scholarly journals Breaking the Vicious Cycle of Antibiotic Killing and Regrowth of Biofilm-ResidingPseudomonas aeruginosa

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Mathias Müsken ◽  
Vinay Pawar ◽  
Timo Schwebs ◽  
Heike Bähre ◽  
Sebastian Felgner ◽  
...  
Keyword(s):  
Treatment Success ◽  
Antimicrobial Treatment ◽  
Vicious Cycle ◽  
Chronic Infections ◽  
Treatment Protocols ◽  
Content Type ◽  
Treatment Regimens ◽  
Biofilm Bacteria ◽  
Time Required

ABSTRACTBiofilm-residing bacteria embedded in an extracellular matrix are protected from diverse physicochemical insults. In addition to the general recalcitrance of biofilm bacteria, high bacterial loads in biofilm-associated infections significantly diminish the efficacy of antimicrobials due to a low per-cell antibiotic concentration. Accordingly, present antimicrobial treatment protocols that have been established to serve the eradication of acute infections fail to clear biofilm-associated chronic infections. In the present study, we applied automated confocal microscopy onPseudomonas aeruginosato monitor dynamic killing of biofilm-grown bacteria by tobramycin and colistin in real time. We revealed that the time required for surviving bacteria to repopulate the biofilm could be taken as a measure for effectiveness of the antimicrobial treatment. It depends on the (i) nature and concentration of the antibiotic, (ii) duration of antibiotic treatment, (iii) application as monotherapy or combination therapy, and (iv) interval of drug administration. The vicious cycle of killing and repopulation of biofilm bacteria could also be broken in anin vivomodel system by applying successive antibiotic dosages at intervals that do not allow full reconstitution of the biofilm communities. Treatment regimens that consider the important aspects of antimicrobial killing kinetics bear the potential to improve control of biofilm regrowth. This is an important and underestimated factor that is bound to ensure sustainable treatment success of chronic infections.

scholarly journals The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Dongzhu Ma ◽  
Jonathan B. Mandell ◽  
Niles P. Donegan ◽  
Ambrose L. Cheung ◽  
Wanyan Ma ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Chronic Infection ◽  
Critical Role ◽  
Antimicrobial Treatment ◽  
Antibiotic Tolerance ◽  
Chronic Infections ◽  
Content Type ◽  
Increased Risk

ABSTRACT Staphylococcus aureus is the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails, leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance of S. aureus biofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function in S. aureus is controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in three S. aureus strains to their corresponding strains with disruption of mazF expression. Strains lacking mazF production showed increased biofilm growth and decreased biofilm antibiotic tolerance. Deletion of icaADBC in the mazF::Tn background suppressed the growth phenotype observed with mazF-disrupted strains, suggesting the phenotype was ica dependent. We confirmed these phenotypes in our murine animal model. Loss of mazF resulted in increased bacterial burden and decreased survival rate of mice compared to its wild-type strain demonstrating that loss of the mazF gene caused an increase in S. aureus virulence. Although lack of mazF gene expression increased S. aureus virulence, it was more susceptible to antibiotics in vivo. Combined, the ability of mazF to inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone. IMPORTANCE Surgical infections are one of the most common types of infections encountered in a hospital. Staphylococcus aureus is the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate, as the bacteria form biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria that are planktonic, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate that mazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allows S. aureus to transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.

scholarly journals Efficacy of Guanabenz Combination Therapy against Chronic Toxoplasmosis across Multiple Mouse Strains

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Jennifer Martynowicz ◽  
J. Stone Doggett ◽  
William J. Sullivan
Keyword(s):  
Limit Of Detection ◽  
Acute Infection ◽  
Antagonistic Effect ◽  
Mouse Strains ◽  
Chronic Infections ◽  
Content Type ◽  
Brain Cyst ◽  
The Brain

