scholarly journals In Vitro Activity of the Bacteriophage Endolysin HY-133 against Staphylococcus aureus Small-Colony Variants and Their Corresponding Wild Types

2019 ◽  
Vol 20 (3) ◽  
pp. 716 ◽  
Author(s):  
Nina Schleimer ◽  
Ursula Kaspar ◽  
Dennis Knaack ◽  
Christof von Eiff ◽  
Sonja Molinaro ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Options ◽  
Nasal Carriage ◽  
Resistance Mechanisms ◽  
Resistance Pattern ◽  
Small Colony Variant ◽  
Small Colony ◽  
Time Kill ◽  
Bacteriophage Endolysin

Nasal carriage of methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) represents both a source and a risk factor for subsequent infections. However, existing MRSA decolonization strategies and antibiotic treatment options are hampered by the duration of administration and particularly by the emergence of resistance. Moreover, beyond classical resistance mechanisms, functional resistance as the formation of the small-colony variant (SCV) phenotype may also impair the course and treatment of S. aureus infections. For the recombinant bacteriophage endolysin HY-133, rapid bactericidal and highly selective in vitro activities against MSSA and MRSA has been shown. In order to assess the in vitro efficacy of HY-133 against the SCV phenotype, minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were evaluated on clinical SCVs, their isogenic wild types, as well as on genetically derived and gentamicin-selected SCVs. For all strains and growth phases, HY-133 MIC and MBC ranged between 0.12 and 1 mg/L. Time-kill studies revealed a fast-acting bactericidal activity of HY-133 resulting in a ≥3 − log10 decrease in CFU/mL within 1 h compared to oxacillin, which required 4–24 h. Since the mode of action of HY-133 was independent of growth phase, resistance pattern, and phenotype, it is a promising candidate for future S. aureus decolonization strategies comprising rapid activity against phenotypic variants exhibiting functional resistance.

Phage Activity Against Planktonic and Biofilm Staphylococcus aureus Periprosthetic Joint Infection Isolates

2021 ◽  
Author(s):  
Katherine M. Caflisch ◽  
Robin Patel
Keyword(s):  
Staphylococcus Aureus ◽  
Successful Treatment ◽  
Periprosthetic Joint Infection ◽  
Joint Infection ◽  
Bacterial Isolates ◽  
Small Colony Variant ◽  
Small Colony ◽  
Planktonic State ◽  
Phage Activity

We recently reported the successful treatment of a case of periprosthetic joint infection (PJI) with phage. Phage activity against bacteria causing PJI has not been systematically evaluated. Here we examined the in vitro activity of seven lytic phages against 122 clinical isolates of Staphylococcus aureus recovered between April 1999 and February 2018 from subjects with PJI. Phages were assessed against planktonic and biofilm phenotypes. Activity of individual phages was demonstrated against up to 73% of bacterial isolates in the planktonic state and up to 100% of biofilms formed by isolates that were planktonically phage-susceptible. Susceptibility to phage was not correlated with small colony variant status. These results demonstrate that phages can infect S. aureus causing PJI in both planktonic and biofilm phenotypes, and thus are worthy of investigation as an alternative or addition to antibiotics in this setting.

scholarly journals Attenuated Vancomycin Bactericidal Activity against Staphylococcus aureus hemB Mutants Expressing the Small-Colony-Variant Phenotype

2008 ◽  
Vol 52 (4) ◽  
pp. 1533-1537 ◽  
Author(s):  
Brian T. Tsuji ◽  
Christof von Eiff ◽  
Pamela A. Kelchlin ◽  
Alan Forrest ◽  
Patrick F. Smith
Keyword(s):  
Staphylococcus Aureus ◽  
Bactericidal Activity ◽  
Pharmacodynamic Model ◽  
Small Colony Variant ◽  
Variant Phenotype ◽  
Small Colony ◽  
Bactericidal Activities

ABSTRACT The in vitro bactericidal activities of vancomycin against Staphylococcus aureus hemB mutants displaying the small-colony-variant phenotype and their parental strains were evaluated. Vancomycin killing activities against hemB mutants were markedly attenuated, demonstrating approximately 50% less effect, a result which was well described by a Hill-type pharmacodynamic model.

