scholarly journals Rapid resistance development to three antistaphylococcal therapies in antibiotic-tolerant staphylococcus aureus bacteremia

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258592
Author(s):  
Christopher R. Miller ◽  
Jonathan M. Monk ◽  
Richard Szubin ◽  
Andrew D. Berti
Keyword(s):  
Staphylococcus Aureus ◽  
Subsequent Development ◽  
Multidrug Resistant ◽  
Blood Cultures ◽  
Therapeutic Interventions ◽  
Prevention Measures ◽  
Beta Lactam ◽  
Resistance Development

Understating how antibiotic tolerance impacts subsequent resistance development in the clinical setting is important to identifying effective therapeutic interventions and prevention measures. This study describes a patient case of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia which rapidly developed resistance to three primary MRSA therapies and identifies genetic and metabolic changes selected in vivo that are associated with rapid resistance evolution. Index blood cultures displayed susceptibility to all (non-beta-lactam) antibiotics with the exception of trimethoprim/ sulfamethoxazole. One month after initial presentation, during the same encounter, blood cultures were again positive for MRSA, now displaying intermediate resistance to vancomycin and ceftaroline and resistance to daptomycin. Two weeks later, blood cultures were positive for a third time, still intermediate resistant to vancomycin and ceftaroline and resistant to daptomycin. Mutations in mprF and vraT were common to all multidrug resistant isolates whereas mutations in tagH, agrB and saeR and secondary mprF mutation emerged sequentially and transiently resulting in distinct in vitro phenotypes. The baseline mutation rate of the patient isolates was unremarkable ruling out the hypermutator phenotype as a contributor to the rapid emergence of resistance. However, the index isolate demonstrated pronounced tolerance to the antibiotic daptomycin, a phenotype that facilitates the subsequent development of resistance during antibiotic exposure. This study exemplifies the capacity of antibiotic-tolerant pathogens to rapidly develop both stable and transient genetic and phenotypic changes, over the course of a single patient encounter.

scholarly journals Staphylococcus aureus infects osteoclasts and replicates intracellularly

2019 ◽  
Author(s):  
Jennifer L Krauss ◽  
Philip M Roper ◽  
Anna Ballard ◽  
Chien-Cheng Shih ◽  
James AJ Fitzpatrick ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Confocal Microscopy ◽  
Bone Tissue ◽  
Post Infection ◽  
Bone Structure ◽  
High Rate ◽  
Therapeutic Interventions ◽  
Intracellular Infection

AbstractOsteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. The majority of OM is caused by Staphylococcus aureus, and even with proper treatment, OM has a high rate of recurrence and chronicity. While S. aureus has been shown to infect osteoblasts, persist intracellularly, and promote the release of pro-osteoclastogenic cytokines, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. In this study, we examined the interaction between S. aureus and OCs, demonstrating internalization of GFP-labeled bacteria by confocal microscopy, both in vitro and in vivo. Utilizing an intracellular survival assay and flow cytometry during OC differentiation from bone marrow macrophages (BMMs), we found that the intracellular burden of S. aureus increases after initial infection in cells with at least 2 days of exposure to the osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand (RANKL). Presence of dividing bacteria was confirmed via visualization by transmission electron microscopy. In contrast, undifferentiated BMMs, or those treated with interferon-γ or IL-4, had fewer internal bacteria, or no change, respectively, at 18 hours post infection, compared to 1.5 hours post infection. To further explore the signals downstream of RANKL, we manipulated NFATc1 and alternative NF-κB, which controls NFATc1 and other factors affecting OC function, finding that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal microscopy in mature OCs showed a range of intracellular infection that correlated inversely with S. aureus and phagolysosome colocalization. The ability of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing S. aureus to evade initial immune regulation and proliferate at the periphery of lesions where OCs and bone remodeling are most abundant.Author SummaryThe inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium Staphylococcus aureus. To date, the bone building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone resorbing cells, osteoclasts, participate. In this study, we show that S. aureus can infect osteoclasts and proliferate inside these cells, whereas macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system. Therapeutic interventions that target osteoclasts specifically might reduce the severity of OM or improve antibiotic responses.

scholarly journals Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity

2012 ◽  
Vol 56 (10) ◽  
pp. 5296-5302 ◽  
Author(s):  
Warren E. Rose ◽  
Lucas T. Schulz ◽  
David Andes ◽  
Rob Striker ◽  
Andrew D. Berti ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Combination Therapy ◽  
Membrane Damage ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Content Type ◽  
Cell Membrane Damage

ABSTRACTAntistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistantStaphylococcus aureus(MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. Anin vitropharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivityin vivoand resulted in clearance of persistent blood cultures. Daptomycin susceptibilityin vitrowas increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Bothin vivo- andin vitro-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initialin vivoisolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.

