scholarly journals Neomycin Sulfate Improves the Antimicrobial Activity of Mupirocin-Based Antibacterial Ointments

2015 ◽  
Vol 60 (2) ◽  
pp. 862-872 ◽  
Author(s):  
Catlyn Blanchard ◽  
Lauren Brooks ◽  
Andrew Beckley ◽  
Jennifer Colquhoun ◽  
Stephen Dewhurst ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Invasive Disease ◽  
Wound Site ◽  
Content Type ◽  
Neomycin Sulfate ◽  
Resistant Strains ◽  
Mupirocin Ointment ◽  
High Level ◽  
Further Development ◽  
New Strategies

ABSTRACTIn the midst of the current antimicrobial pipeline void, alternative approaches are needed to reduce the incidence of infection and decrease reliance on last-resort antibiotics for the therapeutic intervention of bacterial pathogens. In that regard, mupirocin ointment-based decolonization and wound maintenance practices have proven effective in reducingStaphylococcus aureustransmission and mitigating invasive disease. However, the emergence of mupirocin-resistant strains has compromised the agent's efficacy, necessitating new strategies for the prevention of staphylococcal infections. Herein, we set out to improve the performance of mupirocin-based ointments. A screen of a Food and Drug Administration (FDA)-approved drug library revealed that the antibiotic neomycin sulfate potentiates the antimicrobial activity of mupirocin, whereas other library antibiotics did not. Preliminary mechanism of action studies indicate that neomycin's potentiating activity may be mediated by inhibition of the organism's RNase P function, an enzyme that is believed to participate in the tRNA processing pathway immediately upstream of the primary target of mupirocin. The improved antimicrobial activity of neomycin and mupirocin was maintained in ointment formulations and reducedS. aureusbacterial burden in murine models of nasal colonization and wound site infections. Combination therapy improved upon the effects of either agent alone and was effective in the treatment of contemporary methicillin-susceptible, methicillin-resistant, and high-level mupirocin-resistantS. aureusstrains. From these perspectives, combination mupirocin-and-neomycin ointments appear to be superior to that of mupirocin alone and warrant further development.

scholarly journals Native Valve Endocarditis Caused by Corynebacterium striatum with Heterogeneous High-Level Daptomycin Resistance: Collateral Damage from Daptomycin Therapy?

2012 ◽  
Vol 56 (6) ◽  
pp. 3461-3464 ◽  
Author(s):  
Truc T. Tran ◽  
Siraya Jaijakul ◽  
Cole T. Lewis ◽  
Lorena Diaz ◽  
Diana Panesso ◽  
...  
Keyword(s):  
Invasive Disease ◽  
Native Valve ◽  
Positive Skin ◽  
Content Type ◽  
Native Valve Endocarditis ◽  
Corynebacterium Striatum ◽  
Skin Flora ◽  
High Level ◽  
Selection Of

ABSTRACTWe describe a patient who developedCorynebacterium striatumnative valve endocarditis after receiving two 6-week courses of daptomycin for the treatment of methicillin-resistantStaphylococcus aureusbacteremia and osteomyelitis. The organism exhibitedin vitroheteroresistance to daptomycin, with two subpopulations showing daptomycin susceptibility (MIC of ≤0.094 μg/ml) and high-level resistance to daptomycin (MIC of ≥256 μg/ml). The selection of daptomycin-resistant Gram-positive skin flora with the potential of causing invasive disease may be a concern during prolonged courses of daptomycin.

scholarly journals Streptococcus mitis and S. oralis Lack a Requirement for CdsA, the Enzyme Required for Synthesis of Major Membrane Phospholipids in Bacteria

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Hannah M. Adams ◽  
Luke R. Joyce ◽  
Ziqiang Guan ◽  
Ronda L. Akins ◽  
Kelli L. Palmer
Keyword(s):  
Drug Exposure ◽  
Essential Gene ◽  
Model Organisms ◽  
Membrane Phospholipids ◽  
Streptococcus Mitis ◽  
Gram Positive ◽  
Content Type ◽  
Anionic Phospholipids ◽  
Resistant Strains ◽  
High Level

