Treatment Of Methicillin-resistant Staphylococcus Aureus Infections Research Articles

Thymol Inhibits Biofilm Formation, Eliminates Pre-Existing Biofilms, and Enhances Clearance of Methicillin-Resistant Staphylococcus aureus (MRSA) in a Mouse Peritoneal Implant Infection Model.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common human pathogen that causes several difficult-to-treat infections, including biofilm-associated infections. The biofilm-forming ability of S. aureus plays a pivotal role in its resistance to most currently available antibiotics, including vancomycin, which is the first-choice drug for treating MRSA infections. In this study, the ability of thymol (a monoterpenoid phenol isolated from plants) to inhibit biofilm formation and to eliminate mature biofilms, was assessed. We found that thymol could inhibit biofilm formation and remove mature biofilms by inhibiting the production of polysaccharide intracellular adhesin (PIA) and the release of extracellular DNA (eDNA). However, cotreatment with thymol and vancomycin was more effective at eliminating MRSA biofilms, in a mouse infection model, than monotherapy with vancomycin. Comparative histopathological analyses revealed that thymol reduced the pathological changes and inflammatory responses in the wounds. Assessments of white blood cell counts and serum TNF-α and IL-6 levels showed reduced inflammation and an increased immune response following treatment with thymol and vancomycin. These results indicate that combinatorial treatment with thymol and vancomycin has the potential to serve as a more effective therapy for MRSA biofilm-associated infections than vancomycin monotherapy.

Potent trifluoromethoxy, trifluoromethylsulfonyl, trifluoromethylthio and pentafluorosulfanyl containing (1,3,4-oxadiazol-2-yl)benzamides against drug-resistant Gram-positive bacteria.

According to the Centers for Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) affects about 80 000 patients in the US annually and directly causes about 11 000 deaths. Therefore, despite the fact that there are several drugs available for the treatment of MRSA, there is a need for new chemical entities. We previously reported that 1,3,4-oxadiazolyl sulfonamide F6 was bacteriostatic and inhibited MRSA strains with a minimum inhibitory concentration (MIC) of 2 μg mL-1. Here, we report the discovery of trifluoromethoxy (OCF3), trifluoromethylsulfonyl (SO2CF3), trifluoromethylthio (SCF3) and pentafluorosulfanyl (SF5) containing (1,3,4-oxadiazol-2-yl)benzamides exhibiting potent antibacterial activities against MRSA [MIC values as low as 0.06 μg mL-1 against linezolid-resistant S. aureus (NRS 119)]. Interestingly, whereas the OCF3 and SO2CF3 containing oxadiazoles were bacteriostatic, the SCF3 and SF5 containing oxadiazoles were bactericidal. They exhibited a wide spectrum of activities against an extensive panel of Gram-positive bacterial strains, including MRSA, vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-resistant enterococcus (VRE) and methicillin-resistant or cephalosporin-resistant Streptococcus pneumoniae. Furthermore, compounds 6 and 12 outperformed vancomycin in clearing intracellular MRSA in infected macrophages. Moreover, the tested compounds behaved synergistically or additively with antibiotics used for the treatment of MRSA infections.

Levonadifloxacin arginine salt to treat acute bacterial skin and skin structure infection due to S. aureus including MRSA.

Acute bacterial skin and skin structure infections (ABSSSIs) are one of the most common types of infections due to methicillin-resistant Staphylococcus aureus (MRSA). The standard of care for ABSSSI includes glycopeptides such as vancomycin, teicoplanin, oxazolidinones and fluoroquinolones, which are potent broad-spectrum antibacterial agents. Unfortunately, due to indiscriminate utilization, resistance to these agents is rising and identification of novel agents is an urgent unmet medical need. In this context, levonadifloxacin (WCK-771) is a novel, hydrate arginine salt of nadifloxacin with improved bactericidal activity against MRSA as well as fluoroquinolone-resistant S. aureus by targeting bacterial DNA supercoiling enzymes DNA gyrase and topoisomerase IV. Levonadifloxacin displays a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria, atypical bacteria, anaerobic bacteria and bioterror pathogens with a very low frequency of mutation. Levonadifloxacin also displays improved activity under low pH biofilm environments. The drug has successfully completed phase I, phase II and phase III clinical trials in India. The U.S. Food and Drug Administration (FDA) granted a Qualified Infectious Disease Product (QIDP) designation to levonadifloxacin for the treatment of MRSA infections in August 2014.