No evident association of nasal carriage of Staphylococcus aureus or its small-colony variants with cotrimoxazole use or ANCA-associated vasculitis relapses

Rheumatology ◽  
2019 ◽  
Vol 59 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Boun Kim Tan ◽  
Yoann Crabol ◽  
Jason Tasse ◽  
Frédéric Laurent ◽  
Narimane Nekkab ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Nasal Swab ◽  
Microscopic Polyangiitis ◽  
Nasal Carriage ◽  
Small Colony Variant ◽  
Anca Associated Vasculitis ◽  
Small Colony ◽  
Relapse Rates

AbstractObjectiveTo identify the role of Staphylococcus aureus (SA) or its intracellular small-colony variant phenotype (SCV) with co-trimoxazole (CTX) or ANCA-associated vasculitis (AAV) activity.MethodsAll consecutive AAV patients with granulomatosis with polyangiitis (GPA), eosinophilic GPA or microscopic polyangiitis, followed at the French National Vasculitis Referral Center (09/2012–05/2013), and hospitalized non-AAV controls, exclusively for SA/SCV carriage comparisons, were enrolled. All had bilateral anterior nasal swab cultures. Nasal SA or SCV carriage was determined and associations with relapse(s), BVAS, ANCA-positivity, anti-staphylococcal and immunosuppressant use, were analysed ⩾4 years post-inclusion.ResultsNasal SA carriage rates did not differ among AAVs (P = 0.53): GPA (24/80; 30%), EGPA (7/28; 25%) and microscopic polyangiitis (3/11; 27.3%); and the rate was less frequent in controls than in GPA patients not taking CTX (P = 0.04). AAV patients taking CTX prophylaxis had less nasal SA carriage (8.7% vs 36.2%; P = 0.02). Nasal SA carriage or CTX use did not modify relapse rates, BVAS or ANCA-positivity at inclusion or during follow-up. Nasal SCV carriage, found in 15/207 (7.2%) patients, was similar for GPA (10/24; 41.7%), microscopic polyangiitis (2/7; 28.6%) and eosinophilic GPA (2/3; 66.7%), but higher (P = 0.02) than controls (1/14; 7.1%). SCV carriage by AAV groups did not modify relapse rates or ANCA positivity at inclusion or during follow-up; a trend towards higher BVAS was observed only for anti-PR3 ANCA patients.ConclusionNasal SA or SCV carriage was comparable among AAVs but more frequent than in controls. Nasal SA or SCV carriage and CTX use did not modify AAV relapse rates.

scholarly journals Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients

2019 ◽  
Vol 75 (1) ◽  
pp. 126-134
Author(s):  
Melanie Roch ◽  
Maria Celeste Varela ◽  
Agustina Taglialegna ◽  
Adriana E Rosato
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Therapeutic Option ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Small Colony Variant ◽  
The Usa ◽  
Time Kill

Abstract Background Tedizolid is a protein synthesis inhibitor in clinical use for the treatment of Gram-positive infections. Pulmonary MRSA infections are a growing problem in patients with cystic fibrosis (CF) and the efficacy of tedizolid-based therapy in CF pulmonary infections is unknown. Objectives To evaluate the in vitro and in vivo activity of tedizolid and predict the likelihood of tedizolid resistance selection in CF-background Staphylococcus aureus strains. Methods A collection of 330 S. aureus strains (from adult and paediatric patients), either of normal or small colony variant (SCV) phenotypes, gathered at three CF centres in the USA was used. Tedizolid activity was assessed by broth microdilution, Etest and time–kill analysis. In vivo tedizolid efficacy was tested in a murine pneumonia model. Tedizolid in vitro mutants were obtained by 40 days of exposure and progressive passages. Whole genome sequencing of clinical S. aureus strains with reduced susceptibility to tedizolid was performed. Results MRSA strain MIC90s were tedizolid 0.12–0.25 mg/L and linezolid 1–2 mg/L; for MSSA strains, MIC90s were tedizolid 0.12 mg/L and linezolid 1–2 mg/L. Two strains, WIS 441 and Seattle 106, with tedizolid MICs of 2 mg/L and 1 mg/L, respectively, had MICs above the FDA tedizolid breakpoint (0.5 mg/L). Tedizolid at free serum concentrations exhibited a bacteriostatic effect. Mean bacterial burdens in lungs (log10 cfu/g) for WIS 423-infected mice were: control, 11.2±0.5; tedizolid-treated (10 mg/kg), 3.40±1.87; linezolid-treated (40 mg/kg), 4.51±2.1; and vancomycin-treated (30 mg/kg), 5.21±1.93. For WIS 441-infected mice the (log10 cfu/g) values were: control, 9.66±0.8; tedizolid-treated, 3.18±1.35; linezolid-treated 5.94±2.19; and vancomycin-treated, 4.35±1.7. Conclusions These results suggest that tedizolid represents a promising therapeutic option for the treatment of CF-associated MRSA/MSSA infections, having potent in vivo activity and low resistance potential.

Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin

2020 ◽  
Vol 75 (6) ◽  
pp. 1466-1473 ◽  
Author(s):  
Lélia Abad ◽  
Jérôme Josse ◽  
Jason Tasse ◽  
Sébastien Lustig ◽  
Tristan Ferry ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Therapeutic Potential ◽  
Joint Infection ◽  
Small Colony Variant ◽  
Resistance Selection ◽  
Low Concentrations ◽  
Infection Models ◽  
Small Colony

Abstract Background Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated. Objectives To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models. Methods Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in ‘acute’ (24 h) and ‘chronic’ (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT–PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC). Results At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively. Conclusions All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential.

scholarly journals In VitroSusceptibility of ClinicalStaphylococcus aureusSmall-Colony Variants to β-Lactam and Non-β-Lactam Antibiotics

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Evgeny A. Idelevich ◽  
André Kriegeskorte ◽  
Nina Schleimer ◽  
Georg Peters ◽  
Christof von Eiff ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Prolonged Incubation ◽  
Content Type ◽  
Small Colony Variant ◽  
Normal Phenotype ◽  
Gradient Diffusion ◽  
Small Colony ◽  
Inhibition Zones

ABSTRACTTheStaphylococcus aureussmall-colony variant (SCV) phenotype has been associated with relapsing and antibiotic-refractory infections. However, little is known about the activities of antibiotics on clinical SCVs. Here, we demonstrated that SCVs without detectable auxotrophies were at least as susceptible to most β-lactam and non-β-lactam antibioticsin vitroas their corresponding clonally identical strains with a normal phenotype. After prolonged incubation, a regrowth phenomenon has been observed in gradient diffusion inhibition zones irrespective of the strains' phenotype.

scholarly journals Involvement of Small Colony Variant-Related Heme Biosynthesis Genes in Staphylococcus aureus Persister Formation in vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuyang Wang ◽  
Weizheng Li ◽  
Wenjie Wang ◽  
Shiyong Wang ◽  
Tao Xu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Acid Stress ◽  
Heme Biosynthesis ◽  
Rna Seq ◽  
Small Colony Variant ◽  
Persistent Infections ◽  
Allelic Replacement ◽  
Small Colony ◽  
The Relationship

Background: Persisters are important reasons for persistent infections, and they can lead to antibiotic treatment failure in patients and consequently chronic infection. Staphylococcus aureus small colony variants (SCVs) have been shown to be related to persistent infection. Mutations in the genes of the heme biosynthesis pathway lead to the formation of SCVs. However, the relationship between heme production genes and persister has not been tested.Methods:HemA and hemB were knocked out by allelic replacement from S. aureus strain USA500 separately, and then, the heme deficiency was complemented by overexpression of related genes and the addition of hemin. The stress-related persister assay was conducted. RNA-sequencing was performed to find genes and pathways involved in heme-related persister formation, and relative genes and operons were further knocked out and overexpressed to confirm their role in each process.Results: We found that heme biosynthesis deficiency can lead to decreased persister. After complementing the corresponding genes or hemin, the persister levels could be restored. RNA-seq on knockout strains showed that various metabolic pathways were influenced, such as energy metabolism, amino acid metabolism, carbohydrate metabolism, and membrane transport. Overexpression of epiF and operon asp23 could restore USA500∆hemA persister formation under acid stress. Knocking out operon arc in USA500∆hemA could further reduce USA500∆hemA persister formation under acid and oxidative stress.Conclusion: Heme synthesis has a role in S. aureus persister formation.

scholarly journals Diversity of Multidrug Efflux Genes and Phenotypic Evaluation of the In vitro Resistance Dynamics of Clinical Staphylococcus Aureus Isolates Using Methicillin; a Model β-lactam

2017 ◽  
Vol 11 (1) ◽  
pp. 132-141 ◽  
Author(s):  
John F. Antiabong ◽  
Marleen M. Kock ◽  
Nontombi M. Mbelle ◽  
Marthie M. Ehlers
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Options ◽  
Hospital Setting ◽  
Growth Dynamics ◽  
Distribution Patterns ◽  
Clinical Isolates ◽  
Resistance Pattern ◽  
Bacterial Survival ◽  
Phenotypic Resistance