ABSTRACT Synthesis and integrity of the cytoplasmic membrane are fundamental to cellular life. Experimental evolution studies have hinted at unique physiology in the Gram-positive bacteria Streptococcus mitis and S. oralis. These organisms commonly cause bacteremia and infectious endocarditis (IE) but are rarely investigated in mechanistic studies of physiology and evolution. Unlike in other Gram-positive pathogens, high-level (MIC ≥ 256 μg/ml) daptomycin resistance rapidly emerges in S. mitis and S. oralis after a single drug exposure. In this study, we found that inactivating mutations in cdsA are associated with high-level daptomycin resistance in S. mitis and S. oralis IE isolates. This is surprising given that cdsA is an essential gene for life in commonly studied model organisms. CdsA is the enzyme responsible for the synthesis of CDP-diacylglycerol, a key intermediate for the biosynthesis of all major phospholipids in prokaryotes and most anionic phospholipids in eukaryotes. Lipidomic analysis by liquid chromatography-mass spectrometry (LC-MS) showed that daptomycin-resistant strains have an accumulation of phosphatidic acid and completely lack phosphatidylglycerol and cardiolipin, two major anionic phospholipids in wild-type strains, confirming the loss of function of CdsA in the daptomycin-resistant strains. To our knowledge, these daptomycin-resistant streptococci represent the first model organisms whose viability is CdsA independent. The distinct membrane compositions resulting from the inactivation of cdsA not only provide novel insights into the mechanisms of daptomycin resistance but also offer unique opportunities to study the physiological functions of major anionic phospholipids in bacteria.

scholarly journals High-Level Pan-Azole-Resistant Aspergillosis: TABLE 1

2015 ◽  
Vol 53 (7) ◽  
pp. 2343-2345 ◽  
Author(s):  
Jakko van Ingen ◽  
Henrich A. L. van der Lee ◽  
Antonius J. M. M. Rijs ◽  
Eveline Snelders ◽  
Willem J. G. Melchers ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Lung Disease ◽  
Gene Mutation ◽  
Chronic Lung Disease ◽  
Azole Resistance ◽  
Content Type ◽  
High Level ◽  
New Strategies ◽  
Progressive Resistance

High-level pan-azole-resistantAspergillus fumigatuswas recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The high-level pan-azole-resistant phenotypes were not associated with a specificcyp51Agene mutation. New strategies that avoid the development of progressive azole resistance are needed.

scholarly journals Comparative Evaluations of the Pathogenesis of Candida auris Phenotypes and Candida albicans Using Clinically Relevant Murine Models of Infections

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Taissa Vila ◽  
Daniel Montelongo-Jauregui ◽  
Hussian Ahmed ◽  
Taanya Puthran ◽  
Ahmed S. Sultan ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Invasive Disease ◽  
Health Care Facilities ◽  
Murine Models ◽  
Candida Auris ◽  
Pathogenic Potential ◽  
Content Type ◽  
Oral Tissue ◽  
High Level

ABSTRACT The newly emerged Candida species Candida auris is associated with an exponential rise in life-threatening invasive disease in health care facilities worldwide. Unlike other species, C. auris exhibits a high level of transmissibility, multidrug resistance, and persistence in the environment, yet little is known about its pathogenesis largely due to limited data from animal models. Based on in vitro biofilm evaluations and confocal laser scanning microscopy, C. auris phenotypes with different biofilm-forming abilities were identified, indicating potential clinical implications. Using clinically relevant murine models of implanted catheter, oral, and intraperitoneal infections, we comparatively evaluated the host site-specific pathogenic potential of C. auris phenotypes and Candida albicans. Based on the results of microbial recovery and scanning electron microscopy analysis of explanted catheters, compared to C. albicans, C. auris more avidly adhered and formed biofilms on catheters. However, although C. auris adhered to oral tissue ex vivo, unlike C. albicans, it failed to colonize the oral cavity in vivo, as demonstrated by microbial recovery and tissue histopathology analysis. In contrast, recovery from peritoneal lavage fluid and kidneys during time course experiments demonstrated that C. auris persisted longer in the peritoneal cavity and kidneys. Although there were clear niche-specific differences in pathogenic features between C. auris and C. albicans, no significant differences were noted between the C. auris phenotypes in vivo. The combined findings highlight unique niche-specific pathogenic traits for C. auris warranting further investigations. Understanding the factors contributing to the rise of C. auris as a nosocomial pathogen is critical for controlling the spread of this species. IMPORTANCE The newly emerged Candida species C. auris has been associated with an exponential rise in invasive disease in health care facilities worldwide with a mortality rate approaching 60%. C. auris exhibits a high level of transmissibility, multidrug resistance, and persistence in hospital environments, yet little is known about its pathogenesis largely due to limited data from animal studies. We used clinically relevant murine models of infection to comparatively evaluate the host niche-specific pathogenic potential of C. auris and C. albicans. Findings demonstrated that C. auris adheres more avidly, forming robust biofilms on catheters implanted in mice. However, although C. auris adhered to oral tissue ex vivo, it failed to colonize the oral cavity in vivo. In contrast, in the intraperitoneal infection model, C. auris persisted longer in the peritoneal cavity and kidneys. Understanding the host-pathogen factors contributing to the rise of C. auris as a nosocomial pathogen is critical for controlling the spread of this species.

