽  
Paul Vigne ◽  
Jean Philippe Breittmayer ◽  
Christian Frelin
Keyword(s):  
Angiotensin Ii ◽  
Slow Rate ◽  
Rank Order ◽  
Site Occupancy ◽  
Receptor Subtype ◽  
Tension Development ◽  
Biological Responses ◽  
Slow Development ◽  
Nonequilibrium Conditions ◽  
Subtype A

Endothelin peptides (Et) induce slowly developing and long-lasting contractions of rat aortic strips with a rank order of potency (Et-1 = Et-2 > sarafotoxin S6b > Et-3) consistent with the involvement of an EtA-like receptor subtype. A similar profile of action is observed for Et-induced intracellular [Ca2+]i mobilization in cultured aortic myocytes. Modeling the association of Et-1 to its receptor shows that, at concentrations which produce large increases in tension, Et-1 associates rapidly to its receptors and that a slow rate of association is not responsible for the slow rate of tension development. Action of endothelins on [ Ca2+]i was studied using isolated cultured aortic myocytes and compared with that of angiotensin II and vasopressin. Results show that three vasoconstrictors produce similar and rapid changes in [Ca2+]i. The rate-limiting step for the contractile action of Et is a postreceptor event probably distal to early changes in [Ca2+]i. Biological responses to Et are usually characterized by a relative insensitivity to the peptide as compared with & values determined in binding experiments. Data presented show that insensitivity of the early [Ca2+]i responses to Et could be accounted for by the fact that the responses develop under nonequilibrium conditions. Tension amplitude seems also to be determined by nonequilibrium binding conditions. It correlates with the fraction of the Et-1 binding sites occupied 20 s after addition of the peptide and not to the fractional site occupancy at the time of maximum tension development. In conclusion, kinetic parameters of the interaction of Et with their receptors do not determine the slow development of the contractile responses. They may, however, be responsible for the relative insensitivity of the biological responses to Et. angiotensin II; flow cytometry; intracellular calcium; kinetic model; vasopressin Submitted on October 25, 1990 Accepted on June 14, 1991

scholarly journals A decade of toxicological trends: what the papers say

2020 ◽  
Vol 9 (5) ◽  
pp. 676-682
Author(s):  
Phumzile Sikakana ◽  
Ruth A Roberts
Keyword(s):  
Personalized Medicine ◽  
Adverse Outcome ◽  
Rank Order ◽  
Human Microbiome ◽  
Drug Efficacy ◽  
Scientific Culture ◽  
New Concepts ◽  
Microphysiological Systems ◽  
New Ideas ◽  
Adverse Outcome Pathways

Abstract Here we look at popular trends and concepts in toxicology over the decade 2009–2019. The top 10 concepts included methodological approaches such as zebrafish and genomics as well as broader concepts such as personalized medicine and adverse outcome pathways. The total number and rank order for each of the top 10 were tracked year by year via PubMed with >9500 papers contributing to the analysis. The data revealed a slow upward trend in the number of papers across all the concepts from 260 in 2009 to >1700 in 2019. Zebrafish, genomics and personalized medicine remained in the top four slots since 2009 with zebrafish dominating the rankings over the entire decade. Genomics was a strong second until 2013 when it was displaced first by the microbiome in 2014 and secondly by personalized medicine in 2015. Other notable trends were the ascendancy of the microbiome and adverse outcome pathways and the descendancy of hormesis and the 3Rs (replacement, reduction and refinement of animals in testing). The observation that the top four slots have been static over the past 4 years suggests that new ideas are introduced and increase in popularity until they find their place in scientific culture. This may suggest that relatively new concepts such as artificial intelligence and microphysiological systems have yet to find their steady state in the rankings. Similarly, as a relatively new player in toxicology, the full impact of the human microbiome on drug efficacy and safety remains to be seen.

scholarly journals The Neglected Microbial Components of Commercial Probiotic Formulations

2020 ◽  
Vol 8 (8) ◽  
pp. 1177
Author(s):  
Walter Fiore ◽  
Stefania Arioli ◽  
Simone Guglielmetti
Keyword(s):  
Shelf Life ◽  
Clinical Studies ◽  
Actual Number ◽  
Viable Cells ◽  
Biological Responses ◽  
Colony Forming Units ◽  
Minimum Requirements ◽  
Probiotic Product ◽  
Minimum Numbers