Monoclonal antibody anti-PBP2a protects mice against MRSA (methicillin-resistant Staphylococcus aureus) infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant bacterium responsible for serious nosocomial and community-acquired infections worldwide. Since few antibiotics are effective for treating MRSA infections, the development of new therapies is of great importance. Previous studies demonstrated that PBP2a is a target that generates protective antibodies against MRSA. A murine monoclonal antibody (MAb) that recognizes PBP2a from MRSA strains was previously isolated and characterized. In this report, we evaluated the biodistribution of this MAb in blood and tissues, as well as the extent of protection conferred using prophylactic and therapeutic assays compared to vancomycin treatment. Biodistribution was evaluated 12–96 h after MAb administration. It predominantly remained in the serum, but it was also detectable in the kidneys, lungs, and spleen at low concentrations (about 4.5% in the kidneys, 1.9% in the lungs, and 0.7% the spleen) at all observed timepoints. Prophylactic studies in a murine model demonstrated a significant bacterial load reduction in the kidneys of the groups treated with either with IgG (greater than 3 logs) or F(ab’)2 (98%) when compared to that of the control groups (untreated). Mice were challenged with a lethal dose, and the survival rate was higher in the treated mice. Treatment with the MAb resulted in a bacterial load reduction in the kidneys similar to that of mice treated with vancomycin, and a MAb/vancomycin combination therapy was also effective. These results demonstrate that an anti-PBP2a MAb may be a promising therapeutic for treating MRSA infections.

Correlation of Host Range Expansion of Therapeutic Bacteriophage Sb-1 with Allele State at a Hypervariable Repeat Locus.

Staphylococci are frequent agents of health care-associated infections and include methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to first-line antibiotic treatments. Bacteriophage (phage) therapy is a promising alternative antibacterial option to treat MRSA infections. S. aureus-specific phage Sb-1 has been widely used in Georgia to treat a variety of human S. aureus infections. Sb-1 has a broad host range within S. aureus, including MRSA strains, and its host range can be further expanded by adaptation to previously resistant clinical isolates. The susceptibilities of a panel of 25 genetically diverse clinical MRSA isolates to Sb-1 phage were tested, and the phage had lytic activity against 23 strains (92%). The adapted phage stock (designated Sb-1A) was tested in comparison with the parental phage (designated Sb-1P). Sb-1P had lytic activity against 78/90 strains (87%) in an expanded panel of diverse global S. aureus isolates, while eight additional strains in this panel were susceptible to Sb-1A (lytic against 86/90 strains [96%]). The Sb-1A stock was shown to be a mixed population of phage clones, including approximately 4% expanded host range mutants, designated Sb-1M. In an effort to better understand the genetic basis for this host range expansion, we sequenced the complete genomes of the parental Sb-1P and two Sb-1M mutants. Comparative genomic analysis revealed a hypervariable complex repeat structure in the Sb-1 genome that had a distinct allele that correlated with the host range expansion. This hypervariable region was previously uncharacterized in Twort-like phages and represents a novel putative host range determinant.IMPORTANCE Because of limited therapeutic options, infections caused by methicillin-resistant Staphylococcus aureus represent a serious problem in both civilian and military health care settings. Phages have potential as alternative antibacterial agents that can be used in combination with antibiotic drugs. For decades, phage Sb-1 has been used in former Soviet Union countries for antistaphylococcal treatment in humans. The therapeutic spectrum of activity of Sb-1 can be increased by selecting mutants of the phage with expanded host ranges. In this work, the host range of phage Sb-1 was expanded in the laboratory, and a hypervariable region in its genome was identified with a distinct allele state that correlated with this host range expansion. These results provide a genetic basis for better understanding the mechanisms of phage host range expansion.

