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Methicillin-Resistant Staphylococcus aureus Therapy: Past, Present, and Future
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be associated with significant morbidity and mortality. Vancomycin was the “gold standard” of treatment
for serious MRSA infections; however, the emergence of less-susceptible strains, poor clinical outcomes, and increased nephrotoxicity
with high-dose therapy are challenging its current role as first-line therapy. Linezolid is recommended for PO or IV treatment
of skin and skin structure infections (SSSIs) and pneumonia caused by MRSA. Daptomycin (IV) should be considered in patients
with MRSA bacteremia and right-sided endocarditis as well as in complicated SSSIs, but should not be used to treat MRSA pneumonia.
Tigecycline and telavancin are alternative (IV) treatments for SSSIs caused by MRSA; however, safety concerns have limited
use of these agents. Ceftaroline is the newest of the approved parenteral agents for SSSIs caused by MRSA. Several investigational
agents with activity against drug-resistant gram-positive pathogens are being developed primarily for treatment of MRSA infections,
including tedizolid, dalbavancin, and oritavancin.
... This issue is particularly problematic for surfaces that require sterilization, such as medical implants, hospital surfaces, and various medical devices. The severity of this problem is compounded by the growing prevalence of resistance to antibiotics among microbial species, leading to a notable surge in postoperative infections and associated fatalities in recent times [1][2][3][4]. In a glimpse into the future, economic projections paint a distressing picture; if we fail to forge new paths in antibacterial therapies, bacterial infections could be responsible for upward of 10 million deaths per annum by 2050 ( Figure 1) [5]. ...
... After overnight incubation, the bacterial colonies were macroscopically observed. The number of CFUs was assumed to be equivalent to the number of live cells in suspension[58].4.CFU/mL Calculation: The colonies were counted and were used to calculate the CFU/mL (x) in the bacterial suspension (M2 ) with the help of the following equation, ...
Given the growing concern over antibiotic resistance, there is an urgent need to explore alternative antibacterial strategies. Metal oxide nanostructures have emerged as a promising option, and in particular, zinc oxide (ZnO) nanostructures have demonstrated strong antifungal and antibacterial properties. This study focuses on ZnO nanowires (ZnO NWs) and their potential as antibacterial agents against Pseudomonas putida, a Gram-negative bacterium. The objective is to investigate the antibacterial mechanisms and assess their efficiency. The unique shape of ZnO NWs, obtained through hydrothermal growth, may rupture bacterial cells and inhibit bacterial growth. In addition to their morphology, the release of Zn2+ ions from ZnO NWs may contribute to their antibacterial properties. These ions have the potential to disrupt the bacterial cell membrane, further impeding bacterial growth. Moreover, ZnO nanostructures exhibit excellent photocatalytic properties under UV light, enhancing their antibacterial effects. Overall, this study highlights the potential of hydrothermally synthesized ZnO NWs in inhibiting P. putida growth and provides valuable insights into their antibacterial mechanisms. The findings suggest that ZnO nanostructures have the potential to be effective antibacterial agents and could be utilized in various settings to fight microbial infections and maintain hygiene.
... Methicillin-resistant Staphylococcus aureus represents a major health problem in community-associated and hospital-associated infections, with significant morbidity and mortality worldwide. Further, it represents a diagnostic and therapeutic challenge for clinicians 7 . Although empirical antibiotic coverage for MRSA is recommended in patients at risk due to the burden of the disease, the main issue in daily practice concerns which patients really require empirical coverage 7,8 . ...
... Further, it represents a diagnostic and therapeutic challenge for clinicians 7 . Although empirical antibiotic coverage for MRSA is recommended in patients at risk due to the burden of the disease, the main issue in daily practice concerns which patients really require empirical coverage 7,8 . A meta-analysis, comprising 5163 patients, has evaluated the role of nasal screening in rule-out MRSA pneumonia. ...
We present a case of an 87-year-old nonsmoker female who recovered after infection by SARS-CoV2 and was readmitted two weeks later due to respiratory sepsis. Radiological imaging showed a significant radiological worsening with extensive areas of bronchopneumonia and ground-glass opacities suggestive of organizing pneumonia. Empirical treatment with meropenem 1g/8h was started; however, clinical worsening persisted with tachypnea and desaturation requiring heated high-flow nasal cannula oxygen therapy, with poor response. Methicillin-resistant Staphylococcus aureus was isolated both in nare screening and sputum, and 16S rRNA polymerase chain reaction in induced sputum was positive for P. jirovecii. Serum (1-3)-beta-D-glucan was normal, and blood cultures were sterile. Antibiotic therapy was adjusted with intravenous linezolid 600mg/12h and trimethoprim-sulfamethoxazole 1600/320mg/6h, plus methylprednisolone 40mg/day. Unfortunately, the patient had no response to optimized treatment and finally died. Opportunistic and resistant microorganisms superinfections should be aware by clinicians in SARS-CoV2 infection, even more, when corticosteroids are widely used.
... Strains of methicillinresistant S. aureus (MRSA) are particularly problematic owing to their prevalence in nosocomial and community-acquired infections, increased rates of morbidity and death, as well as elevated healthcare costs 1 . MRSA is notorious for its ability to acquire resistance to not only β-lactams but also many other classes of antibiotics 1, 9 . The drugs typically used to treat MRSA infections, such as vancomycin, are less effective, more toxic and are subject to established and growing resistance mechanisms as evidenced in vancomycin-resistant S. aureus strains [9][10][11] . ...
... MRSA is notorious for its ability to acquire resistance to not only β-lactams but also many other classes of antibiotics 1, 9 . The drugs typically used to treat MRSA infections, such as vancomycin, are less effective, more toxic and are subject to established and growing resistance mechanisms as evidenced in vancomycin-resistant S. aureus strains [9][10][11] . Despite some progress in the development of new therapeutics 1 , S. aureus has recently been estimated to cause more than a quarter of all mortality attributed to antimicrobial resistance in economically developed countries 2 , demonstrating that improved treatment options are urgently required. ...
Broad-spectrum β-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden 1,2 . In clinical strains, resistance is largely controlled by BlaR1 ³ , a receptor that senses β-lactams through the acylation of its sensor domain, inducing transmembrane signalling and activation of the cytoplasmic-facing metalloprotease domain ⁴ . The metalloprotease domain has a role in BlaI derepression, inducing blaZ (β-lactamase PC1) and mecA (β-lactam-resistant cell-wall transpeptidase PBP2a) expression 3–7 . Here, overcoming hurdles in isolation, we show that BlaR1 cleaves BlaI directly, as necessary for inactivation, with no requirement for additional components as suggested previously ⁸ . Cryo-electron microscopy structures of BlaR1—the wild type and an autocleavage-deficient F284A mutant, with or without β-lactam—reveal a domain-swapped dimer that we suggest is critical to the stabilization of the signalling loops within. BlaR1 undergoes spontaneous autocleavage in cis between Ser283 and Phe284 and we describe the catalytic mechanism and specificity underlying the self and BlaI cleavage. The structures suggest that allosteric signalling emanates from β-lactam-induced exclusion of the prominent extracellular loop bound competitively in the sensor-domain active site, driving subsequent dynamic motions, including a shift in the sensor towards the membrane and accompanying changes in the zinc metalloprotease domain. We propose that this enhances the expulsion of autocleaved products from the active site, shifting the equilibrium to a state that is permissive of efficient BlaI cleavage. Collectively, this study provides a structure of a two-component signalling receptor that mediates action—in this case, antibiotic resistance—through the direct cleavage of a repressor.
... Treatment of S. aureus can be challenging not only due to the nature of the infection that it causes, which ranges from bacteremia to biofilm formation, but also due to the ability of the pathogen to evade antibiotic treatment (2). Resistance to safe and effective antibiotics such as NGBs compels clinicians often to opt for alternatives that are known for having lower efficacy and adverse side effects (39). For the past several decades, mecA or mecC has been the hallmark of high-level NGB resistance in S. aureus, thus restricting the use of NGBs for treatment (8). ...
Infections caused by Staphylococcus aureus are a leading cause of mortality worldwide. S. aureus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are particularly difficult to treat due to their resistance to next-generation β-lactams (NGBs) such as methicillin, nafcillin, and oxacillin. Resistance to NGBs, which is alternatively known as broad-spectrum β-lactam resistance, is classically mediated by PBP2a, a penicillin-binding protein encoded by mecA (or mecC) in MRSA. Thus, presence of mec genes among S. aureus spp. serves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated, mecA-deficient S. aureus strains can also exhibit NGB resistance. These strains, which are collectively termed as methicillin-resistant lacking mec (MRLM), are currently being identified in increasing numbers among natural resistant isolates of S. aureus. The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs, can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance toward NGBs at levels comparable to those of MRSAs. Our study provides a fresh new perspective about alternative mechanisms of NGB resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance in S. aureus. It thus suggests reconsideration of the current approach toward diagnosis and treatment of β-lactam-resistant S. aureus infections.