scholarly journals Antibiotic Treatment of Experimental Pneumonic Plague in Mice

1998 ◽  
Vol 42 (3) ◽  
pp. 675-681 ◽  
Author(s):  
William R. Byrne ◽  
Susan L. Welkos ◽  
M. Louise Pitt ◽  
Kelly J. Davis ◽  
Ralf P. Brueckner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Antibiotic Treatment ◽  
Survival Rates ◽  
Blood Cultures ◽  
High Dose ◽  
Beta Lactam ◽  
Pneumonic Plague ◽  
Beta Lactam Antibiotics

ABSTRACT A mouse model was developed to evaluate the efficacy of antibiotic treatment of pneumonic plague; streptomycin was compared to antibiotics with which there is little or no clinical experience. Infection was induced by inhalation of aerosolized Yersinia pestisorganisms. Antibiotics were administered by intraperitoneal injection every 6 hours for 5 days, at doses that produced levels of drug in serum comparable to those observed in humans treated for other serious infections. These studies compared in vitro to in vivo activity and evaluated the efficacy of antibiotics started at different times after exposure. Early treatment (started 24 h after challenge, when 0 of 10 mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, ceftriaxone, ceftazidime, aztreonam, ampicillin, and rifampin (but not cefazolin, cefotetan, or ceftizoxime) demonstrated efficacy comparable to streptomycin. Late treatment (started 42 h after exposure, when five of five mice tested had positive blood cultures) with netilmicin, ciprofloxacin, ofloxacin, and a high dose (20 mg/kg of body weight every 6 h) of gentamicin produced survival rates comparable to that with streptomycin, while all of the beta-lactam antibiotics (cefazolin, cefotetan, ceftriaxone, ceftazidime, aztreonam, and ampicillin) and rifampin were significantly inferior to streptomycin. In fact, all groups of mice treated late with beta-lactam antibiotics experienced accelerated mortality rates compared to normal-saline-treated control mice. These studies indicate that netilmicin, gentamicin, ciprofloxacin, and ofloxacin may be alternatives for the treatment of pneumonic plague in humans. However, the beta-lactam antibiotics are not recommended, based upon poor efficacy in this mouse model of pneumonic plague, particularly when pneumonic plague may be associated with bacteremia.

scholarly journals Development of a Conserved Chimeric Vaccine for Induction of Strong Immune Response against Staphylococcus aureus Using Immunoinformatics Approaches

Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1038
Author(s):  
Rahul Chatterjee ◽  
Panchanan Sahoo ◽  
Soumya Ranjan Mahapatra ◽  
Jyotirmayee Dey ◽  
Mrinmoy Ghosh ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Multidrug Resistant ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Population Coverage ◽  
Strong Immune Response ◽  
Chimeric Vaccine

Staphylococcus aureus is one of the most notorious Gram-positive bacteria with a very high mortality rate. The WHO has listed S. aureus as one of the ESKAPE pathogens requiring urgent research and development efforts to fight against it. Yet there is a major layback in the advancement of effective vaccines against this multidrug-resistant pathogen. SdrD and SdrE proteins are attractive immunogen candidates as they are conserved among all the strains and contribute specifically to bacterial adherence to the host cells. Furthermore, these proteins are predicted to be highly antigenic and essential for pathogen survival. Therefore, in this study, using the immunoinformatics approach, a novel vaccine candidate was constructed using highly immunogenic conserved T-cell and B-cell epitopes along with specific linkers, adjuvants, and consequently modeled for docking with human Toll-like receptor 2. Additionally, physicochemical properties, secondary structure, disulphide engineering, and population coverage analysis were also analyzed for the vaccine. The constructed vaccine showed good results of worldwide population coverage and a promising immune response. For evaluation of the stability of the vaccine-TLR-2 docked complex, a molecular dynamics simulation was performed. The constructed vaccine was subjected to in silico immune simulations by C-ImmSim and Immune simulation significantly provided high levels of immunoglobulins, T-helper cells, T-cytotoxic cells, and INF-γ. Lastly, upon cloning, the vaccine protein was reverse transcribed into a DNA sequence and cloned into a pET28a (+) vector to ensure translational potency and microbial expression. The overall results of the study showed that the designed novel chimeric vaccine can simultaneously elicit humoral and cell-mediated immune responses and is a reliable construct for subsequent in vivo and in vitro studies against the pathogen.

SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance

2021 ◽  
Author(s):  
Chieh-Hsien Lu ◽  
Chung-Wai Shiau ◽  
Yung-Chi Chang ◽  
Hsiu-Ni Kung ◽  
Jui-Ching Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mode Of Action ◽  
Cytoplasmic Membrane ◽  
Resistance Development ◽  
Antibiotic Resistant ◽  
Atp Production ◽  
The Past ◽  
Ht 29

Abstract Objectives In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound. Methods The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry. Results SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters. Conclusions Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.

Rationally designed curcumin based ruthenium(ii) antimicrobials effective against drug-resistant Staphylococcus aureus

2019 ◽  
Vol 48 (31) ◽  
pp. 11822-11828 ◽  
Author(s):  
Payal Srivastava ◽  
Manjulika Shukla ◽  
Grace Kaul ◽  
Sidharth Chopra ◽  
Ashis K. Patra
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Polypyridyl Complexes

Two curcumin conjugated ruthenium(ii) polypyridyl complexes, [Ru(NN)2(cur)](PF6) (1, 2), were systematically exploited for their antimicrobial activity in vitro and in vivo and potential selectivity against multidrug resistant S. aureus strains.

scholarly journals In Vitro and In Vivo Antibacterial Activity of Gliotoxin Alone and in Combination with Antibiotics against Staphylococcus aureus

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 85
Author(s):  
Patricia Esteban ◽  
Sergio Redrado ◽  
Laura Comas ◽  
M. Pilar Domingo ◽  
M. Isabel Millán-Lou ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Antimicrobial Drugs ◽  
Hospital Acquired ◽  
Antibiotic Efficacy

Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital-acquired and community infections and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin (GT) is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that GT shows antimicrobial activity against S. aureus in vitro, albeit its efficacy against multidrug-resistant strains such as MRSA or vancomycin-intermediate S. aureus (VISA) strainsis not known. This work aimed to evaluate the antibiotic efficacy of GT as monotherapy or in combination with other therapeutics against MRSA in vitro and in vivo using a Caenorhabditis elegans infection model.

scholarly journals Erianin against Staphylococcus aureus Infection via Inhibiting Sortase A

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 385 ◽  
Author(s):  
Ping Ouyang ◽  
Xuewen He ◽  
Zhong-Wei Yuan ◽  
Zhong-Qiong Yin ◽  
Hualin Fu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Hydrophobic Interactions ◽  
Multidrug Resistant ◽  
Vital Role ◽  
Surface Proteins ◽  
Dynamics Simulation ◽  
Sortase A

With continuous emergence and widespread of multidrug-resistant Staphylococcus aureus infections, common antibiotics have become ineffective in treating these infections in the clinical setting. Anti-virulence strategies could be novel, effective therapeutic strategies against drug-resistant bacterial infections. Sortase A (srtA), a transpeptidase in gram-positive bacteria, can anchor surface proteins that play a vital role in pathogenesis of these bacteria. SrtA is known as a potential antivirulent drug target to treat bacterial infections. In this study, we found that erianin, a natural bibenzyl compound, could inhibit the activity of srtA in vitro (half maximal inhibitory concentration—IC50 = 20.91 ± 2.31 μg/mL, 65.7 ± 7.2 μM) at subminimum inhibitory concentrations (minimum inhibitory concentrations—MIC = 512 μg/mL against S. aureus). The molecular mechanism underlying the inhibition of srtA by erianin was identified using molecular dynamics simulation: erianin binds to srtA residues Ile182, Val193, Trp194, Arg197, and Ile199, forming a stable bond via hydrophobic interactions. In addition, the activities of S. aureus binding to fibronectin and biofilm formation were inhibited by erianin, when co-culture with S. aureus. In vivo, erianin could improve the survival in mice that infected with S. aureus by tail vein injection. Experimental results showed that erianin is a potential novel therapeutic compound against S. aureus infections via affecting srtA.

scholarly journals Histatin-Derived Monomeric and Dimeric Synthetic Peptides Show Strong Bactericidal Activity towards Multidrug-Resistant Staphylococcus aureus In Vivo

2007 ◽  
Vol 51 (9) ◽  
pp. 3416-3419 ◽  
Author(s):  
Mick M. Welling ◽  
Carlo P. J. M. Brouwer ◽  
Wim van ′t Hof ◽  
Enno C. I. Veerman ◽  
Arie V. Nieuw Amerongen
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
Bactericidal Activity ◽  
Synthetic Peptides ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Drug Resistant Bacteria

ABSTRACT Homodimerization of histatin-derived peptides generally led to improved bactericidal activity against Staphylococcus aureus in vitro. In vivo, monomers and dimers were equally active in killing bacteria in mice with a soft tissue infection. Altogether, these peptides are promising compounds for the development of novel therapeutics against infections with drug-resistant bacteria.

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