Producers of probiotic products are legally required to indicate on the label only the minimum numbers of viable microorganisms at the end of shelf life expressed as colony-forming units (CFUs). Label specifications, however, describe only a fraction of the actual microbiological content of a probiotic formulation. This paper describes the microbiological components of a probiotic product that are not mentioned on the label, such as the actual number of CFUs, the presence of viable cells that cannot generate colonies on agar plates, and the abundance of dead cells. These “hidden” microbial fractions in probiotic products, the abundance of which may change during the shelf life, can promote biological responses in the host. Therefore, they should not be ignored because they may influence the efficacy and can be relevant for immunocompromised or fragile consumers. In conclusion, we propose the minimum requirements for microbiological characterization of probiotic products to be adopted for label specifications and clinical studies.

scholarly journals In Vitro Sensitivities of Plasmodium falciparum to Different Antimalarial Drugs in Uganda

2010 ◽  
Vol 54 (3) ◽  
pp. 1200-1206 ◽  
Author(s):  
Samuel L. Nsobya ◽  
Moses Kiggundu ◽  
Sarah Nanyunja ◽  
Moses Joloba ◽  
Bryan Greenhouse ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Inhibitory Concentration ◽  
Drug Efficacy ◽  
New Combination ◽  
Efficacy Trial ◽  
Wide Range ◽  
Highly Correlated ◽  
Multiple Drugs ◽  
Combination Regimens

ABSTRACT The control of malaria is challenged by resistance of Plasmodium falciparum to multiple drugs. New combination regimens are now advocated for the treatment of uncomplicated falciparum malaria, but the extent of resistance to newer agents is incompletely understood. We measured the in vitro sensitivity of P. falciparum parasites cultured from children enrolled in a drug efficacy trial in Kampala, Uganda, from 2006 to 2008. Sensitivities were measured by comparing levels of histidine-rich protein-2 in parasites incubated with different concentrations of drugs with those in untreated controls. The cultured parasites exhibited a wide range of sensitivities to chloroquine (CQ); monodesethylamodiaquine (MDAQ), the major active metabolite of amodiaquine; and quinine (QN). Mean 50% inhibitory concentration (IC50) results were above standard cutoffs for resistance for CQ and MDAQ. Parasites were generally sensitive to dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ). For CQ, MDAQ, and QN but not the other drugs, activities against individual strains were highly correlated. We also assessed known resistance-mediating polymorphisms in two putative transporters, pfcrt and pfmdr1. When parasites that were least and most sensitive to each drug were compared, the pfmdr1 86Y mutation was significantly more common in parasites that were most resistant to CQ and MDAQ, and the pfmdr1 D1246Y mutation was significantly more common in parasites that were most resistant to MDAQ and QN. In summary, we demonstrated in parasites from Kampala a range of sensitivities to older drugs; correlation of sensitivities to CQ, MDAQ, and QN; and good activity against nearly all strains for DHA, LM, and PQ.

scholarly journals Proposed multidimensional pain outcome methodology to demonstrate analgesic drug efficacy and facilitate future drug approval for piglet castration

2021 ◽  
pp. 1-14
Author(s):  
Angela Baysinger ◽  
Sherrie R. Webb ◽  
Jennifer Brown ◽  
Johann F. Coetzee ◽  
Sara Crawford ◽  
...  
Keyword(s):  
Drug Efficacy ◽  
Drug Approval ◽  
The United States ◽  
Indirect Measurement ◽  
Mitigation Strategies ◽  
Analgesic Drug ◽  
Biological Responses ◽  
Gait Parameters ◽  
Pain Outcome ◽  
Future Drug

Abstract Castration of male piglets in the United States is conducted without analgesics because no Food and Drug Administration (FDA) approved products are labeled for pain control in swine. The absence of approved products is primarily due to a wide variation in how pain is measured in suckling piglets and the lack of validated pain-specific outcomes individually indistinct from other biological responses, such as general stress or inflammation responses with cortisol. Simply put, to measure pain mitigation, measurement of pain must be specific, quantifiable, and defined. Therefore, given the need for mitigating castration pain, a consortium of researchers, veterinarians, industry, and regulatory agencies was formed to identify potential animal-based outcomes and develop a methodology, based on the known scientific research, to measure pain and the efficacy of mitigation strategies. The outcome-based measures included physiological, neuroendocrine, behavioral, and production parameters. Ultimately, this consortium aims to provide a validated multimodal methodology to demonstrate analgesic drug efficacy for piglet castration. Measurable outcomes were selected based on published studies suggesting their validity, reliability, and sensitivity for the direct or indirect measurement of pain associated with surgical castration in piglets. Outcomes to be considered are observation of pain behaviors (i.e. ethogram defined behaviors and piglet grimace scale), gait parameters measured with a pressure mat, infrared thermography of skin temperature of the cranium and periphery of the eye, and blood biomarkers. Other measures include body weight and mortality rate. This standardized measurement of the outcome variable's primary goal is to facilitate consistency and rigor by developing a research methodology utilizing endpoints that are well-defined and reliably measure pain in piglets. The resulting methodology will facilitate and guide the evaluation of the effectiveness of comprehensive analgesic interventions for 3- to 5-day-old piglets following surgical castration.