Efficacy of newly generated short antimicrobial cationic lipopeptides against methicillin-resistant Staphylococcus aureus (MRSA)

IntroductionInfection caused by methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) is a serious clinical challenge and research to develop new antimicrobials is imperative. MethodsThis study investigated the in vitro and in vivo efficacy of the short cationic dialkyl lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2. The antibacterial efficacy of (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 was evaluated in representative clinical methicillin-susceptible S. aureus and MRSA strains by both in vitro (MIC, time-kill curve) and in vivo (wax worms model) approaches. ResultsThese studies revealed that both (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 have rapid bactericidal activity, with a decrease of > 3 log10 colony forming units (CFU)/mL achieved in the first 6 hours of treatment. Furthermore, (C10)2-KKKK-NH2 performed similarly to daptomycin, with a sustained bacterial killing after 24 hours. Wax worms infected and treated with these lipopeptides showed a decreased survival rate of 90% to 50% within the first day of treatment. Scanning electron microscopy determined that the effect of the short lipopeptides in S. aureus was associated with important morphological structural changes that may suggest cell membrane perturbation. ConclusionThese findings suggest that the short lipopeptides (C10)2-KKKK-NH2 and (C12)2-KKKK-NH2 may be potential new options for treating MRSA infections.

Effect of Ceftaroline, Vancomycin, Gentamicin, Macrolides, and Ciprofloxacin against Methicillin-Resistant Staphylococcus aureus Isolates: An In Vitro Study.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) infection remains a challenging threat because of limited treatment options. Ceftaroline was identified as having potent anti-MRSA activity. Aim: To evaluate the susceptibility of MRSA to gentamicin, macrolides, ciprofloxacin, vancomycin, and ceftaroline and to perform molecular characterization of different resistance genes as aminoglycoside modifying enzyme genes, ermA and ermC, and vanA and vanB genes. Patients and Methods: One hundred non-duplicate MRSA strains were isolated from different samples of hospitalized patients in Cairo University teaching hospitals from November 2015 to August 2016. Determination of antibiotic susceptibility was done using disk diffusion test and minimum inhibitory concentration followed by detection of resistance genes by multiplex polymerase chain reaction (PCR). Results: Of 100 MRSA isolates, 63 (63%) were resistant to gentamicin, erythromycin, clindamycin, and ciprofloxacin, however, all were sensitive to ceftaroline. Fifteen isolates (15%) were vancomycin intermediate resistant and were sensitive to ceftaroline as well. Conclusion: Ceftaroline was potent against MRSA, which was found to be non-susceptible to vancomycin, ciprofloxacin, erythromycin, clindamycin, and gentamicin and it may represent a successful treatment for MRSA infections.

Two optimized antimicrobial peptides with therapeutic potential for clinical antibiotic-resistant Staphylococcus aureus

The rapid increase of Methicillin-resistant Staphylococcus aureus (MRSA) infections and the cross-resistance of MRSA to other antibiotics create an urgent demand for new therapeutic agents. Antimicrobial peptides (AMPs) are one of the most promising options for next-generation antibiotics. In this study, novel peptides were designed based on antimicrobial peptide fragments derived from Aristicluthys nobilia interferon-I to promote anti-MRSA activity and decrease adverse effects. Design strategies included substitutions of charged or hydrophobic amino acid residues for noncharged polar residues to promote amphipathicity. Two designed peptides, P5 (YIRKIRRFFKKLKKILKK-NH2) and P9 (SYERKINRHFKTLKKNLKKK-NH2), showed potent antimicrobial activities against both sensitive Staphylococcus aureus clinical isolates and MRSA strains without significant hemolysis or cytotoxicity to human hemocytes and renal epithelial cells. Scanning Electronic Microscopy (SEM) and qRT-PCR were employed to investigate the effects of P5 and P9 on S. aureus biofilm formation, morphology, and virulence-related gene expression. P5 and P9 significantly inhibited the biofilm and destroyed the cell membrane integrity, in addition to down-regulating several virulence factor genes and biofilm formation-related genes including spa, hld, and sdrC. P5 and P9 could be promising candidate antibacterial agents for the treatment of MRSA infections.