IMPORTANCE
In Staphylococcus aureus, high-level, broad-spectrum resistance to β-lactams such as methicillin, also referred to as methicillin resistance, is largely attributed to mecA. This study demonstrates that S. aureus strains that lack mecA but contain mutations that functionally alter PBP4 and GdpP can also mediate high-level, broad-spectrum resistance to β-lactams. Resistance brought about by the synergistic action of functionally altered PBP4 and GdpP was phenotypically comparable to that displayed by mecA, as seen by increased bacterial survival in the presence of β-lactams. An analysis of mutations detected in naturally isolated strains of S. aureus revealed that a significant proportion of them had similar pbp4 and GGDEF domain protein containing phosphodiesterase (gdpP) mutations, making this study clinically significant. This study not only identifies important players of non-classical mechanisms of β-lactam resistance but also indicates reconsideration of current clinical diagnosis and treatment protocols of S. aureus infections.
... Sự đề kháng đối với tất cả những kháng sinh khác cũng chiếm tỉ lệ cao bao gồm penicillin, oxacillin và erythromycin. Clindamycin trước đây là kháng sinh điều trị theo kinh nghiệm đối với nhiễm trùng bàn tay do MRSA bằng đường uống cũng như đường tiêm [16]. Mặc dù chúng tôi không thể trả lời trực tiếp tại sao có sự đề kháng ngày càng tăng đối với clidamycin như vậy, nhưng chúng tôi cho rằng việc sử dụng quá mức clidamycin đối với MRSA có thể là nguyên nhân ban đầu. ...
Đặt vấn đề: Tụ cầu vàng kháng Methicillin (MRSA) được báo cáo là tác nhân gây nhiễm trùng nhiều nhất ở bàn tay tại những trung tâm y khoa hàng đầu trên thế giới. Xu hướng nhạy kháng sinh của tụ cầu vàng vẫn chưa được nắm rõ. Mục tiêu của nghiên cứu: Đánh giá tỉ lệ nhiễm MRSA trong nhiễm trùng bàn tay và xác định xu hướng đề kháng kháng sinh do MRSA, từ đó đưa ra khuyến cáo cho việc điều trị kháng sinh theo kinh nghiệm dựa trên độ nhạy kháng sinh đồ tại Bệnh viện Chấn thương Chỉnh hình. Phương pháp: Một nghiên cứu hồi cứu, cắt dọc được thực hiện trên tất cả những ca nhiễm trùng bàn tay cấy dương tính được thực hiện tại Bệnh viện Chấn thương Chỉnh hình từ năm 2019 - 2023. Tỉ lệ của tất cả vi khuẩn được tính toán và thu thập mỗi năm. Nhiễm trùng MRSA được phân tích thêm về độ nhạy kháng sinh. Kết quả: Có 369 ca nhiễm trùng bàn tay cấy dương tính được xác định từ năm 2019 đến năm 2023. Nhìn chung, MRSA mọc trong 38% ca. Bên cạnh MRSA thì Pseudomonas và Enterobacter là 2 tác nhân chiếm tỉ lệ cao tiếp theo với lần lượt là 24% và 20%. Tỉ lệ nhiễm MRSA được ghi nhận giảm trong thời gian 3 năm đầu, sau đó lại tăng đáng kể trong 2 năm trở lại đây. Có sự tăng dần trong việc nhiễm trùng đa vi khuẩn trong thời gian bốn năm, từ năm 2020 đến năm 2023. Đề kháng clindamycin tăng dần trong 3 năm trở lại đây, bắt đầu từ 53.85% trong năm 2021 nhưng tăng đến 78.26% trong năm 2023. Tương tự, đề kháng levofloxacin cũng ở mức độ cao trong 4 năm đầu, với đạt đỉnh 60.71% trong năm 2019, tuy nhiên, lại giảm đột ngột với 29.17% vào năm 2023. Kết luận: Tỉ lệ nhiễm MRSA hàng năm trong nhiễm trùng bàn tay vẫn là tác nhân phổ biến nhất, tiếp theo là Pseudomonas và Enterobacter. Có sự gia tăng khác về nhiễm trùng đa vi khuẩn. Sự đề kháng MRSA đối với clindamycin và levofloxacin tăng phù hợp trong giai đoạn nghiên cứu. Liệu pháp kháng sinh theo kinh nghiệm đối với nhiễm trùng bàn tay không những nên tránh penicillin và họ beta-lactams khác mà còn nên tránh sử dụng clindamycin và levofloxacin trong điều trị theo kinh nghiệm.
... Mupirocin is a topical antibiotic used for treatment of skin and soft tissue infections caused by MRSA and decolonization of MRSA in carriers. 11,12 It inhibits protein synthesis by binding specifically to iso-leucyl-tRNA synthetase enzyme. 13 Study aimed to determine min inhibitory concentration of currently used therapeutic agents in management of MRSA infections namely vancomycin, tigecycline, linezolid, daptomycin, ceftaroline and mupirocin. ...
Background: Staphylococcus aureus infections are one of the most common and serious hospital-acquired infections seen in developing countries. Methicillin resistant Staphylococcus aureus (MRSA) is an important human pathogen and normally colonized in body parts including skin, nose, perineum and throat. MRSA is resistant not only to all β-lactam groups but also other antibiotics including aminoglycosides, tetracycline and macrolides. In the present study the efficacy of agents used in the management of MRSA infections was determined by antibiotic gradient testing.
Methods: A total of 60 clinical isolates of MRSA strains were collected from various diagnostic labs in central Kerala. Clinical isolates were reconfirmed as MRSA by gram staining, yellow-coloured colonies on mannitol salt Agar (MSA). Antibiotic susceptibility testing was done by disc diffusion method as recommended by CLSI guidelines. S. aureus isolates resistant to cefoxitin (30 µg) was identified as MRSA. Antibiotic gradient testing was performed to determine the MIC of vancomycin, tigecycline, linezolid, daptomycin, ceftaroline and mupirocin against MRSA isolates.
Results: All the 60 MRSA isolates tested were sensitive to vancomycin, tigecycline, linezolid, daptomycin, ceftaroline and mupirocin (100%) and none of the MRSA isolates show resistance.
Conclusions: Results of present study indicates that these agents may be used alongside vancomycin in management of infection caused by MRSA
... Serial dilutions of the extracts were prepared in an appropriate growth medium (90 µL), ranging from 4 to 512 µg/mL, using a manual multichannel pipette (Eppendorf, Wesseling-Berzdorf, Germany). The plates were inoculated with a bacterial suspension at a final density of 5 × 10 5 ...
Antibiotic resistance in staphylococcal strains and its impact on public health and agriculture are global problems. The development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resistance. In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle under various nutritional treatments were assessed for in vitro anti-staphylococcal effects. The results showed that all the cannabis extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphylococcus aureus, including antibiotic-resistant and antibiotic-sensitive forms. The highest antibacterial activity of the extracts was observed from the 5th to the 13th week of plant growth across all the nutritional treatments tested, with minimum inhibitory concentrations ranging from 32 to 64 µg/mL. Using HPLC, Δ⁹-tetrahydrocannabinolic acid (THCA) was identified as the most abundant cannabinoid in the ethanolic extracts. A homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%. These findings suggest that the cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved efficacy.
... 2 Vancomycin and linezolid are recommended to treat methicillin-resistant Staphylococcus aureus (MRSA) infections, whereas mupirocin is used to treat skin and soft-tissue infections and decolonize carriers. 3 The drug mupirocin is used topically to treat infections affecting the skin and soft tissues caused by MRSA. Mupirocin has been authorized for MRSA nasal colonization treatment. ...
Background: Antimicrobial susceptibility among bacterial isolates varies from center to center. Mupirocin is a topical antibacterial antibiotic used to treat wound infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Aim and Objectives: This study was conducted to know the prevalence of high and low levels of mupirocin resistance along with antimicrobial susceptibility in MRSA isolates from skin and soft-tissue infection in patients admitted to a tertiary care hospital in North India. Materials and Methods: A total of 97 non-repetitive isolates of MRSA from various pus samples over a period of 1 year were included in this study. These strains were identified as per standard laboratory protocols given by the Clinical Laboratory Standards Institute. High- and low-level mupirocin resistance of the isolates was tested by using mupirocin discs of 200 μg and 5 μg, respectively. Mupirocin strips of 256 μg and 512 μg were used for the E-test to detect low-level and high-level mupirocin resistance, respectively. The isolates were reported as sensitive to mupirocin, with minimum inhibitory concentrations of <4 mg/L. Results: Overall, 9.27% of mupirocin resistance was found, of which 2.06% of isolates were high-level resistant to mupirocin, while 7.21% had low-level resistance. All MRSA strains were susceptible to vancomycin, followed by linezolid (94.84%), teicoplanin (91.75%), and fusidic acid (88.65%). Conclusion: Regular monitoring, good infection control practices, and proper awareness about utilizing mupirocin therapeutically and prophylactically may help prevent the emergence of mupirocin resistance in health-care facilities.