scholarly journals Evaluation of Field Sampling Techniques for Environmental Microbial Exposure: Assessing Efficacy and Feasibility

2020 ◽  
Author(s):  
Kathryn R. Dalton ◽  
Kristoffer Spicer ◽  
Shanna Ludwig ◽  
Dorothy Clemons-Erby ◽  
Timothy Green ◽  
...  
Keyword(s):  
Health Outcomes ◽  
Surface Area ◽  
Sampling Techniques ◽  
Bacterial Burden ◽  
Field Sampling ◽  
Childhood Health ◽  
Test Sensitivity ◽  
Surface Areas ◽  
Colony Forming Units ◽  
Protocol Standardization

AbstractEnvironmental exposures in schools, including microbial exposures, can lead to detrimental childhood health outcomes. We evaluated two sampling techniques – standard flocked swabs versus sterile electrostatic cloths – to quantify Staphylococcus bacterial burden from school surfaces. Electrostatic cloths demonstrated higher test sensitivity and yielded higher surface area-standardized colony forming units compared to swabs. Despite protocol standardization, consistently larger surface areas were sampled with electrostatic cloths. This suggest that electrostatic cloths were more effective and practical for fieldwork.

scholarly journals Susceptibility of selected murine and microtine species to infection by a wild strain of Francisella tularensis subsp. holoarctica

2009 ◽  
Vol 54 (No. 2) ◽  
pp. 64-74 ◽  
Author(s):  
H. Bandouchova ◽  
J. Sedlackova ◽  
M. Hubalek ◽  
M. Pohanka ◽  
L. Peckova ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Wild Strain ◽  
Common Vole ◽  
Mammalian Host ◽  
Bacterial Burden ◽  
Apodemus Flavicollis ◽  
Microtus Arvalis ◽  
Colony Forming Units ◽  
The Common ◽  
Common Voles

The purpose of this study was to compare susceptibility of BALB/c mice, common voles (<i>Microtus arvalis</i>) and yellow-necked mice (<i>Apodemus flavicollis</i>) to infection by a virulent <i>Francisella tularensis</i> subsp. <i>holarctica</i> strain. Median survival in these three species following experimental infection with 320 colony forming units of <i>F. tularensis</i> (both intraperitoneally and subcutaneously) amounted to 4.5, 7 and 4 days, respectively. Survival curves of BALB/c and yellow-necked mice were very similar and were significantly different from that of common voles. LD50 was 0.5 and 37.9 colony forming units in BALB/c mice and common voles, respectively. The bacterial burden in the spleen, liver, lung, kidney and blood of common voles started to develop later post exposure and amounted to lower levels (except in kidneys) than in BALB/c mice. The results demonstrate that yellow-necked mice are even more susceptible to infection by <i>F. tularensis</i> than BALB/c mice and that the common vole is a small mammalian host with a susceptibility which is two-orders-of-magnitude lower.

Antibiotic Exposure Is Not Associated With Clearance of Bronchoalveolar Growth: Results From a Prospective Ventilator-Associated Pneumonia Study

2020 ◽  
pp. 000313482096628
Author(s):  
Richard D. Betzold ◽  
Bradley M. Dennis ◽  
Seth A. Bellister ◽  
Christopher A. Guidry ◽  
Oscar D. Guillamondegui ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Trauma Patients ◽  
Ventilator Associated Pneumonia ◽  
Antibiotic Exposure ◽  
Bacterial Burden ◽  
Surveillance Cultures ◽  
Colony Forming Units ◽  
Chi Squared