scholarly journals Anti-Candida Activity of Fluoxetine Alone and Combined with Fluconazole: a Synergistic Action against Fluconazole-Resistant Strains

2014 ◽  
Vol 58 (7) ◽  
pp. 4224-4226 ◽  
Author(s):  
Ana S. Oliveira ◽  
Carlos A. Gaspar ◽  
Rita Palmeira-de-Oliveira ◽  
José Martinez-de-Oliveira ◽  
Ana Palmeira-de-Oliveira
Keyword(s):  
Antimicrobial Activity ◽  
Synergistic Action ◽  
Vulvovaginal Candidiasis ◽  
Lethal Concentration ◽  
Synergistic Activity ◽  
Content Type ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACTThe purpose of this work was to determine the antimicrobial activity of fluoxetine, alone and combined with fluconazole, against 29Candidastrains isolated from patients with vulvovaginal candidiasis. MIC and minimum lethal concentration values ranged from 9.8 to 625 μg/ml for all strains tested. The combination of fluconazole with fluoxetine resulted in synergistic activity against sixCandidastrains, with fractional inhibitory index (FIX) values between 0.15 and 0.31. An indifferent effect was found for the remaining strains, with FIX values between 0.63 and 1.

scholarly journals A Novel Mechanism of High-Level, Broad-Spectrum Antibiotic Resistance Caused by a Single Base Pair Change in Neisseria gonorrhoeae

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Elizabeth A. Ohneck ◽  
Yaramah M. Zalucki ◽  
Paul J. T. Johnson ◽  
Vijaya Dhulipala ◽  
Daniel Golparian ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Resistance ◽  
Neisseria Gonorrhoeae ◽  
Base Pair ◽  
Health Concern ◽  
Content Type ◽  
Single Base ◽  
Single Base Pair ◽  
Resistant Strains ◽  
High Level

ABSTRACTThe MtrC-MtrD-MtrE multidrug efflux pump ofNeisseria gonorrhoeaeconfers resistance to a diverse array of antimicrobial agents by transporting these toxic compounds out of the gonococcus. Frequently in gonococcal strains, the expression of themtrCDEoperon is differentially regulated by both a repressor, MtrR, and an activator, MtrA. ThemtrRgene lies 250 bp upstream of and is transcribed divergently from themtrCDEoperon. Previous research has shown that mutations in themtrRcoding region and in themtrR-mtrCDEintergenic region increase levels of gonococcal antibiotic resistance andin vivofitness. Recently, a C-to-T transition mutation 120 bp upstream of themtrCstart codon, termedmtr120, was identified in strain MS11 and shown to be sufficient to confer high levels of antimicrobial resistance when introduced into strain FA19. Here we report that this mutation results in a consensus −10 element and that its presence generates a novel promoter formtrCDEtranscription. This newly generated promoter was found to be stronger than the wild-type promoter and does not appear to be subject to MtrR repression or MtrA activation. Although rare, themtr120mutation was identified in an additional clinical isolate during sequence analysis of antibiotic-resistant strains cultured from patients with gonococcal infections. We propose thatcis-acting mutations can develop in gonococci that significantly alter the regulation of themtrCDEoperon and result in increased resistance to antimicrobials.IMPORTANCEGonorrhea is the second most prevalent sexually transmitted bacterial infection and a worldwide public health concern. As there is currently no vaccine againstNeisseria gonorrhoeae, appropriate diagnostics and subsequent antibiotic therapy remain the primary means of infection control. However, the effectiveness of antibiotic treatment is constantly challenged by the emergence of resistant strains, mandating a thorough understanding of resistance mechanisms to aid in the development of new antimicrobial therapies and genetic methods for antimicrobial resistance testing. This study was undertaken to characterize a novel mechanism of antibiotic resistance regulation inN. gonorrhoeae. Here we show that a single base pair mutation generates a second, stronger promoter formtrCDEtranscription that acts independently of the known efflux system regulators and results in high-level antimicrobial resistance.

scholarly journals Geographic Differences in the Contribution ofubiAMutations to High-Level Ethambutol Resistance in Mycobacterium tuberculosis

2016 ◽  
Vol 60 (7) ◽  
pp. 4101-4105 ◽  
Author(s):  
Subramanya Lingaraju ◽  
Leen Rigouts ◽  
Aditi Gupta ◽  
Jongseok Lee ◽  
Alaine Nyaruhirira Umubyeyi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
South Korea ◽  
Tuberculosis Treatment ◽  
African Countries ◽  
Content Type ◽  
South Korean ◽  
Multistep Process ◽  
Resistant Strains ◽  
Geographic Differences ◽  
High Level