Photothermal Killing of Methicillin-Resistant Staphylococcus aureus by Bacteria-Targeted Polydopamine Nanoparticles with Nano-Localized Hyperpyrexia

Bacterial infections caused by antibiotic-resistant pathogens have become intractable problems to public health. Therefore, there is an imperious demand for developing new approaches to effectively kill antibiotic-resistant bacteria. In this work, we report a kind of bacteria-targeted polydopamine nanoparticle exhibiting great photothermal killing ability toward methicillin-resistant Staphylococcus aureus (MRSA) by nano-localized hyperpyrexia under low-power near-infrared (NIR) light irradiation. These bacteria-targeted nanoparticles (PDA-PEG-Van) are prepared by modifying polydopamine nanoparticles with thiol-poly(ethylene glycol) (mPEG-SH) and vancomycin (Van) molecules. The PEG shell endows the nanoparticles with excellent long-term circulation stability. Due to the multivalent hydrogen-bond interactions between vancomycin and the MRSA cell wall, the vancomycin-modified polydopamine nanoparticles can specifically target MRSA rather than mammalian cells. These bacteria-targeted nanoparticles are employed as a nano-localized heat source to kill MRSA via disrupting the bacterial cell wall and membrane under irradiation of low-power NIR light. More importantly, the surrounding healthy tissues suffer bare damage, owing to the absence of any targeting effect of PDA-PEG-Van toward mammalian cells and the low power of NIR light used in the therapeutic process. Given the above advantages, the bacteria-targeted polydopamine nanoparticles proposed in this work show tremendous potential to treat MRSA infections, because they can effectively limit localized heating in the infection sites to kill bacteria and cut down damage to healthy tissues.

Self-assembled oleylamine grafted hyaluronic acid polymersomes for delivery of vancomycin against methicillin resistant Staphylococcus aureus (MRSA)

MRSA infections are a major global healthcare problem associated with high morbidity and mortality. The application of novel materials in antibiotic delivery has efficiently contributed to the treatment of MRSA infections. The aim of the study was to develop novel hyaluronic acid-oleylamine (HA-OLA) conjugates with 25–50% degrees of conjugation, for application as a nano-drug carrier with inherent antibacterial activity. The biosafety of synthesized novel HA-OLA conjugates was confirmed by in vitro cytotoxicity assay. Drug carrying ability of HA-OLA conjugates was confirmed by 26.1–43.12% of vancomycin (VCM) encapsulation in self-assembled polymersomes. These polymersomes were dispersed in nano-sized range (196.1–360.9 nm) with a negative zeta potential. Vancomycin loaded polymersomes were found to have spherical and bilayered morphology. The VCM loaded polymersomes displayed sustained drug release for 72 h. In vitro studies showed moderate antibacterial activity for HA-OLA conjugates against both S. aureus and MRSA with minimum inhibitory concentration (MIC) of 500 μg/mL. The VCM loaded HA-OLA polymersomes displayed four-fold lower MIC (1.9 μg/mL) than free VCM (7.8 μg/mL) against MRSA. Furthermore, synergism was observed for VCM and HA-OLA against MRSA. Flow cytometry showed 1.8-fold higher MRSA cell death in the population for VCM loaded polymersomes relative to free drug, at concentration of 1.95 μg/mL. Bacterial cell morphology showed that the drug loaded polymersomes had stronger impact on MRSA membrane, compared to free VCM. These findings suggest that, HA-OLA conjugates are promising nano-carriers to function as antibiotic delivery vehicles for the treatment of bacterial/MRSA infections.

Distribution of SCCmec types, tetracycline and aminoglycoside resistance genes in hospital-associated methicillin-resistant Staphylococcus aureus strains