... There are antimicrobial agents available for treating infections caused by MDR MRSA infections (e.g., daptomycin, linezolid). However, safety concerns have been raised for some of these compounds, and resistance against these agents has been described, albeit rarely (3)(4)(5)(6). The recently approved agent ceftaroline-fosamil has a good safety profile and is approved by the U.S. Food and Drug Administration (in 2010) and the European Medicines Agency (in 2012) for the treatment of infections caused by S. aureus (7)(8)(9)(10). ...
Ceftaroline, the active metabolite of the prodrug ceftaroline-fosamil, is an advanced-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). This investigation provides in vitro susceptibility data for ceftaroline against 1,971 S. aureus isolates collected in 2012 from seven countries (26 centers) in the Asia-Pacific region as part of the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) program. Broth microdilution as recommended by the CLSI was used to determine susceptibility. In all, 62% of the isolates studied were MRSA, and the ceftaroline MIC90 for all S. aureus isolates was 2 μg/ml (interpretive criteria: susceptible, ≤1 μg/ml). The overall ceftaroline susceptibility rate for S. aureus was 86.9%, with 100% of methicillin-sensitive S. aureus isolates and 78.8% of MRSA isolates susceptible to this agent. The highest percentages of ceftaroline-nonsusceptible MRSA isolates came from China (47.6%), all of which showed intermediate susceptibility, and Thailand (37.1%), where over half (52.8%) of isolates were resistant to ceftaroline (MIC, 4 μg/ml). Thirty-eight ceftaroline-nonsusceptible isolates (MIC values of 2 to 4 μg/ml) were selected for molecular characterization. Among the isolates analyzed, sequence type 5 (ST-5) was the most common sequence type encountered; however, all isolates analyzed from Thailand were ST-228. Penicillin-binding protein 2a (PBP2a) substitution patterns varied by country, but all isolates from Thailand had the Glu239Lys substitution, and 12 of these also carried an additional Glu447Lys substitution. Ceftaroline-fosamil is a useful addition to the antimicrobial agents that can be used to treat S. aureus infections. However, with the capability of this species to develop resistance to new agents, it is important to recognize and monitor regional differences in trends as they emerge.
... In treating situations like SSSIs and nosocomial pneumonia, linezolid may still be preferable to vancomycin, but this is still up for discussion. Recent research has confirmed the clinical effectiveness of linezolid in cSSSIs, including DFIs without osteomyelitis (Liu et al., 2011;Rodvold and McConeghy, 2014;Wunderink et al., 2012). ...
... Aunque también cuenta con aprobación de Vedia L y otros. ISSN para el tratamiento de neumonía adquirida en la comunidad, en el estudio realizado para esta indicación (FOCUS I y II) se excluyeron pacientes con infección por SAMR (89). La experiencia clínica con ceftarolina en otro tipo de infecciones invasivas por SAMR es limitada, por lo que su eventual uso en ellas deberá ser sumamente prudente. ...
Las infecciones por Staphylococcus aureus meticilino resistente adquirido en la comunidad (SAMR-AC) constituyen un problema emergente debido a su elevada virulencia y gran capacidad de diseminación. Para las infecciones invasivas, las recomendaciones publicadas sugieren vancomicina como droga de elección. Sin embargo, no está claro si otras alternativas pudieran ser mejores en determinadas situaciones, o si el uso de combinaciones de antibióticos sería beneficioso. No se han realizado trabajos que sugieran que alguna alternativa terapéutica sea preferible a otra para el tratamiento de pacientes con infecciones invasivas por SAMR-AC, por lo que las decisiones a tomar se basan en la extrapolación de datos de estudios realizados en otros contextos o en la opinión de expertos. Por tal motivo, se presenta esta revisión, con el objeto de poner en manos de los infectólogos y otros especialistas la evidencia disponible, a fin de intentar encontrar las mejores alternativas de tratamiento para estas infecciones.
... A total of 23 S. aureus infections were found; 15/23 (65.2%) of the isolates were resistant to penicillinase-stable penicillins, and 52.17% were MDR. In comparison to other African [41] and Mediterranean [42] nations, previous investigations have indicated that Egypt has the highest MRSA scores. Vancomycin has long been acknowledged as the cornerstone of MRSA infection treatment [43]. ...
Fever of unknown origin (FUO) is a medical term describing fever that lasts for at least three weeks without a diagnosis being reached after extensive diagnostic evaluation. Therefore, this study aimed to identify the common pathogens causing FUO in patients admitted to Abbasia Fever Hospital in Egypt from January 2020 to December 2022, their antimicrobial susceptibility profiles, and associated resistance genes. The study also aimed to investigate the burden of multidrug-resistant (MDR) pathogens and the priority pathogens nominated by the World Health Organization (WHO) for posing the greatest threat to human health due to antibiotic resistance. During the study period, about 726 patients were diagnosed with FUO. After extensive investigations, the cause of the FUO was found to be infectious diseases in 479/726 patients (66.0%). Of them, 257 patients had positive bacterial cultures, including 202 Gram-negative isolates that comprised Klebsiella pneumoniae (85/202; 42.1%), Escherichia coli (71/202; 35.1%), Acinetobacter baumannii (26/202; 12.9%), and Pseudomonas aeruginosa (14/202; 6.9%) and 55 Gram-positive isolates, including Staphylococcus aureus (23/55; 41.8%), Streptococcus pneumoniae (7/55; 12.7%), and Enterococcus spp. (25/55; 45.5%). The MDR phenotype was shown by 68.3% and 65.5% of the Gram-negative and Gram-positive isolates, respectively. Carbapenem resistance (CR) was shown by 43.1% of the Gram-negative isolates. Of the 23 S. aureus isolates obtained from research participants, 15 (65.2%) were methicillin-resistant S. aureus (MRSA). A high-level aminoglycoside resistance (HLAR) phenotype was found in 52.0% of the Enterococcus sp. isolates. The PCR screening of resistance genes in the MDR isolates showed that blaOXA−48 was the most prevalent (84%) among the carbapenemase-coding genes, followed by blaVIM (9%) and then blaIMP (12%). The ESBL-coding genes blaTEM, blaCTX-M,aac(6′)-Ib, and blaSHV, were prevalent in 100%, 93.2%, 85,% and 53.4% of the MDR isolates, respectively. This study updates the range of bacteria that cause FUO and emphasizes the burden of multidrug resistance and priority infections in the region. The obtained data is of relevant medical importance for the implementation of evidence-based antimicrobial stewardship programs and tailoring existing empirical treatment guidelines.
... As shown in Table 2, overall, antibacterial activities of LLA were most effective against tested strains with MIC and MBC values of 1.56 μg/mL followed by LLC with MIC and MBC values of 3.12 μg/mL and 6.25 μg/mL as well as CSA with MIC and MBC values of 6.25 μg/mL and 6.25-12.5 μg/mL. Van, generally believed as a highly potent antibiotic (Rodvold and McConeghy 2014), was chosen as the positive control in this present work with MIC and MBC values of 0.78-1.56 μg/mL and 1.56-3.12 ...
Cajaninstilbene acid (CSA), longistylin A (LLA), and longistylin C (LLC) are three characteristic stilbenes isolated from pigeon pea. The objective of this study was to evaluate the antibacterial activity of these stilbenes against Staphylococcus aureus and even methicillin-resistant Staphylococcus aureus (MRSA) and test the possibility of inhibiting biofilm formation. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of these stilbenes were evaluated. And the results showed that LLA was most effective against tested strains with MIC and MBC values of 1.56 μg/mL followed by LLC with MIC and MBC values of 3.12 μg/mL and 6.25 μg/mL as well as CSA with MIC and MBC values of 6.25 μg/mL and 6.25–12.5 μg/mL. Through growth curve and cytotoxicity analysis, the concentrations of these stilbenes were determined to be set at their respective 1/4 MIC in the follow-up research. In an anti-biofilm formation assay, these stilbenes were found to be effectively inhibited bacterial proliferation, biofilm formation, and key gene expressions related to the adhesion and virulence of MRSA. It is the first time that the anti-S. aureus and MRSA activities of the three stilbenes have been systematically reported. Conclusively, these findings provide insight into the anti-MRSA mechanism of stilbenes from pigeon pea, indicating these compounds may be used as antimicrobial agents or additives for food with health functions, and contribute to the development as well as application of pigeon pea in food science.
... The ability of this pathogen to rapidly develop and acquire antibiotic resistance has led to the emergence of multidrugresistant strains such as methicillin-resistant S. aureus (MRSA). At present, vancomycin (VAN) remains the last resort for the treatment of MRSA infections [1]. However, reports regarding MRSA strains that have developed resistance to VAN have emerged in many parts of the world, with the first such strain reported in USA two decades ago [2]. ...
