Concept: Vancomycin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed. Marinopyrrole A was reported to show antibiotic activity against MRSA in 2008. After we reported the first total synthesis of (±)-marinopyrrole A, we designed and synthesized a series of marinopyrrole derivatives. Our structure activity relationship (SAR) studies of these novel derivatives against a panel of Gram-positive pathogens in antibacterial assays have revealed that a para-trifluoromethyl analog (33) of marinopyrrole A is ≥63-, 8-, and 4-fold more potent than vancomycin against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA, respectively. The results provide valuable information in the search for new-generation antibiotics.
Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract “430D-F5” against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC50 2-32 μg mL(-1)) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.
The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant Staphylococcus aureus (MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta-lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the mecA gene encoding methicillin resistance carried on an SCCmec element, was horizontally transferred to an intrinsically sensitive strain of S. aureus.
Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections caused by isolates with a high but ‘susceptible’ minimum inhibitory concentration (MIC) to vancomycin may suffer poor outcomes. The aim of this study was to determine the association of high compared to low vancomycin MICs and clinical outcomes (treatment failure and mortality) in patients with MRSA infections.
Previously, the treatment of Staphylococcus aureus infections was less complex, as most of those isolated were susceptible to β-lactam antibiotics. In recent years, there has been a marked increase in the incidence of invasive community-acquired (CA) methicillin-resistant S. aureus (MRSA) among children worldwide. However, data on the clinical characteristics and outcomes related to pediatric bone and joint infections caused by CA-S. aureus are very limited in India. In this tertiary hospital-based study, 74 patients with invasive S. aureus less than 18 years of age were identified between January 2004 and December 2008. All patients fulfilled the case definition of CA-S. aureus with evidence of infection before admission; they presented to our hospital without previous antibiotic use and were culture positive for S. aureus within 48 h of admission. All data including demographics, clinical features, treatment protocol, laboratory findings, and antimicrobial susceptibilities were recorded and compared using the SPSS 11.5 statistical software. Of the 74 patients with culture-positive S. aureus bone and joint infection, 41 had MRSA (55%). Forty-nine patients (66.2%) had osteomyelitis, of whom 29 (59.18%) had MRSA and 25 (33.7%) had septic arthritis, of whom 12 (48%) had MRSA. The MRSA group had a significantly higher erythrocyte sedimentation rate, C-reactive protein value, neutrophil count, and white blood cell count (P<0.05). The MRSA group also had longer duration of febrile days, hospital stay, and antibiotic course compared with the methicillin-susceptible S. aureus (MSSA) group (P<0.05). A clinical predictive algorithm was developed using seven significant independent multivariate predictors, with the probability of MRSA being 94% if all seven predictors were positive and 9% if five predictors were positive. Resistance to many classes of antibiotics was noted among S. aureus isolates including trimethoprim-sulfamethoxazole (MRSA 80%, MSSA 24%), erythromycin (MRSA 83%, MSSA 67%), clindamycin (MRSA 54%, MSSA 34%), and ciprofloxacin (MRSA 61%, MSSA 48%). No vancomycin resistance was observed. The morbidity associated with MRSA bone and joint infection in children is significantly higher than that caused by MSSA. Early diagnosis at the primary healthcare level and treatment with appropriate antistaphylococcal therapy are crucial to achieve optimal clinical outcomes. High levels of antimicrobial resistance of both MSSA and MRSA isolates to several classes of antibiotics are a major concern warranting the need for antimicrobial stewardship and ongoing surveillance.
To compare the in vitro antibacterial efficacy and resistance profile of rifampicin-based combinations against methicillin-resistant Staphylococcus aureus (MRSA) in a biofilm model. The antibacterial activities of vancomycin, teicoplanin, daptomycin, minocycline, linezolid, fusidic acid, fosfomycin, and tigecycline alone or in combination with rifampicin against biofilm-embedded MRSA were measured. The rifampicin-resistant mutation frequencies were evaluated. Of the rifampicin-based combinations, rifampicin enhances the antibacterial activities of and even synergizes with fusidic acid, tigecycline, and, to a lesser extent, linezolid, fosfomycin, and minocycline against biofilm-embedded MRSA. Such combinations with weaker rifampicin resistance induction activities may provide a therapeutic advantage in MRSA biofilm-related infections.
Drug resistance has become a global threat and if not addressed we may enter into the pre-antibiotic era. A way to overcome growing incidence of global antibiotic resistance issue is to introduce compounds belonging to classes that are new to the clinic. During the screening of marine microbial extract library for new antibiotics, one of the extract showed promising anti-gram positive antibacterial activity. Bioactivity guided isolation and characterization of active metabolite, led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterised from a marine sponge associated actinobacterium strain of the genus Kocuria (MTCC 5269). The compound exhibited a potent in vitro antibacterial activity against a broad range of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin resistant enterococci (VRE). The minimum inhibitory concentration (MIC) values evaluated for the compound were found to be in few nano-molar range. In vivo studies of PM181104 in Balb/c murine septicemia model the compound displayed an ED100 value of 2.5 and 5.0 mg/kg against MRSA and 10.0 mg/kg against VRE. In this report, in vitro and in vivo studies of PM181104 are described.
MRSA infections represent a major threat world-wide and there are still several concerns regarding its treatment. Although vancomycin is the drug of choice, clinical failure in patients with serious gram-positive infections have been increasingly reported with an higher risk with increasing vancomycin MICs, well within the susceptible range. We tested daptomycin and telavancin in vitro activity against MRSA strains with vancomycin MIC 2 µg/ml selection. Daptomycin and telavancin seems to represent a good alternative for the treatment of infections caused by MRSA strains with a vancomycin MIC 2 µg/ml even in the presence of cell wall thickening.
This clinical case reports the emergence of a daptomycin-resistant Staphylococcus aureus isolate during daptomycin treatment in a patient with right-sided infective endocarditis who had never been treated with vancomycin.
The current study identified bacterial factors that may improve management of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Isolates were obtained from 386 patients enrolled in a randomized-controlled study of antibiotic efficacy. Isolates were screened for production of virulence factors and for vancomycin susceptibility. After adjustment for host factors, such as severity of illness and treatment modality, cytotoxic activity was strongly and inversely associated with mortality; however, it had no effect on clinical cure. Isolates having low cytotoxicity, which were derived largely from healthcare-associated clones, exhibited a greater prevalence of vancomycin-heteroresistance, and they were recovered more often from patients who were older and frailer. Additionally, a clone with low cytotoxic activity was associated with death and poor clinical improvement. Clone specificity and attenuated virulence appear to be associated with outcome. To our knowledge, these are the first correlations between MRSA virulence and mortality in nosocomial pneumonia.