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common bacterial diseases in hospitals around the world. Treatment of MRSA infections is complicated by acquire and rapid development of multiple resistance to a wide range of antibiotics including tetracyclines and aminoglycosides. We sought to evaluate the rate of tetracycline and aminoglycoside resistance genes and the distribution of staphylococcal cassette chromosome mec (SCCmec) types among MRSA strains recovered from nosocomial infections in Tehran, Iran. A total of 95 MRSA isolates were collected from various clinical samples and were subjected to culture, standard biochemical tests and the presence of the nuc gene. Cefoxitin disk diffusion method was applied to screen the MRSA strains with subsequent molecular confirmation for the presence of the mecA gene by polymerase chain reaction (PCR) assay. The phenotypic antimicrobial susceptibility of MRSA isolates against tetracycline and aminoglycoside antibiotics was determined by agar disk diffusion method. Genotypic determinants of resistance to tetracycline and aminoglycosides were detected by PCR assay. Isolates were genotyped using multiplex-PCR for SCCmec typing. The mecA gene was present in all MRSA isolates. Resistance to gentamicin, kanamycin, amikacin, tobramycin, netilmicin, tetracycline, doxycycline, and minocycline was found in 75.8, 70.5, 64.2, 37.9, 30.5, 53.7, 18.9, and 6.3% of the isolates, respectively. The frequency of aac(6′)-Ie/aph(2″)-I, ant (4′)-Ia, aph(3′)-IIIa, aph(2′)-Ib and aph(2′)-Ic genes among MRSA strains, were 71.6, 52.6, 46.3, 2.1, and 2.1%, respectively. The most prevalent tet genes were tet(M) (45.3%) followed by tet(K) (41.1%), tet(L) (2.1%) and tet(O) (2.1%). Totally five distinct SCCmec patterns, numbered MRSA-I to MRSA-V, with the majority of SCCmec type III (42.1%) were observed. Our results illustrated a decreased sensitivity of MRSA to the antibiotics used which is a great concern in human infections supporting the view that treatment strategies must be changed in Iran.

Methicillin-Resistant Staphylococcus aureus in Diabetic Foot Infection in India: A Growing Menace.

Diabetic foot infection (DFI) is a serious and common complication of diabetes mellitus. These infections are potentially disastrous and rapidly progress to deeper spaces and tissues. If not treated promptly and appropriately, DFI can be incurable or even lead to septic gangrene, which may require foot amputation. Mostly, these infections are polymicrobial, where Gram-positive pathogens mainly Staphylococcus aureus play a dominant causative role. Methicillin-resistant Staphylococcus aureus (MRSA) is present in 10% to 32% of diabetic infections and is associated with a higher rate of treatment failure, morbidity, and hospitalization cost in patients with DFIs. The increasing resistance of bacteria and the adverse effects pertaining to the safety and tolerability towards currently available anti-MRSA agents have limited the available treatment options for patients with DFI. Infection control, antimicrobial stewardship, and rapid diagnostics based on the microbiological culture and the antimicrobial susceptibility testing results are important components in helping curb this disturbing trend. Emphasis to revisit a vigorous research effort in order to improve the therapeutic options for the increasingly resistant and highly adaptable MRSA is the need of hour. Through this review article, we have made an attempt to explore the ongoing therapeutic trends in the management of DFI and highlighted the challenges in treatment of DFI. We have also given a brief overview of a few novel drugs that are under development to treat MRSA infections.

Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus

Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and β-lactam antibiotic resistance in Staphylococcus aureus. Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on β-lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of β-lactam antibiotics (e.g., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced sarA expression, and subsequently decreased mecA, and virulence-related regulators (e.g., agr RNAⅢ) and genes (e.g., fnbA and hla) expression in the studied MRSA strain. Importantly, the in vitro synergistic effect of hypericin with β-lactam antibiotic (e.g., oxacillin) translated into in vivo therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of β-lactam resistance against MRSA through sarA inhibition, and may allow us to repurpose the use of β-lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (e.g., oxacillin).

Tolerability and Pharmacokinetics of Contezolid at Therapeutic and Supratherapeutic Doses in Healthy Chinese Subjects, and Assessment of Contezolid Dosing Regimens Based on Pharmacokinetic/Pharmacodynamic Analysis

PurposeThis study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. MethodsA Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus, Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. FindingsSingle-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC50 and MIC90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). ImplicationsContezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074.