Staphylococcus aureus has caused life-threatening infections and developed resistance against conventional antimicrobials, posing a significant threat to human health worldwide. Biofilms that surround the bacteria cells act as a protective layer, allowing cells inside the biofilm to be resistant to external stresses such as antimicrobials. Therefore, biofilms further complicate treatment available for infections caused by multi-drug resistant Staphylococcus aureus. A previous study on alpha-amyrin (AM), derived from ursane, was reported to significantly reduce the biomass and inhibit the metabolic activity of reference strain methicillin-resistant and methicillin-sensitive S. aureus (MRSA and MSSA, respectively). In this study, the antibiofilm activity of AM was extended to include clinical isolates of MSSA and MRSA, and laboratory-generated vancomycin-intermediate S. aureus (VISA) collected from University Kebangsaan Malaysia Medical Center (PPUKM) and Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI). Pre-formed biofilms of biofilm-forming isolates identified from the Congo Red Agar (CRA) assay were then exposed to AM, vancomycin and oxacillin, and evaluated using the crystal violet and resazurin assays. The results showed that AM reduced the biofilm biomass of three isolates of MSSA, eight isolates of MRSA and four isolates of VISA but increased the metabolic activity in certain MSSA, MRSA and VISA isolates, indicating AM may possess biofilm reduction effects but not bactericidal effects. Based on these findings, AM could be further studied and developed as a potential therapeutic agent for chronic S. aureus infections.
... The rate of antibiotic resistance in MRSA is substantially higher. Currently, vancomycin is used as a last-resort therapy for severe MRSA infections (Rodvold and Mcconeghy, 2014). Additionally, MRSA is resistant to the majority of antibiotics (Diekema et al., 2001). ...
Staphylococcus aureus is an opportunistic pathogen. Due to the widespread use and abuse of antibiotics, various drug-resistant strains of S. aureus have emerged, with methicillin-resistant Staphylococcus aureus (MRSA) being the most prevalent. Bacterial biofilm is a significant contributor to bacterial infection and drug resistance. Consequently, bacterial biofilm formation has emerged as a therapeutic strategy. In this study, the chemical constituents, antimicrobial and antibiofilm properties of tannins isolated from Penthorum chinense Pursh (TPCP) were investigated. In vitro , TPCP exhibited antimicrobial properties. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA were 156.25 and 312.5 μg/mL, and 312.5 and 625 μg/mL, respectively. According to the growth curves, TPCP significantly inhibited the growth of MSSA and MRSA. The results of the crystal violet biofilm assay in conjunction with confocal laser scanning and scanning electron microscopy demonstrated that TPCP destroyed preformed MSSA and MRSA biofilms. TPCP significantly decreased the secretion of exopolysaccharides and extracellular DNA. Subsequently, the mechanism was investigated using RT-PCR. Examining the expression of ica A, cid A, sig B, agr A, and sar A genes in MRSA, we discovered that TPCP inhibited biofilm formation by affecting the quorum-sensing system in bacteria. Our study demonstrates that TPCP exerts antibacterial effects by disrupting the formation of bacterial biofilms, suggesting that TPCP has clinical potential as a novel antibacterial agent for the prevention and treatment of MSSA and MRSA infections.
... The usage and effectiveness of current anti-bacterial medications will be impacted as a result. 2 In 2017, S. aureus was linked to approximately 119,247 cases of bloodstream infections in the United States, which led to 19,832 deaths. Between 2005 and 2012, there was a consistent and significant annual decrease of 17.1% in hospital-acquired MRSA bloodstream infections. ...
Background: Methicillin resistant Staphylococcus aureus (MRSA) has become one of the most important human pathogens associated with hospital infections globally. It is responsible for a considerable number of infections but has received inadequate attention in our local communities. Objective: To determine the occurrence of Methicillin Resistance Staphylococcus aureus (MRSA) isolates from bed contact surfaces and bed sheets in the male and female surgical wards of State Specialist Hospital Gombe, Nigeria. Results: A total of 100 samples were collected purposively for the study. Overall, 79/100 (79%) were positive for S. aureus, and out of these, 42/50(84%) were from the male surgical ward and 37/50 (74%) from the female surgical wards (χ2=1.5, p=0.22). The Male surgical ward bed contact surfaces had the highest S. aureus colonization (92%), and the least affected was the female surgical ward bed contact surfaces (72%), and the difference was not statistically significant (χ2=3.388, p= 0.07). Out of the 79 samples that yielded S. aureus, 56(56%) were positive for MSRA while the remaining 23(23%) were MSSA. Comparing the two wards, we found that the rate of MRSA in the FSW (60%) was higher than that of the MSW (56%), but the difference was not statistically significant (χ2=0.65, p=0.42). The antibiotic sensitivity of the S. aureus isolated from the bed sheet of the MSW was higher (78.3%) compared to those isolated from the bed sheets of the FSW (38.9%) with χ2=6.58 and p value=0.01. However, there was no significant difference in the antibiotic sensitivity to (cefoxitin and ampicillin) of S. aureus isolated from the bed surface contacts of the MSW and FSW. Conclusion: This study reports a high occurrence rate of both S. aureus and the MRSA variant among the two wards studied. Regular fumigation and disinfection may help control the transmission via contact surfaces. Staff training on hospital sanitation and occupational safety will serve as an additional effort to ensure patients and visitors safety.
... Furthermore, the start of antimicrobial resistance was recognized a few years afterward when Methicillin Resistant Staph Aureus (MRSA) was first described. 2 Over the last decades, community, as well as hospitalacquired MRSA, emerged as a significant global threat to healthcare mainly because of rapid and ease of transmission, wide spectrum of disease presentation as well as significant morbidity and mortality. 3 The distinction between community and hospital-acquired MRSA is usually evident based on the affected population, microbiological characteristics as well as different clinical presentations. 4 While community-acquired MRSA (CA-MRSA) tends to affect young and healthy individuals and is usually less resistant, hospital-acquired disease (HA-MRSA) tends to affect older patients, particularly those with chronic comorbidities as well as being more resistant and aggressive. ...
Panton‐Valentine leucocidin toxin‐producing methicillin‐resistant staphylococcus aureus is an important uncommon cause of community‐acquired pneumonia; we describe a case of necrotizing pneumonia presenting as respiratory failure necessitating early initiation of extracorporeal membrane oxygenation, acute kidney injury and rhabdomyolysis, awareness, prompt recognition and appropriate management are crucial due to possible significant pathology.
... Next, we used CRE to evaluate the renal function (Fig. 6c). Van was significantly antibacterial, but caused significant renal function impairment [56]. As shown in Fig. 6d, after 21 days, numerous yellow abscesses were seen in the muscle in MRSA and MRSA + US groups compared with that of the control group from the images of infected leg sites. ...
Rapid disinfection and promotion of bone regeneration are two crucial aspects of the clinical treatment of osteomyelitis. There is an urgent need to develop highly efficient bioactive sonosensitizers for sonodynamic therapy (SDT). Herein, a type of two-dimensional (2D) Nb2C nanosheet-decorated porphyrin metal–organic framework hollow nanotubes (HNTM/Nb2C) was designed to simultaneously eliminate infection and accelerate bone regeneration under ultrasound (US) irradiation. Building a Schottky junction between HNTM and Nb2C nanosheets allowed enough reactive oxygen species (ROS) to be produced because of the rapid charge transfer and suppressed recombination of electron-hole pairs under US irradiation. The sonosensitizer accelerated the osteoblastic differentiation of stem cells. RNA-seq indicated that the HNTM/Nb2C nanoplatform induced stem cell differentiation via cation transport and ATP-synthesis-coupled electron transport through an ultrasonic current. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the Nb ion may further improve osteogenesis via the activation of Wnt signaling. Our study provides novel strategies for improving SDT efficiency by simultaneously eliminating infections and promoting bone regeneration through US-current-combined ion therapy for osteomyelitis treatment.
... It is also a therapeutic challenge as the treatment is costly due to the scarce availability of effective antibiotic drugs and their ever-increasing prices. The ever-varying epidemiological patterns of MRSA infections, changing resistance to antibiotics of common use, and involvement of community centers and hospitals in spreading infections have influenced the utilization and clinical results of presently available antibiotic drugs (Rodvold and McConeghy 2014). ...
Antibiotic resistance among mastitis pathogens.
... However, nephrotoxicity and emerging resistance have limited its clinical use. Linezolid, as the first oxazolidinone antibiotic available in clinical practice, is effective for managing the infections caused by MRSA (Rodvold and McConeghy, 2014) or vancomycin-resistant S. aureus (VRSA). However, longer treatment duration (>2 weeks) is linked to increased incidence of myelosuppression and other side effects (Gerson et al., 2002). ...
Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.
... Staphylococcus aureus is a leading causative agent in pneumonia and other respiratory tract infections surgical site prosthetic joint and cardiovascular infections as well as nosocomial bacteremia [37]. Methicillin-Resistant Staphylococcus aureus is a major public health problem worldwide and it is responsible for both hospital and community-associated infections and is a therapeutic challenge to treat [38] [39]. ...