ABSTRACT Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we and others have discovered drugs capable of significantly reducing the brain cyst burden in latently infected mice, but not to undetectable levels. In this study, we examined the use of novel combination therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and endochin-like quinolones (ELQs) and were administered to two different mouse strains in an attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these drug treatments: pyrimethamine-guanabenz showed synergistic efficacy in C57BL/6 mice yet did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between guanabenz and ELQ-334 in vivo. While we were unable to completely eliminate the brain cyst burden, we found that a combination treatment with ELQ-334 and pyrimethamine impressively reduced the brain cyst burden by 95% in C57BL/6 mice, which approached the limit of detection. These analyses highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help inform further preclinical studies of cocktail therapies designed to treat chronic toxoplasmosis.

scholarly journals In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Genki Kimura ◽  
Takahiro Nakaoki ◽  
Thomas Colley ◽  
Garth Rapeport ◽  
Pete Strong ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Interleukin 17 ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Once Daily ◽  
Content Type ◽  
Treatment Regimens ◽  
Biomarker Analysis ◽  
Immunocompromised Mice

ABSTRACT PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 μg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans.

scholarly journals Antimicrobial Treatment Options for Granulomatous Mastitis Caused by Corynebacterium Species

2015 ◽  
Vol 53 (9) ◽  
pp. 2895-2899 ◽  
Author(s):  
Hazel C. Dobinson ◽  
Trevor P. Anderson ◽  
Stephen T. Chambers ◽  
Matthew P. Doogue ◽  
Lois Seaward ◽  
...  
Keyword(s):  
Antimicrobial Therapy ◽  
Breast Tissue ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Antimicrobial Treatment ◽  
Granulomatous Mastitis ◽  
Sensitivity Testing ◽  
Treatment Protocols ◽  
Content Type ◽  
16S Rna

Corynebacteriumspecies are increasingly recognized as important pathogens in granulomatous mastitis. Currently, there are no published treatment protocols forCorynebacteriumbreast infections. This study describes antimicrobial treatment options in the context of other management strategies used for granulomatous mastitis.Corynebacteriumspp. isolated from breast tissue and aspirate samples stored from 2002 to 2013 were identified and determined to the species level using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), 16S RNA sequencing, andrpoBgene targets. The MICs for 12 antimicrobials were performed using Etest for each isolate. Correlations of these with antimicrobial characteristics, choice of antimicrobial, and disease outcome were evaluated.Corynebacteriumspp. from breast tissue and aspirate samples were confirmed in 17 isolates from 16 patients. Based on EUCAST breakpoints,Corynebacterium kroppenstedtiiisolates (n= 11) were susceptible to seven antibiotic classes but resistant to β-lactam antibiotics.Corynebacterium tuberculostearicumisolates (n= 4) were multidrug resistant. Two nonlipophilic species were isolated,Corynebacterium glucuronolyticumandCorynebacterium freneyi, both of which have various susceptibilities to antimicrobial agents. Short-course antimicrobial therapy was common (median, 6 courses per subject; range, 1 to 9 courses). Patients withC. kroppenstedtiipresented with a hot painful breast mass and underwent multiple surgical procedures (median, 4 procedures; range, 2 to 6 procedures). The management ofCorynebacteriumbreast infections requires a multidisciplinary approach and includes culture and appropriate sensitivity testing to guide antimicrobial therapy. Established infections have a poor outcome, possibly because adequate concentrations of some drugs will be difficult to achieve in lipophilic granulomata. Lipophilic antimicrobial therapy may offer a therapeutic advantage. The role of immunotherapy has not been defined.

scholarly journals d-Amino Acids Enhance the Activity of Antimicrobials against Biofilms of Clinical Wound Isolates of Staphylococcus aureus and Pseudomonas aeruginosa

2014 ◽  
Vol 58 (8) ◽  
pp. 4353-4361 ◽  
Author(s):  
Carlos J. Sanchez ◽  
Kevin S. Akers ◽  
Desiree R. Romano ◽  
Ronald L. Woodbury ◽  
Sharanda K. Hardy ◽  
...  
Keyword(s):  
Amino Acids ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Clinical Isolates ◽  
Chronic Infections ◽  
Content Type ◽  
Log Reduction ◽  
Viable Bacteria ◽  
Biofilm Bacteria