Background Ventilator-associated pneumonia is poorly understood in trauma. Ventilated trauma patients can develop bacterial burden without symptoms; the factors that influence this are unknown. Methods Injured adults ventilated for > 2 days were enrolled. Mini-bronchoalveolar lavage was performed for 14 days or until extubation. Semi-quantitative cultures were blinded from clinicians. All cultures with > 104 colony forming units (CFU) were assessed for antibiotic exposure (ABXE) and spectrum of coverage. mBAL CFU was assessed daily. Results 60 patients were ventilated for 9 days (median). There were 75 with > 104 CFU. 46 had > 104 CFU and no ABXE on the sample day. 74% had clearance or a decrease (CoD) in CFU without ABXE. 29 had > 104 CFU and ABXE on the sample day. 19 had ABXE with pathogen coverage. 84% had CoD in CFU. 10 had ABXE with no spectrum of coverage. 1/10 had increased CFU and the remaining 9/10 CoD in CFU. The three groups were not statistically different on chi-squared analysis. Conclusion Clearance of pathogens on surveillance cultures was unaffected by ABXE.

scholarly journals 820. Impact of pulsed xenon ultraviolet (PX-UV) light disinfection for reduction of pathogens on high touch surfaces following hospitalization

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S452-S453
Author(s):  
Joud N Jarrah ◽  
Oscar I Martinez ◽  
Susmita jain ◽  
Piyali Chatterjee ◽  
Hosoon Choi ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Bacterial Contamination ◽  
Uv Light ◽  
Bacterial Species ◽  
Veterans Affairs ◽  
Department Of Veterans Affairs ◽  
Bacterial Burden ◽  
Colony Forming Units ◽  
Additional Reduction ◽  
Research Grant

Abstract Background Ultraviolet (UV) light disinfection following a manual terminal cleaning process for hospital rooms has been proposed as an additional method to reduce the bacterial burden on surfaces. The impact of UV light disinfection and the level of interdependence between the modalities remains unclear. Methods Samples were collected from 5 high touch surfaces from 10 patients room following discharge prior to manual disinfection, following manual disinfection, and following pulsed xenon UV disinfection using Rodac contact plates (total 150 samples). Colonies were identified using MALDI-TOF mass spectrometry. The bacterial colony counts were recorded and analyzed as pathogenic or commensal organisms (based on CDC criteria) to assess the efficacy of the disinfection process. Results Average colony counts for the rooms prior to disinfection, post disinfection, and post UV light were 185.8 CFU +/- SD 280, 43 CFU +/- 121, and 20 CFU +/- 36.7 respectively. The average drop in colony-forming units of the five high touch areas in patient’s rooms can be seen in table 1. Twelve commensal bacterial species were isolated: Bacillus species (sp.), Corynebacterium sp., Enhydrobacter sp., Kocuria sp., Lysinibacillus sp., Macrococcus sp., Micrococcus sp., Paenibacillus sp., Pantoea sp., Psychrobacter sp., Siccibacter sp., Coagulase negative staphylococcus. Seven pathogenic bacteria were isolated: Acinetobacter sp., Brucella sp., Proteus sp., Staphylococcus aureus, Escherichia sp., Enterococcus, and Pseudomonas aeruginosa. Reductions in the predominant bacterial species following disinfection modality are noted in table 2. Table 1: Colony forming units (CFUs) average Pre-disinfection (Pre-Dis), Post Disinfection (Post-Dis), and Post PX-UV Light (PX-UV). Table 2: Sub-analysis of commensal and pathogen isolation Pre-Disinfection (Pre-Dis), Post-Disinfection (Post-Dis), and Post PX-UV light (PX-UV). Conclusion A combination of manual disinfection and UV has shown a notable additional reduction in overall bacterial contamination of the patient rooms, including the majority of high touch areas as compared with manual disinfection alone. No additional reduction in commensal bacteria isolates was noted after UV light, however a further decrease in pathogenic bacteria (Acinetobacter and Enterococcus) was noted. UV light may be considered as an additional room disinfection method to reduce overall bacterial burden and pathogenic bacterial contamination of rooms as a comprehensive strategy to reduce nosocomial infections. Disclosures Mark Stibich, n/a, Xenex Germ-Zapping Robots (Board Member, Grant/Research Support) Chetan Jinadatha, MD, MPH, AHRQ (Research Grant or Support)Department of Veterans Affairs (Other Financial or Material Support, Owner: Department of Veterans Affairs. Licensed to: Xenex Disinfection System, San Antonio, TX)Inventor (Other Financial or Material Support, Methods for organizing the disinfection of one or more items contaminated with biological agents)NiH/NINR (Research Grant or Support)NSF (Research Grant or Support)Xenex Healthcare Services (Research Grant or Support)

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