... However, the bacteria rapidly acquired resistance by producing penicillinase to hydrolyse the beta-lactam ring of penicillin and encode the low-affinity penicillin binding protein PBP2a. More seriously, methicillin resistance is resistance to broad beta-lactam antibiotics [6], and methicillin-resistant S. aureus (MRSA) has spread rapidly and widely around the world [7,8] and has become a major public health problem [5,9]. In 2019, MRSA directly caused more than 100,000 deaths in 204 countries and territories [10] and was named as a priority II pathogen that needs to be prioritized for new antibiotic research and discovery by the World Health Organization [11,12]. ...
The epidemic of methicillin-resistant Staphylococcus aureus (MRSA) infections has created a critical health threat. The drug resistance of MRSA makes the development of drugs with new modes of action particularly urgent. In this study, we found that a natural product derivative pyrimirhodomyrtone (PRM) exerted antibacterial activity against S. aureus, including MRSA, both in vitro and in vivo. Genetic and biochemical studies revealed the interaction between PRM and N-acetylglucosamine-6-phosphate deacetylase (NagA) and the inhibitory effect of PRM on its deacetylation activity. We also found that PRM causes depolarization and destroys the integrity of the cell membrane. The elucidation of the antibacterial mechanism will inspire the subsequent development of new anti-MRSA drugs based on PRM.
... and Pseudomonas aeruginosa, tigecycline exhibits powerful antibacterial activity against MDR and XDR, including the methicillinresistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), carbapenem-resistant Enterobacterales, extended-spectrum β-lactamase-producing Enterobacterales and MDR Acinetobacter spp. [17][18][19][20][21][22] Tigecycline is recommended for community-acquired pneumonia, complicated intra-abdominal infections and complicated skin or soft tissue infections caused by sensitive bacteria, with its indications still rapidly expanding. ...
Background:
Although tigecycline is an effective drug against drug-resistant bacteria, it demonstrated a higher all-cause mortality than comparator antibiotics and a high incidence of coagulation disorders which can be accompanied by severe bleeding. At present, a predictive model for tigecycline-related coagulopathy is not readily available, and the prognostic value of coagulopathy in tigecycline-administered patients has not been elucidated. In this paper, we investigate the association between tigecycline-related coagulopathy and in-hospital mortality to develop a nomogram for the prediction of tigecycline-related coagulopathy.
Methods:
This retrospective cohort study includes 311 adults prescribed with tigecycline from 2018 to 2020. The primary cohort and validation cohort were constructed by dividing the participants in a ratio of 7:3. The endpoint is tigecycline-related coagulopathy, defined as a condition with no abnormality in coagulation prior to tigecycline application but developed the following symptoms upon prescription: activated partial thromboplastin time (APTT) extended by >10 s than the upper limit of normal (ULN), prothrombin time (PT) prolonged for >3 s than the ULN or reduced serum level of fibrinogen to <2.0 g/L. A predictive nomogram based on logistic regression was subsequently constructed.
Results:
Tigecycline intake for over 7 days, combined other antibiotics, initial PT, initial fibrinogen and estimated glomerular filtration rate (eGFR), are independent prognostic factors of tigecycline-related coagulopathy. The primary and validation cohort each has an area under the receiver operating characteristic curve (AUC) of 0.792 (0.732-0.851) and 0.730 (0.629-0.832) for nomogram, respectively. Furthermore, the fitted calibration curve illustrated adequate fit of the model, while the decision curve analysis demonstrated good clinical value. Survival curves showed a high mortality rate among patients with tigecycline-related coagulopathy.
Conclusion:
This nomogram exhibited helpful clinical value in predicting tigecycline-related coagulopathy that could reduce the high mortality rate of patients prescribed with tigecycline.
... Except for the latest fifth-generation cephalosporins, such as ceftaroline, MRSA showed resistance to almost all β-lactams. MRSA also developed resistance to other types of antibiotics, including vancomycin, linezolid, and daptomycin (DAP) [8][9][10], which are considered the last resort for the treatment of severe MRSA infections, further complicating the treatment of MRSA [11,12]. Given the increase in the number of multidrug resistant MRSA strains and the slowdown in the antimicrobial drug development process, we urgently need new alternative treatments to fight against bacterial infections. ...
Methicillin-resistant Staphylococcus aureus (MRSA) has posed a severe global health threat. In this study, we screened an antibiotic and non-antibiotic combination that provides a viable strategy to solve this issue by broadening the antimicrobial spectrum. We found that chenodeoxycholic acid (CDCA) could synergistically act with carbapenem antibiotics to eradicate MRSA-related infections. This synergy specifically targets MRSA and was also validated using 25 clinical MRSA strains using time–kill analysis. We speculated that the underlying mechanism was associated with the interaction of penicillin-binding proteins (PBPs). As a result, the synergistic efficiency of CDCA with carbapenems targeting PBP1 was better than that of β-lactams targeting PBPs. Moreover, we showed that CDCA did not affect the expression level of PBPs, but sensitized MRSA to carbapenems by disrupting the cell membrane. In our study, we have revealed a novel synergistic combination of antibiotics and non-antibiotics to combat potential bacterial infections.
... The MRSA infection remains a significant issue all over the globe and also a therapeutic challenge due to the scarcity and high cost of antibacterial agents. The increasing existence of MRSA infections, changing antibiotic resistance, and involvement in hospital and community infections have an influence on the use and treatment outcomes of previously existing anti-infective compounds [39]. ...
Infections caused by the group of Staphylococcus bacteria are commonly called Staph infections, and over 30 types of Staphylococcal bacteria exist with Staphylococcus aureus causing about 90% of the infections from the genus. Staphylococcus aureus (S. aureus) is a major cause of both hospital- and community-acquired infections with major concern arising from its strain of species that is resistant to many antibiotics. One of such strain is the Methicillin-resistant Staphylococcus aureus (MRSA) that has been described to be a resistance to methicillin drugs. Another is glycopeptides-resistant emerging from the increased use of glycopeptides drugs. This continuous emergence and spread of new resistant strains of S. aureus is a major challenge which makes the search for novel anti-resistant agents imperative. The development of vaccines from natural and synthetic products is some of the measures being proposed for the protection against the infections. Also, the development of monoclonal or polyclonal antibodies for passive immunization is sought for, and attentions with regard to arriving at successful trials have been directed back to medicinal plant research as an alternative. This review discusses the treatment strategies of MRSA, the antibacterial property of various medicinal plants, and the influence of their active compounds on methicillin-resistant S. aureus (MRSA), as well as to recommend the path to future research in this area.
... Increasing evidence shows that MRSA is not only resistant to β-lactams and aminoglycosides, but also to other traditional treatment agents such as quinolones and macrolides [6,7]. Although glycopeptide antibiotic vancomycin remains one of the last options for the treatment of severe MRSA infections, some S. aureus strains have started to exhibit increased resistance to vancomycin; these are known as vancomycin intermediate-resistant S. aureus (VISA) and vancomycin-resistant S. aureus [8,9]. ...
Methicillin-resistant Staphylococcus aureus (MRSA)-caused infection is difficult to treat because of its resistance to commonly used antibiotic, and poses a significant threat to public health. To develop new anti-bacterial agents to combat MRSA-induced infections, we synthesized novel squaric amide derivatives and evaluated their anti-bacterial activity by determining the minimum inhibitory concentration (MIC). Additionally, inhibitory activity of squaric amide 2 (SA2) was measured using the growth curve assay, time-kill assay, and an MRSA-induced skin infection animal model. A scanning electron microscope and transmission electron microscope were utilized to observe the effect of SA2 on the morphologies of MRSA. Transcriptome analysis and real-time PCR were used to test the possible anti-bacterial mechanism of SA2. The results showed that SA2 exerted bactericidal activity against a number of MRSA strains with an MIC at 4–8 µg/mL. It also inhibited the bacterial growth curve of MRSA strains in a dose-dependent manner, and reduced the colony formation unit in 4× MIC within 4–8 h. The infective lesion size and the bacterial number in the MRSA-induced infection tissue of mice were reduced significantly within 7 days after SA2 treatment. Moreover, SA2 disrupted the bacterial membrane and alanine dehydrogenase-dependent NAD+/NADH homeostasis. Our data indicates that SA2 is a possible lead compound for the development of new anti-bacterial agents against MRSA infection.
... This organism colonizes the nasopharynx, perineum, and skin, and it can migrate into the circulatory system and lead to hematogenous spread if the cutaneous barrier is disrupted or damaged. The diagnosis of purulent pericarditis from MRSA is extremely rare, with only a few case reports thus far [2][3][4][5][6][7][8]. However, the mortality rate for untreated patients can approach 100% but decreases to 40% in those patients who are appropriately treated with antibiotics and source control [9]. ...
Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A 76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and Streptococcus anginosus. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin.