ABSTRACTWithin wounds, microorganisms predominantly exist as biofilms. Biofilms are associated with chronic infections and represent a tremendous clinical challenge. As antibiotics are often ineffective against biofilms, use of dispersal agents as adjunctive, topical therapies for the treatment of wound infections involving biofilms has gained interest. We evaluatedin vitrothe dispersive activity ofd-amino acids (d-AAs) on biofilms from clinical wound isolates ofStaphylococcus aureusandPseudomonas aeruginosa; moreover, we determined whether combinations ofd-AAs and antibiotics (clindamycin, cefazolin, oxacillin, rifampin, and vancomycin forS. aureusand amikacin, colistin, ciprofloxacin, imipenem, and ceftazidime forP. aeruginosa) enhance activity against biofilms.d-Met,d-Phe, andd-Trp at concentrations of ≥5 mM effectively dispersed preformed biofilms ofS. aureusandP. aeruginosaclinical isolates, an effect that was enhanced when they were combined as an equimolar mixture (d-Met/d-Phe/d-Trp). When combined withd-AAs, the activity of rifampin was significantly enhanced against biofilms of clinical isolates ofS. aureus, as indicated by a reduction in the minimum biofilm inhibitory concentration (MBIC) (from 32 to 8 μg/ml) and a >2-log reduction of viable biofilm bacteria compared to treatment with antibiotic alone. The addition ofd-AAs was also observed to enhance the activity of colistin and ciprofloxacin against biofilms ofP. aeruginosa, reducing the observed MBIC and the number of viable bacteria by >2 logs and 1 log at 64 and 32 μg/ml in contrast to antibiotics alone. These findings indicate that the biofilm dispersal activity ofd-AAs may represent an effective strategy, in combination with antimicrobials, to release bacteria from biofilms, subsequently enhancing antimicrobial activity.

scholarly journals High Staphylococcus aureus Colonization Prevalence among Patients with Skin and Soft Tissue Infections and Controls in an Urban Emergency Department

2014 ◽  
Vol 53 (3) ◽  
pp. 810-815 ◽  
Author(s):  
Neha Kumar ◽  
Michael Z. David ◽  
Susan Boyle-Vavra ◽  
Julia Sieth ◽  
Robert S. Daum
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
The United States ◽  
Antimicrobial Treatment ◽  
Soft Tissue Infections ◽  
Content Type ◽  
Treatment Regimens ◽  
Commensal Species ◽  
High Prevalence

Staphylococcus aureusis a commensal species that can also be a formidable pathogen. In the United States, an epidemic of community-acquired methicillin-resistantStaphylococcus aureus(MRSA) infections has been occurring for the last 15 years. In the context of a study in which we identified patients with skin and soft tissue infections (SSTIs) and randomized them to receive one of two antimicrobial treatment regimens, we assessedS. aureuscolonization in the nares, throat, and perianal skin on the day of enrollment and 40 days after therapy. We compared the prevalence of colonization between the SSTI patients and an uninfected control population. A total of 144 subjects and 130 controls, predominantly African American, participated in this study, and 116 returned for a 40-day follow-up visit. Of the SSTI patients, 76% were colonized withS. aureusat enrollment, as were 65% of the controls. Patients were more likely than the controls to be colonized with USA300 MRSA (62/144 [43.1%] versus 11/130 [8.5%], respectively;P< 0.001). The nares were not the most common site of colonization. The colonization prevalence diminished somewhat after antibiotic treatment but remained high. The isolates that colonized the controls were more likely than those in the patients to be methicillin-susceptibleS. aureus(MSSA) (74/84 [88.1%] versus 56/106 [52.8%], respectively;P< 0.001). In conclusion, the prevalence ofS. aureuscolonization among SSTI patients was high and often involved USA300 MRSA. The prevalence diminished somewhat with antimicrobial therapy but remained high at the 40-day follow-up visit. Control subjects were also colonized at a high prevalence but most often with a genetic background not associated with a clinical infection in this study.S. aureusis a commensal species and a pathogen. Plans for decolonization or eradication should take this distinction into account.