Network meta-analysis and pharmacoeconomic evaluation of antibiotics for the treatment of patients infected with complicated skin and soft structure infection and hospital-acquired or ventilator-associated penumonia

BackgroundInfections due to methicillin-resistant Staphylococcus aureus (MRSA) cause serious health risks and significant economic burdens and the preferred drugs are still controversial.MethodsWe performed a network meta-analysis (NMA) to compare the efficacy and safety of antibiotics used to treat inpatients with complicated skin and soft structure infections (cSSSI) or hospital-acquired or ventilator-associated pneumonia (HAP/VAP). We also developed a decision tree model to assess the cost-effectiveness of antibiotics.ResultsForty-nine randomized controlled trials met the inclusion criteria (34 for cSSSI, 15 for HAP/VAP) and compared the efficacy and safety of 16 antibiotics. For cSSSI, NMA indicated that for clinical cure, linezolid was superior than vancomycin (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.19–2.02), while tedizolid (OR 1.39, CI 0.70–2.76) was similar to vancomycin. In terms of safety, there were no significant differences between any two interventions on total adverse events. Based on drug and hospital costs in America, the incremental cost-effectiveness ratios (ICERs) per life-year saved for linezolid and tedizolid compared with vancomycin were US$2833 and US$5523. For HAP/VAP, there were no significant effects either for clinical cure or for safety endpoints between linezolid and vancomycin in NMA. ICERs per life-year saved for linezolid compared with vancomycin were US$2185.ConclusionIn these clinical trials, considering efficacy, safety, and cost-effectivenes, linezolid and tedizolid showed their superiority in MRSA cSSSI; while linezolid might be recommended to treat MRSA pneumonia. Although vancomycin was not cost-effective in pharmacoeconomic evaluation, it is still the first-line treatment for MRSA infection in the clinical practice. This study might provide new insights of therapeutic choices for patients with MRSA infections whilst awaiting the arrival of higher quality evidence.

Evaluation of treatment options for methicillin-resistant Staphylococcus aureus infections in the obese patient.

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major cause of infection in both the hospital and community setting. Obesity is a risk factor for infection, and the prevalence of this disease has reached epidemic proportions worldwide. Treatment of infections in this special population is a challenge given the lack of data on the optimal antibiotic choice and dosing strategies, particularly for treatment of MRSA infections. Obesity is associated with various physiological changes that may lead to altered pharmacokinetic parameters. These changes include altered drug biodistribution, elimination, and absorption. This review provides clinicians with a summary of the literature pertaining to the pharmacokinetic and pharmacodynamic considerations when selecting antibiotic therapy for the treatment of MRSA infections in obese patients.

Photolysis of Staphyloxanthin in Methicillin-Resistant Staphylococcus aureus Potentiates Killing by Reactive Oxygen Species.

Confronted with the severe situation that the pace of resistance acquisition is faster than the clinical introduction of new antibiotics, health organizations are calling for effective approaches to combat methicillin‐resistant Staphylococcus aureus (MRSA) infections. Here, an approach to treat MRSA through photolysis of staphyloxanthin, an antioxidant residing in the microdomain of S. aureus membrane, is reported. This photochemistry process is uncovered through transient absorption imaging and quantitated by absorption spectroscopy, Raman spectroscopy, and mass spectrometry. Photolysis of staphyloxanthin transiently elevates the membrane permeability and renders MRSA highly susceptible to hydrogen peroxide attack. Consequently, staphyloxanthin photolysis by low‐level 460 nm light eradicates MRSA synergistically with hydrogen peroxide and other reactive oxygen species. The effectiveness of this synergistic therapy is well validated in MRSA planktonic culture, MRSA‐infected macrophage cells, stationary‐phase MRSA, persisters, S. aureus biofilms, and two mice wound infection models. Collectively, the work demonstrates that staphyloxanthin photolysis is a new therapeutic platform to treat MRSA infections.

Sensitizing of β-lactam resistance by tannic acid in methicillin-resistant S. aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections treatment of which is hard and failed, due to being resistant to all types of β-lactams, have been emerged in hospitals and community. Long-term usage of antibiotics and over doses of antibiotics used in the treatment of infections cause bacteria to develop resistance to antibiotics. β-lactams combined with tannic acid can be a good alternative to sensitize the resistance of β-lactams used in the treatment of MRSA, due to their synergistic activities. In this study, after minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of sole tannic acid and β-lactam were investigated for each isolate, the synergistic activities of β-lactams combined with tannic acid against one MRSA ATCC 43300 and four MRSA clinical isolates were investigated with the concentrations starting at four fold of MICs of sole treatments of tannic acid and β-lactam by using checkerboard assay. To investigate sole and combination activities of tannic acid and β-lactams, MIC and MBCs were observed. Results of this study showed that the activities of β-lactams combined with tannic acid were synergistic and partially synergistic against MRSA isolates with FIC indexes ranged from 0.174 to 0.477 and 0.562 to 0.850, respectively. MIC of β-lactams were decreased 2-16 fold by sub-inhibitory concentrations of tannic acid without toxicity. Alternative treatment options of natural compounds such as tannic acid and β-lactams must be investigated further and developed to overcome the emergence of β-lactam resistance and treat MRSA infections by sensitizing the resistance of β-lactams.