ABSTRACTEthambutol (EMB) resistance can evolve through a multistep process, and mutations in theubiA(Rv3806c) gene appear to be responsible for high-level EMB resistance inMycobacterium tuberculosis. We evaluated the prevalence ofubiAandembB(Rv3795) mutations in EMB-resistant strains originating from Africa and South Korea. No differences inembBmutation frequencies were observed between strains from both origins. However,ubiAmutations were present in 45.5% ± 6.5% of the African EMB-resistant isolates but in only 9.5% ± 1.5% of the South Korean EMB-resistant isolates. TheubiAmutations associated with EMB resistance were localized to regions encoding the transmembrane domains of the protein, whereas theembBmutations were localized to regions encoding the extramembrane domains. Larger studies are needed to investigate the causes of increasedubiAmutations as a pathway to high-level EMB resistance in African countries, such as extended EMB usage during tuberculosis treatment.

scholarly journals Evolution of Clonal and Susceptibility Profiles of Serotype 19A Streptococcus pneumoniae among Invasive Isolates from Children in Spain, 1990 to 2008

2011 ◽  
Vol 55 (5) ◽  
pp. 2297-2302 ◽  
Author(s):  
David Tarragó ◽  
Lorenzo Aguilar ◽  
Raquel García ◽  
María-José Gimenez ◽  
Juan-José Granizo ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Invasive Disease ◽  
Rapid Expansion ◽  
Reference Laboratory ◽  
Content Type ◽  
Lineal Regression ◽  
High Level ◽  
Susceptibility Profiles ◽  
Increasing Trends ◽  
Sequence Types

ABSTRACTThe genetic structure and antibiotic nonsusceptibility of all serotype 19AStreptococcus pneumoniaepediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n= 471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2= 0.872;P= 0.001). Decreasing trends (P< 0.03) were found for ST202 (R2= 0.774) and ST81 (R2= 0.559), and increasing trends (P< 0.03) for ST878 (R2= 0.544) and ST320 (R2= 0.530), both belonging to the clonal complex (CC) Denmark14-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2= 0.704) and ST4461 (R2= 0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90= 8/8 μg/ml) and 43.5% cefotaxime (MIC50/MIC90= 1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P< 0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008;R2= 0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008;R2= 0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease.

scholarly journals Antimicrobial Activity of CXA-101, a Novel Cephalosporin Tested in Combination with Tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis Strains Having Various Resistance Phenotypes

2011 ◽  
Vol 55 (5) ◽  
pp. 2390-2394 ◽  
Author(s):  
Helio S. Sader ◽  
Paul R. Rhomberg ◽  
David J. Farrell ◽  
Ronald N. Jones
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antimicrobial Activity ◽  
Klebsiella Pneumoniae ◽  
Bacteroides Fragilis ◽  
Broth Microdilution ◽  
Content Type ◽  
Clinical Strains ◽  
Extended Spectrum ◽  
The Family ◽  
Resistant Strains

ABSTRACTCXA-101, a novel oxyimino-aminothiazolyl cephalosporin, CXA-201 (CXA-101 combined with tazobactam), and various comparators were susceptibility tested by broth microdilution methods against 1,301 well-characterized clinical strains collected worldwide, including ceftazidime-resistant members of the familyEnterobacteriaceaeandKlebsiella pneumoniaecarbapenemase (KPC)- and extended-spectrum β-lactamase (ESBL)-producing strains ofPseudomonas aeruginosaandBacteroides fragilis. CXA-201 was 2- to 32-fold more active than ceftazidime and piperacillin-tazobactam against ceftazidime-resistantEnterobacteriaceaespecies but less active than cefepime for some species. CXA-101 and CXA-201 were very active againstP. aeruginosa(MIC50, 1 μg/ml for both compounds), including imipenem-resistant strains.

scholarly journals In VitroAntimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains

2015 ◽  
Vol 60 (2) ◽  
pp. 729-734 ◽  
Author(s):  
Naoki Kohira ◽  
Joshua West ◽  
Akinobu Ito ◽  
Tsukasa Ito-Horiyama ◽  
Rio Nakamura ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Enterobacter Aerogenes ◽  
Clinical Isolates ◽  
Side Chain ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class B ◽  
Resistant Strains ◽  
Cephalosporin Antibiotic ◽  
Catechol Moiety

ABSTRACTS-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 againstEnterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90values of S-649266 against the first set ofEscherichia coli,Klebsiella pneumoniae,Serratia marcescens,Citrobacter freundii,Enterobacter aerogenes, andEnterobacter cloacaeisolates were all ≤1 μg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of ≥8 μg/ml. In the second set, the MIC values of S-649266 were ≤4 μg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of ≤2 μg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity againstEnterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1.

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