... The traditional solution to the antibiotic resistance problem would be to develop new antibiotics with greater efficacy against the resistant bacteria. In the past decades, several drugs (linezolid, daptomycin, tigecycline, telavancin) against methicillin-resistant Staphylococcus aureus (MRSA) strains have been developed [5]. However, despite the success, the scepticism is prevalent on the possibilities for a new antibiotic solution that can address the multidrugresistant bacteria. ...
This study aims to evaluate the effects of bioactive metabolites produced by lactic acid bacteria against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. A total of six lactic acid bacteria (LAB) were selected to evaluate the antimicrobial activity against MRSA ATCC 43300, a skin pathogen that is highly resistant to most antibiotics. The K014 isolate from a fermented vegetable recorded the highest inhibition against MRSA ATCC 43300 at 91.93 ± 0.36%. 16S rRNA sequencing revealed the K014 isolate is closely related to L. plantarum and the sequence was subsequently deposited in the GenBank database with an accession number of MW180960, named as Lactiplantibacillus plantarum K014. The cell-free supernatant (CFS) of L. plantarum K014 had tolerance to high temperature as well as acidic pH. The bioactive metabolites, such as hydrogen peroxide, lactic acid and hyaluronic acid, were produced by L. plantarum K014. Result from ABTS assay showed higher antioxidant activity (46.28%) as compared to that obtained by DPPH assay (2.97%). The CFS had showed anti-inflammatory activity for lipoxygenase (LOX) assay at 43.66%. The bioactive metabolites of L. plantarum K014 showed very promising potential to be used topical skin pathogens.
... In recent years, the emergence and spread of methicillinresistant S. aureus (MRSA) infections has limited the clinical value of oxacillin [11,12], with its utility currently restricted to the treatment of methicillin-sensitive S. aureus (MSSA) infections [13,14]. Combination therapy with a synergistic drug offers a strategy for repurposing antibiotics that have been rendered clinically ineffective due to resistance [15][16][17]. ...
Oxacillin is a first-line antibiotic for the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) infections but is ineffective against methicillin-resistant S. aureus (MRSA) due to resistance. Here we present results showing that co-administering oxacillin with the FtsZ-targeting prodrug TXA709 renders oxacillin efficacious against MRSA. The combination of oxacillin and the active product of TXA709 (TXA707) is associated with synergistic bactericidal activity against clinical isolates of MRSA that are resistant to current standard-of-care antibiotics. We show that MRSA cells treated with oxacillin in combination with TXA707 exhibit morphological characteristics and PBP2 mislocalization behavior similar to that exhibited by MSSA cells treated with oxacillin alone. Co-administration with TXA709 renders oxacillin efficacious in mouse models of both systemic and tissue infection with MRSA, with this efficacy being observed at human-equivalent doses of oxacillin well below that recommended for daily adult use. Pharmacokinetic evaluations in mice reveal that co-administration with TXA709 also increases total exposure to oxacillin. Viewed as a whole, our results highlight the clinical potential of repurposing oxacillin to treat MRSA infections through combination with a FtsZ inhibitor.
Oxacillin Kills Vancomycin-Resistant Staphylococcus aureus (VRSA) When Combined with the FtsZ Inhibitor TXA707
... At present, antibiotic therapy for MRSA is limited due to the strong antibiotic resistance. Combined with poor clinical effects, the minimal inhibitory concentration (MIC) keeps constantly increasing, non-negligible side effects, and expensive pharmacy expenses (Rodvold and McConeghy, 2014). As a result, it is critical to pursue novel therapeutic strategies that can effectively compensate for the shortcomings of traditional antibiotics. ...
Due to powerful drug resistance and fatal toxicity of methicillin-resistant Staphylococcus aureus (MRSA), therapeutic strategies against virulence factors present obvious advantages since no evolutionary pressure will induce bacterial resistance. Alpha-hemolysin (Hla) is an extracellular toxin secreted by Staphylococcus aureus and contributes to bacterial pathogenicity. Herein, we identified a natural product 2,3-dehydrokievitone (2,3-DHKV) for inhibiting Hla activity of MRSA strain USA300 but not affecting bacteria growth. 2,3-DHKV significantly decreased hemolysin expression in a dose-dependent manner, but it did not potently neutralize hemolysin activity. Subsequently, cellular thermal shift and heptamer formation assays confirmed that 2,3-DHK affects hemolytic activity through indirect binding to Hla. RT-qPCR and western blot revealed that 2,3-DHKV suppressed Hla expression at the mRNA and protein levels, and further decreased accessory gene regulator A (agrA) transcription levels. We also observed that 2,3-DHK significantly attenuated the damage of A549 cells by S. aureus and reduced the release of lactate dehydrogenase (LDH). Moreover, in the MRSA-induced pneumonia mouse model, 2,3-DHK treatment prolonged the life span of mice and reduced the bacterial load in the lungs, which significantly alleviated the damage to the lungs. In summary, this study proved that 2,3-DHK as a Hla inhibitor is a potential antivirulence agent against MRSA infection.
Developing models for individualized, time-varying treatment optimization from observational data with large variable spaces, e.g., electronic health records (EHR), is problematic because of inherent, complex bias that can change over time. Traditional methods such as the g-formula are robust, but must identify critical subsets of variables due to combinatorial issues. Machine learning approaches such as causal survival forests have fewer constraints and can provide fine-tuned, individualized counterfactual predictions. In this study, we aimed to optimize time-varying antibiotic treatment –identifying treatment heterogeneity and conditional treatment effects– against invasive methicillin-resistant Staphylococcus Aureus (MRSA) infections, using statewide EHR data collected in Florida, USA. While many previous studies focused on measuring the effects of the first empiric treatment (i.e., usually vancomycin), our study focuses on dynamic sequential treatment changes, comparing possible vancomycin switches with other antibiotics at clinically relevant time points, e.g., after obtaining a bacterial culture and susceptibility testing. Our study population included adult individuals admitted to the hospital with invasive MRSA. We collected demographic, clinical, medication, and laboratory information from the EHR for these patients. Then, we followed three sequential antibiotic choices (i.e., their empiric treatment, subsequent directed treatment, and final sustaining treatment), evaluating 30-day mortality as the outcome. We applied both causal survival forests and g-formula using different clinical intervention policies. We found that switching from vancomycin to another antibiotic improved survival probability, yet there was a benefit from initiating vancomycin compared to not using it at any time point. These findings show consistency with the empiric choice of vancomycin before confirmation of MRSA and shed light on how to manage switches on course. In conclusion, this application of causal machine learning on EHR demonstrates utility in modeling dynamic, heterogeneous treatment effects that cannot be evaluated precisely using randomized clinical trials.
Infections caused by Staphylococcus aureus are a leading cause of mortality worldwide. S. aureus infections caused by Methicillin-Resistant Staphylococcus aureus (MRSA) are particularly difficult to treat due to their resistance to Next Generation β-lactams (NGB) such as Methicillin, Nafcillin, Oxacillin etc. Resistance to NGBs, which is alternatively known as broad-spectrum β-lactam resistance is classically mediated by PBP2a, a Penicillin-Binding Protein encoded by mecA (or mecC) in MRSA. Thus, presence of mec genes among S. aureus serves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated, mecA deficient S. aureus strains can also exhibit NGB resistance. These strains, which are collectively termed as Methicillin-Resistant Lacking mec (MRLM) are currently being identified in increasing numbers among natural resistant isolates of S. aureus. The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance towards NGBs at levels comparable to that of MRSAs. Our study, provides a fresh new perspective about alternative mechanisms of NGBs resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance in S. aureus. It thus suggests reconsideration of the current approach towards diagnosis and treatment of β-lactam resistant S. aureus infections.
Aims
Disabling bacterial virulence with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The von Willebrand factor-binding protein of S. aureus was identified previously as a key virulence determinant. Our objective was to discover a vWbp inhibitor distinct from the antibiotics used to prevent infections resulting from S. aureus.
Methods and Results
Using coagulation assays we found that the sesquiterpene trilactone bilobalide blocks coagulation mediated by vWbp, but has no impact on the growth of S. aureus at a concentration of 128 μg ml −1. Moreover, a mouse model of pneumonia caused by S. aureus indicated that bilobalide could attenuate S. aureus virulence in vivo. This effect is achieved not by interfering with the expression of vWbp but by binding to vWbp, as demonstrated by Western blotting, thermal shift assays (TSAs) and fluorescence quenching assays. Using molecular dynamic simulations and point mutagenesis analysis, we identified that the Q17A and R453A residues are key residues for the binding of bilobalide to vWbp.
Conclusions
Overall, we tested the ability of bilobalide to inhibit S. aureus infections by targeting vWbp and explored the potential mechanism of this activity.