The antibacterial mechanism of oridonin against methicillin-resistant Staphylococcus aureus (MRSA)

Context: Methicillin-resistant Staphylococcus aureus (MRSA) is a very harmful bacterium. Oridonin, a component in Rabdosia rubescens (Hemsl.) Hara (Lamiaceae), is widely used against bacterial infections in China.Objective: We evaluated oridonin effects on MRSA cell membrane and wall, protein metabolism, lactate dehydrogenase (LDH), DNA and microscopic structure.Materials and methods: Broth microdilution and flat colony counting methods were used to measure oridonin minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against USA300 strain. Electrical conductivity and DNA exosmosis were analysed to study oridonin effects (128 μg/mL) on cell membrane and wall for 0, 1, 2, 4 and 6 h. Sodium dodecyl sulphate polyacrylamide gel electrophoresis was used to detect effects on soluble protein synthesis after 6, 10 and 16 h. LDH activity was examined with an enzyme-linked immunosorbent assay. Effects of oridonin on USA300 DNA were investigated with DAPI staining. Morphological changes in MRSA following oridonin treatment were determined with scanning electron microscopy (SEM) and transmission electron microscopy (TEM).Results: Oridonin MIC and MBC values against USA300 were 64 and 512 μg/mL, respectively. The conductivity and DNA exosmosis level of oridonin-treated USA300 improved by 3.20±0.84% and increased by 58.63 ± 1.78 μg/mL, respectively. LDH and soluble protein levels decreased by 30.85±7.69% and 27.51 ± 1.39%, respectively. A decrease in fluorescence intensity was reported with time. Oridonin affected the morphology of USA300.Conclusions: Oridonin antibacterial mechanism was related to changes in cell membrane and cell wall permeability, disturbance in protein and DNA metabolism, and influence on bacterial morphology. Thus, oridonin may help in treating MRSA infection.

Methicillin-resistant Staphylococcus aureus (MRSA) and anti-MRSA activities of extracts of some medicinal plants: A brief review.

The increasing emergence of multidrug-resistant infection causing microorganisms has become a significant burden globally. Despite the efforts of pharmaceuticals in producing relatively new antimicrobial drugs, they have resulted in a high rate of mortality, disability and diseases across the world especially in developing countries. Supporting this claim was the report of the Centre for Disease Control and Prevention (CDC) who estimated that over 2 million illnesses and 23,000 deaths per year are attributable to antibiotic resistant pathogens in the United States. They include Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-intermediate Staphylococcus aureus (VISA), Vancomycin-resistant Staphylococcus aureus (VRSA), Vancomycin-resistant enterococci (VRE), Extended spectrum beta-lactamases (ESBLs) producing gram-negative bacilli, Multidrug-resistant Streptococcus pneumoniae (MDRSP), Carbapenem-resistant Enterobacteriaceae (CRE) and Multidrug-resistant Acinetobacter baumannii. For MRSA, resistance is as a result of Methicillin-sensitive S. aureus (MSSA) strains that have acquired Staphylococcal Cassette Chromosome mec (SCCmec) which carries mecA gene. The gene encodes the penicillin-binding protein (PBP2a) which confers resistance to all β-lactam antibiotics. Vancomycin was previously the widely preferred drug for the treatment of MRSA infections. It is no longer the case with the emergence of S. aureus strains with reduced vancomycin sensitivity limiting the conventional treatment options for MRSA infections to very scanty expensive drugs. Presently, many researchers have reported the antibacterial activity of many plant extracts on MRSA. Hence, these medicinal plants might be promising candidates for treatment of MRSA infections. This work is a brief review on Methicillin-resistant Staphylococcus aureus (MRSA) and the anti-MRSA activities of extracts of selected medicinal plants.