scholarly journals In VivoMonitoring of Staphylococcus aureus Biofilm Infections and Antimicrobial Therapy by [18F]Fluoro-Deoxyglucose–MicroPET in a Mouse Model

2014 ◽  
Vol 58 (11) ◽  
pp. 6660-6667 ◽  
Author(s):  
Victoria Garrido ◽  
María Collantes ◽  
Montserrat Barberán ◽  
Iván Peñuelas ◽  
Javier Arbizu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Regional Lymph Node ◽  
Strain Differences ◽  
Antimicrobial Treatment ◽  
Matrix Composition ◽  
Content Type ◽  
New Therapeutic Approaches ◽  
Image Technique

ABSTRACTA mouse model was developed forin vivomonitoring of infection and the effect of antimicrobial treatment againstStaphylococcus aureusbiofilms, using the [18F]fluoro-deoxyglucose–MicroPET ([18F]FDG-MicroPET) image technique. In the model, sealed Vialon catheters were briefly precolonized withS. aureusstrains ATCC 15981 or V329, which differ in cytotoxic properties and biofilm matrix composition. After subcutaneous implantation of catheters in mice, theS. aureusstrain differences found in bacterial counts and the inflammatory reaction triggered were detected by the regular bacteriological and histological procedures and also by [18F]FDG-MicroPET image signal intensity determinations in the infection area and regional lymph node. Moreover, [18F]FDG-MicroPET imaging allowed the monitoring of the rifampin treatment effect, identifying the periods of controlled infection and those of reactivated infection due to the appearance of bacteria naturally resistant to rifampin. Overall, the mouse model developed may be useful for noninvasivein vivodeterminations in studies onS. aureusbiofilm infections and assessment of new therapeutic approaches.

Knowledge transferring and small and medium enterprise’s (SME's) effectiveness: emerging insights and future directions

2021 ◽  
Vol 27 (6) ◽  
pp. 1747-1774
Author(s):  
Roberto Biloslavo ◽  
Rosa Lombardi
Keyword(s):  
Qualitative Research ◽  
Knowledge Transfer ◽  
Financial Incentives ◽  
Research Approach ◽  
Content Type ◽  
Group Interviews ◽  
Time Required ◽  
Organisational Factors ◽  
Why Questions

PurposeThis paper aims to define knowledge transfer and small and medium enterprise’s (SME's) effectiveness. This research framework examines how employees understand, create and apply knowledge in a day-to-day working context, and how knowledge and other organisational factors influence knowledge transfer within the organisation.Design/methodology/approachA qualitative research approach was applied. The authors conducted semi-structured group interviews with the members of three departments of a small hi-tech company. All collected data were manually coded, using in vivo coding and discussed among the authors. As the continuation of the semi-structured group interview, the technique of cognitive maps was applied.FindingsAccording to the results, the critical elements of knowledge transfer within small hi-tech companies seem (1) available slack time, (2) reciprocity and level of trust among employees, (3) social capital of employees and (4) practically oriented technical knowledge. It is also noted that the knowledge transfer is carried out to solve the problems identified by the employees, and these seek knowledge directly from the knowledge bearers who represent a kind of organisational memory.Practical implicationsKnowledge transfer in SMEs occurs almost exclusively face-by-face, and individuals involved pay attention to the time required by this process. The co-creation of an organisational space that allows and supports an open discussion within and between departments is therefore of fundamental importance in order not to preclude organisational learning. In addition, non-financial incentives must be established to help transfer tacit knowledge. This allows to overcome the difficulty of employees in recognising the organisational knowledge base that they see above all in themselves.Originality/valueThis paper throws additional light on understanding how knowledge transfer happens within small hi-tech companies. The applied qualitative research methods allow a better understanding of the “how” and “why” questions associated with the social processes surrounding knowledge transfer.