Background: Skin and soft-tissue infections (SSI) caused by Staphylococcus aureus remain a significant concern in both community and hospital settings. Mupirocin resistance among these isolates poses challenges for infection management and control strategies. Aims and Objectives: The aim of this study was to determine the prevalence and patterns of mupirocin resistance among staphylococcus isolates responsible for cutaneous and soft-tissue infections in patients attending a tertiary health-care facility. Along with that, the study investigated into mupirocin resistance prevalence and identified risk factors. Materials and Methods: A prospective study was conducted at a medical college, including 256 non-consecutive staphylococcal isolates from SSI. Antibiotic susceptibility testing was performed using Clinical and Laboratory Standards Institute recommended methods. Mupirocin resistance was determined through disk diffusion testing using 5 μg and 200 μg Mupirocin disks for low-level and high-level resistance, respectively. Results: Among the samples, 16.4% were methicillin-resistant S. aureus (MRSA) and 9.37% were methicillin-resistant coagulase-negative staphylococci. Mupirocin high-level resistance was found in 16.6% of S. aureus isolates, and mupirocin low-level resistance in 19% of MRSA isolates. The prevalence of resistance was lower in inpatient departments compared to outpatient departments. Associations were observed between resistance and patient demographics, history of mupirocin use, surgical site infections, hospitalization history, and diabetes. Conclusion: Mupirocin resistance presents a multifaceted challenge in the context of both patient demographics and clinical settings. The prevalence of resistance was influenced by factors such as patient age, gender, and prior mupirocin usage.
Staphylococcus aureus is a Gram-positive bacterium, which can cause serious bacterial infections in humans. It constitutes an important etiological factor of many diseases, for instance, soft tissue and skin infections (including skin boils and abscesses), as well as life-threatening necrotizing pneumonia or toxic shock syndrome. It is estimated that about 25–30% of people are carriers of S. aureus mainly in the anterior nostrils. A smaller percentage of people are carriers of methicillin-resistant S. aureus (MRSA). In accordance with its definition, methicillin-resistant S. aureus is resistant to almost all β-lactam antibiotics. This phenomenon is mainly caused by the presence of penicillin-binding protein in the cell wall – PBP2a, which is the product of the mecA gene, which is part of the complex called SCCmec (staphylococcal cassette chromosome mec ). Methicillin-resistant S. aureus (MRSA) results in endemic in hospitals around the world and are one of the leading causes of morbidity and mortality in society. Infections initiated by hospital strains of MRSA (health care-associated MRSA, HA-MRSA) concern mainly immunocompromised patients after surgery. In addition, there are populations of acommunity-associated MRSA (CA-MRSA) strains and populations of livestock-associated MRSA (LA-MRSA) strains. The treatment of infections with MRSA etiology, after exhausting the possibilities of standard antibiotic therapy with the use of i.e. vancomycin, is based on treatment with new-generation antibiotics, such as dalbavacin.
Cajaninstilbene acid (CSA), Longistylin A (LLA) and Longistylin C (LLC) are three characteristic stilbenes isolated from pigeon pea, exhibiting antibacterial activities against Staphylococcus aureus and even methicillin-resistant Staphylococcus aureus (MRSA). The results showed that LLA had the highest antibacterial activity against the tested strains following by LLC and CSA. Besides, the results implied that these stilbenes effectively inhibited the levels of adhesion and virulence genes and downregulate the production of ɑ -hemolysin. This study showed that stilbenes from pigeon pea have anti-Staphylococcus potential, and they also inhibited bacterial proliferation, biofilm formation, and key gene expressions related to adhesion and virulence of MRSA. It is the first time that the anti- S. aureus and MRSA activities of the three stilbenes has been systematically reported. These current findings provide insight into the anti-MRSA mechanism of stilbenes from pigeon pea, indicating these compounds may be used as antimicrobial agents or additives for food with health functions, and contribute to the development as well as application of pigeon pea in food science.
Polymeric materials that have been extensively applied in medical devices, wearable electronics, and food packaging are readily contaminated by bothersome pathogenic bacteria. Bioinspired mechano-bactericidal surfaces can deliver lethal rupture for contacted bacterial cells through mechanical stress. However, the mechano-bactericidal activity based only on polymeric nanostructures is not satisfactory, especially for the Gram-positive strain which is generally more resistant to mechanical lysis. Here, we show that the mechanical bactericidal performance of polymeric nanopillars can be significantly enhanced by the combination of photothermal therapy. We fabricated the nanopillars through the combination of low-cost anodized aluminum oxide (AAO) template-assisted method with an environment-friendly Layer-by-Layer (LbL) assembly technique of tannic acid (TA) and iron ion (Fe3+). The fabricated hybrid nanopillar exhibited remarkable bactericidal performances (more than 99%) toward both Gram-negative Pseudomonas aeruginosa (P. aeruginosa) and stubborn Gram-positive Staphylococcus aureus (S. aureus) bacteria. Notably, this hybrid nanostructured surface displayed excellent biocompatibility for murine L929 fibroblast cells, indicating a selective biocidal activity between bacterial cells and mammalian cells. Thus, the concept and antibacterial system described here present a low-cost, scalable, and highly repeatable strategy for the construction of physical bactericidal nanopillars on polymeric films with high performance and biosafety, but without any risks of causing antibacterial resistance.
Aim: Emergence of vancomycin (Van) resistance, and usage of its higher dose and short half-life are posing a serious concern. Slow and sustained release of Van using a nanodelivery system may overcome these problems. Materials & methods: Arginine-α,β-dehydrophenylalanine (RΔF) was synthesized using solution-phase synthesis which self-assembled into nanospheres. Van was entrapped in the nanoparticles (NPs). In vitro and in vivo efficacy of Van-RΔF was determined using broth microdilution and the mouse thigh infection model, respectively. Results & conclusion: Van-RΔF NPs efficiently inhibited bacterial growth (Staphylococcus aureus), while Van alone showed limited growth inhibition in in vitro. Intravenous administration of Van-RΔF in mice with bacterial thigh infection showed enhanced efficacy (double) compared with Van alone, which indicates its high potential for further development.
Objectives
Antimicrobial resistance (AMR) is a global concern among infectious diseases. Bloodstream infections can potentially become life-threatening if they become untreatable with conventional antimicrobials. This review aims to provide an understanding of the AMR prevalence and trends of common bacteremic pathogens, namely Escherichia coli and Staphylococcus aureus in the WHO Africa region.
Methods
PubMed and Google scholar was searched using relevant keywords for published human studies (excluding case reports and reviews) reporting bacteremic AMR data on the pathogens of interest between 2008 and 2019. Two reviewers independently screened the articles against a pre-defined eligibility criterion. Data extraction and analysis were achieved with different platforms – Covidence, Excel, R version 3.6.3 and QGIS v3.4.5. The pooled prevalence, 95% confidence intervals, I² index (a measure of heterogeneity) were calculated for the various pathogen-antibiotic combinations.
Results
562 papers were retrieved, with 27 papers included in the final analysis. Only 23.4% (11/47) of member states of the WHO African region had reports on AMR in bacteremia. CLSI (78.5%) was the most common standard used in the region. For E. coli the pooled resistance was: cefotaxime (42%), imipenem (4%), meropenem (0%) and colistin (0%). For S. aureus, the calculated pooled resistance was cloxacillin (34%), oxacillin (12%) and vancomycin (0%). There was a high degree of variation across studies (I² > 90%).
Conclusion
The pooled resistance rates indicate a concerning degree of methicillin-resistant and ESBL-producing pathogens. The paucity of AMR data also presents challenges for a comprehensive understanding of the situation in the region. Continent-wide and standardized surveillance efforts need strengthening.
Background:
The impetuous usage of antibiotics has led to the perpetual rise of methicillin-resistant Staphylococcus aureus (MRSA), which has garnered the interest of potential drug alternatives, including nanomaterials.
Purpose:
The present study investigates the stability, toxicity, and antibacterial potential of gallic acid-loaded graphene oxide (GAGO) on several MRSA strains.
Methods:
The stability of a synthesized and characterized GAGO was monitored in different physiological media. The toxicity profile of GAGO was evaluated in 3T3 murine fibroblast cells and the embryonic zebrafish model. The antibacterial activity of GAGO against MRSA, methicillin-susceptible S. aureus (MSSA), and community-acquired MRSA; with or without Panton-valentine leucocidin gene (MRSA-pvl+ and MRSA-pvl-) was investigated through disk diffusion, CFU counting method, time-kill experiment, and high-resolution transmission electron microscopy (HRTEM) observation.
Results:
A stable GAGO nanocomposite has shown an improved toxicity profile in 3T3 murine fibroblast cells and zebrafish embryos, besides exhibiting normal ROS levels than graphene oxide (GO) and GA (gallic acid). The nanocomposite inhibited the growth of all bacterial strains employed. The effectiveness of the GAGO nanocomposite was comparable to cefoxitin (CFX), at ≥150 µg/mL in MRSA and MSSA. GAGO exhibited a significantly delayed response towards MRSA-pvl+ and MRSA-pvl-, with increased inhibition following 8 to 24 h of exposure, while comparable activity to native GA was only achieved at 24 h. Meanwhile, for MRSA and MSSA, GAGO had a comparable activity with native GA and GO as early as 2 h of exposure. HRTEM observation further reveals that GAGO-exposed cells were membrane compromised.