Objectives:Methicillin-resistantStaphylococcus aureus(MRSA) across the world often leave clinicians with little or no choice of treatment options. The multi-drug efflux (MDE) genes are bacterial survival mechanisms responsible for the pumping out of antibiotics and other biocides from the cytoplasm. Whilst effort is being made in the development of antibiotic adjuvants such as efflux pumps inhibitors, information is needed on the diversity of these MDEs in the circulatingS. aureusand on the growth dynamics of the clinical isolates in response to antibiotics is not regularly examined.Methods:Here, we evaluated the diversity of MDEs in cinicalS. aureusrecovered in a tertiary academic hospital, Pretoria, South African hospital using PCR and also employed visual minimum inhibitory concentration and quantitative analysis of spectrophometric measurements of bacterial growth in the presence of a model β lactam antibiotic (methicillin), to phenotypically elucidate the resistance pattern of these isolates in response to methicillin.Results:Three major distribution patterns of MDEs were observed in the clinical isolates evaluated. Moreover,norA,norB andtet38 were present in 98.9% of the isolates while other MDE were present in different proportions ranging from 40 to 98.6% of the isolates. In addition,S. aureusisolates, be it of MRSA or MSSA genotype did not habour the same set of MDEs despite being recovered from the same hospital setting. Finally, we showed that MSSA displayed phenotypic resistance to methicilllin despite the non-detection of themecA resistance gene.Conclusions:Our data suggest that the growth ofS. aureusmay be enhanced by β lactams (methicillin) and that MSSA may also display resistance to methicillin and perhaps other β lactam antibiotics. The high prevalence of MDEs suggestive of resistance to a broad spectrum of biocides and fluoroquinolones are particularly disturbing.

Bacterial brothers in arms: cooperation of Staphylococcus aureus and Pseudomonas aeruginosa during antimicrobial exposure

2019 ◽  
Vol 74 (9) ◽  
pp. 2657-2665 ◽  
Author(s):  
Justin R Lenhard ◽  
Nicholas M Smith ◽  
Christine D Quach ◽  
Tuan Q Nguyen ◽  
Linh H Doan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Polymyxin B ◽  
Bacterial Killing ◽  
Small Colony Variant ◽  
Killing Rate ◽  
Small Colony ◽  
Time Kill ◽  
Significant Protective Effect ◽  
Selection Of

Abstract Objectives The optimal selection of antibacterials during polymicrobial infections is poorly defined. The objective of the current investigation was to quantify the pharmacodynamics of relevant antimicrobials during co-culture of Pseudomonas aeruginosa with two separate Staphylococcus aureus phenotypes. Methods Time–kill experiments were conducted against co-cultures of the P. aeruginosa strain PA01 paired with either the normal phenotype (NP) MRSA isolate COL or the small colony variant phenotype (SCVP) MRSA isolate Ia48. The killing by levofloxacin, gentamicin, clindamycin, vancomycin and polymyxin B was evaluated to investigate drugs with activity against one or both pathogens. A Hill-type function and a mechanism-based model were used to describe bacterial killing. Results P. aeruginosa attenuated the activity of clindamycin against NP MRSA, with a reduction in the Emax (maximal killing) from 3.67 (95% CI 2.79–4.56) in monoculture to 1.86 (95% CI 1.35–2.37) during co-culture, whereas a significant protective effect was not observed for other antibacterials. The reduction in NP MRSA killing by clindamycin was described well by a mechanism-based model that generated a maximal killing rate constant of clindamycin against the susceptible NP MRSA subpopulation of 0.267 h−1 in monoculture and 0.0395 h−1 in the presence of P. aeruginosa. During exposure to gentamicin, P. aeruginosa was the dominant organism in co-culture experiments regardless of the drug concentration or S. aureus phenotype; however, the SCVP MRSA was able to dominate the joint population beginning at a levofloxacin concentration of 1.5 mg/L. Conclusions The anti-staphylococcal activity of clindamycin was attenuated by the presence of P. aeruginosa.

scholarly journals Comparative In Vitro Activity of Ceftobiprole against Staphylococci Displaying Normal and Small-Colony Variant Phenotypes

2005 ◽  
Vol 49 (10) ◽  
pp. 4372-4374 ◽  
Author(s):  
Christof von Eiff ◽  
Alexander W. Friedrich ◽  
Karsten Becker ◽  
Georg Peters
Keyword(s):  
Staphylococcus Aureus ◽  
Vitro Activity ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
In Vitro Activity ◽  
Small Colony Variant ◽  
Antistaphylococcal Activity ◽  
Agar Dilution ◽  
Small Colony

ABSTRACT The antistaphylococcal activity of ceftobiprole was compared with those of cefuroxime, linezolid, and moxifloxacin by using the agar dilution method. Apart from three strains with small-colony variant phenotypes, all Staphylococcus aureus isolates tested were inhibited by ≤2 μg/ml of ceftobiprole. This compound exhibited an excellent antistaphylococcal activity, comparable to that of linezolid.

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