Implantation of human meningiomas into the subrenal capsule of the nude mouse

1989 ◽  
Vol 71 (4) ◽  
pp. 545-550 ◽  
Author(s):  
Azedine Medhkour ◽  
Melinda Van Roey ◽  
Raymond A. Sobel ◽  
Howard J. Fingert ◽  
Jungkyo Lee ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Nude Mouse ◽  
Cell Cultures ◽  
Solid Tumor ◽  
Early Passage ◽  
Content Type ◽  
Treatment Regimens ◽  
Human Meningiomas ◽  
Subrenal Capsule

✓ To develop a reproducible in vivo model for the growth of human meningiomas, meningiomas from 16 patients were implanted into the subrenal capsule of the nude mouse. In eight experiments solid tumor implants taken directly from surgical specimens were used, in four experiments the implants were made from early-passage monolayer cell cultures, and in four experiments both techniques were used. Successful tumor growth was observed in 10 (83%) of the 12 solid tumor implants and in six (75%) of the eight implants from cell cultures. The size and neovascularization of these tumors were serially determined over a 3-month period. Tumor doubling occurred in 1 to 3 weeks in all of the solid tumor implant group. In the group of six tumors successfully implanted from cell cultures, three doubled in 1 to 3 weeks and three grew more rapidly, reaching 10 to 20 times their original volume. Neovascularity occurred in the tumors within 3 weeks of implantation. Each of the solid tumor implants had a histological pattern similar to that of the corresponding original specimen. Only three of those implanted from cell cultures were similar to the original tumor; the other three displayed features characteristic of malignant meningioma. These studies suggest that implantation of human meningiomas in the subrenal capsule of the nude mouse is a feasible model that may be useful for evaluating hormonal or genetic modulation of tumor growth and for testing potential treatment regimens.

scholarly journals 2,3-Dihydroxybenzoic Acid-Containing Nanofiber Wound Dressings Inhibit Biofilm Formation by Pseudomonas aeruginosa

2014 ◽  
Vol 58 (4) ◽  
pp. 2098-2104 ◽  
Author(s):  
Jayesh J. Ahire ◽  
Leon M. T. Dicks
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Iron Chelator ◽  
Wound Dressings ◽  
Tissue Destruction ◽  
Dihydroxybenzoic Acid ◽  
Chronic Infections ◽  
Content Type ◽  
Cell Numbers ◽  
Time Required

ABSTRACTPseudomonas aeruginosaforms biofilms in wounds, which often leads to chronic infections that are difficult to treat with antibiotics. Free iron enhances biofilm formation, delays wound healing, and may even be responsible for persistent inflammation, increased connective tissue destruction, and lipid peroxidation. Exposure ofP. aeruginosaXen 5 to the iron chelator 2,3-dihydroxybenzoic acid (DHBA), electrospun into a nanofiber blend of poly(d,l-lactide) (PDLLA) and poly(ethylene oxide) (PEO), referred to as DF, for 8 h decreased biofilm formation by approximately 75%. This was shown by a drastic decline in cell numbers, from 7.1 log10CFU/ml to 4.8 log10CFU/ml when biofilms were exposed to DF in the presence of 2.0 mM FeCl36H2O. A similar decline in cell numbers was recorded in the presence of 3.0 mM FeCl36H2O and DF. The cells were more mobile in the presence of DHBA, supporting the observation of less biofilm formation at lower iron concentrations. DHBA at MIC levels (1.5 mg/ml) inhibited the growth of strain Xen 5 for at least 24 h. Our findings indicate that DHBA electrospun into nanofibers inhibits cell growth for at least 4 h, which is equivalent to the time required for all DHBA to diffuse from DF. This is the first indication that DF can be developed into a wound dressing to treat topical infections caused byP. aeruginosa.

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