Conclusion:
In summary, the present study indicates the antibacterial potential of GAGO against MRSA strains, but further study is warranted to understand the mechanism of action of GAGO and its resistance in MRSA strains.
Although lactation mastitis (LM) has been extensively researched, the incidence rate of LM remains a salient clinical problem. To reduce this incidence rate and achieve a better prognosis, early and specific quantitative indicators are particularly important. It has been found that milk electrolyte concentrations (chloride, potassium, and sodium) and electrical conductivity (EC) significantly change in the early stages of LM in an animal model. Several studies have evaluated EC for the detection of subclinical mastitis in cows. EC, chloride, and sodium content of milk were more accurate for predicting infection status than were other variables. In the early stages of LM, lactic sodium, chloride, and EC increase, but potassium decreases. However, these indicators have not been reported in the diagnosis of LM in humans. This review summarizes the pathogenesis and the mechanism of LM in terms of milk electrolyte concentration and EC, and aim to provide new ideas for the detection of sub-clinical mastitis in humans.
Antimicrobial resistance (AMR) occurs when microbes no longer respond to any pharmacological agents, rendering the conventional antimicrobial agents ineffective. AMR has been classified as one of the top 10 life-threatening global health problems needed multilevel attention and global cooperation to attain the Sustainable Development Goals (SDGs) according to the World Health Organization (WHO), making the discovery of a new and effective antimicrobial agent a priority. The recommended treatments for drug-resistant microbes are available but limited. Furthermore, the transformation of microbes over time increases the risk of developing drug resistance. Hence, plant metabolites such as terpenes, phenolic compounds and alkaloids are widely studied due to their antibacterial, antiviral, antifungal and antiparasitic effects. Plant-derived antimicrobials are preferred due to their desirable efficacy and safety profile. Plant metabolites work by targeting microbial cell membranes, interfering with the synthesis of microbial DNA/RNA/enzymes and disrupting quorum sensing and efflux pump expression. They also work synergistically with conventional antibiotics to enhance antimicrobial effects. Accordingly, this review aims to identify currently available pharmacological therapies against microbes and AMR, as well as to discuss the importance of plant and secondary metabolites as a possible solution for AMR together with their mechanisms of action. All the information was obtained from government databases, WHO websites, PubMed, Springer, Google Scholar and Science Direct. Based on the information obtained, AMR is regarded as a significant warning to global healthcare. Plant derivatives such as secondary metabolites may be considered as potential therapeutic targets to mitigate the non-ending AMR.
The emergence of multidrug resistant (MDR) microorganisms has led to the development of alternative approaches for providing relief from microbial attacks. The mechano-bactericidal action as a substitute for antimicrobials has become the focus of intensive research. In this work, nanostructure-conjugated hydrogel are explored as a flexible dressing against Staphylococcus aureus (S. aureus)-infected skin wounds. Herein gold nanostars (AuNst) with spike lengths reaching 120 nm are probed for antibacterial action. The bacterial killing of >95% is observed for Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli), while up to 60% for Gram-positive S. aureus. AuNst conjugated hydrogel (AuNst120@H) reduced >80% colonies of P. aeruginosa and E. coli. In comparison, around 35.4% reduction of colonies are obtained for S. aureus. The viability assay confirmed the presence of about 85% of living NIH-3T3 cells when grown with hydrogels. An animal wound model is also developed to assess the efficiency of AuNst120@H. A significant reduction in wound size is observed on the 10th day in AuNst120@H treated animals with fully formed epidermal layers, hair follicles, new blood vessels, and arrector muscles. These findings suggest that novel dressing materials can be developed with antimicrobial nanotextured surfaces.
The time has come for a global commitment to develop new antibacterial drugs. Current data document the impending disaster
due to the confluence of decreasing investment in antibacterial drug research and development concomitant with the documented
rapid increase in the level of resistance to currently licensed drugs. Despite the good faith efforts of many individuals,
professional societies, and governmental agencies, the looming crisis has only worsened over the past decade.
Background:
Guidelines recommend that agents other than vancomycin be considered for some types of infection due to methicillin-resistant Staphylococcus aureus (MRSA) when the minimum inhibitory concentration (MIC) to vancomycin is 2 μg/mL or more. Alternative therapeutic options include daptomycin and linezolid, 2 relatively new and expensive drugs, and trimethoprim/sulfamethoxazole (TMP/SMX), an old and inexpensive agent.
Objective:
To compare the clinical efficacy and potential cost savings associated with use of TMP/SMX compared to linezolid and daptomycin.
Methods:
A retrospective study was conducted at Detroit Medical Center. For calendar year 2009, unique adults (age >18 years) with infections due to MRSA with an MIC to vancomycin of 2 μg/mL were included if they received 2 or more doses of TMP/SMX and/or daptomycin and/or linezolid. Data were abstracted from patient charts and pharmacy records.
Results:
There were 328 patients included in the study cohort: 143 received TMP/SMX alone, 89 received daptomycin alone, 75 received linezolid alone, and 21 patients received a combination of 2 or more of these agents. In univariate analysis, patients who received TMP/SMX alone had significantly better outcomes, including in-hospital (p = 0.003) and 90-day mortality (p < 0.001) compared to patients treated with daptomycin or linezolid. Patients receiving TMP/SMX were also younger (p < 0.001), had fewer comorbid conditions (p < 0.001), had less severe acute severity of illness (p < 0.001), and received appropriate therapy more rapidly (p = 0.001). In multivariate models the association between TMP/SMX treatment and mortality was no longer significant. Antimicrobial cost savings associated with using TMP/SMX averaged $2067.40 per patient.
Conclusions:
TMP/SMX monotherapy compared favorably to linezolid and daptomycin in terms of treatment efficacy and mortality. Use of TMP/SMX instead of linezolid or daptomycin could potentially significantly reduce antibiotic costs. TMP/SMX should be considered for the treatment of MRSA infection with MIC of 2 μg/mL to vancomycin.
The oxazolidinone antibiotic linezolid has demonstrated potent antimicrobial activity against Gram-positive bacterial pathogens, including methicillin-resistant staphylococci. This article systematically reviews the published literature for reports of linezolid-resistant Staphylococcus (LRS) infections to identify epidemiological, microbiological and clinical features for these infections. Linezolid remains active against >98% of Staphylococcus, with resistance identified in 0.05% of Staphylococcus aureus and 1.4% of coagulase-negative Staphylococcus (CoNS). In all reported cases, patients were treated with linezolid prior to isolation of LRS, with mean times of 20.0 ± 47.0 months for S. aureus and 11.0 ± 8.0 days for CoNS. The most common mechanisms for linezolid resistance were mutation (G2576T) to the 23S rRNA (63.5% of LRSA and 60.2% of LRCoNS) or the presence of a transmissible cfr ribosomal methyltransferase (54.5% of LRSA and 15.9% of LRCoNS). The emergence of linezolid resistance in Staphylococcus poses significant challenges to the clinical treatment of infections caused by these organisms, and in particular CoNS.
Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections
(ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and
decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve
the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National
Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational
trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent
early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response
endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug
development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable,
and reflective of how patients feel, function, or survive.
Emerging data suggest that vancomycin may be less effective against serious methicillin-resistant Staphylococcus aureus (MRSA) infections with minimum inhibitory concentration (MIC) values at the higher end of the susceptibility range. The purpose of this review is to examine the strength of these associations.
All relevant studies pertaining to treatment outcomes or mortality associated with vancomycin MIC were retrieved from the medical literature from January 1996 through August 2011 and analyzed according to Cochrane guidelines.
Of the 270 studies identified, 48 studies were reviewed, with 22 studies included in the final meta-analysis. Vancomycin MIC was significantly associated with mortality for MRSA infection irrespective of the source of infection or MIC methodology (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.14-2.37; P < .01). This mortality association was predominantly driven by bloodstream infections (BSIs; OR, 1.58; 95% CI, 1.06-2.37; P = .03) and isolates with a vancomycin MIC of 2 μg/mL by Etest (OR, 1.72; 95% CI, 1.34-2.21; P < .01). Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology (OR, 2.69; 95% CI, 1.60-4.51; P < .01).
High vancomycin MIC was associated with a higher mortality rate in MRSA BSI. Thus, institutions should consider conducting Etest MICs on all MRSA BSI isolates. Although these data highlight concerns about vancomycin, currently, there are no data to support better survival rates with alternative antibiotics. Data are sorely needed to determine whether other agents can remedy these outcomes observed with vancomycin for MRSA infections with elevated vancomycin MIC values.
Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia.
This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated.
Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%).
For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.
Reports have found a link between vancomycin treatment failure in methicillin-resistant Staphyloccocus aureus (MRSA) bloodstream infections (BSIs) and higher vancomycin minimum inhibitory concentrations (MICs), despite MICs being below the susceptibility breakpoint of 2 μg/mL. Consensus guidelines recommend considering use of alternative agents for infections involving a higher vancomycin MIC, despite few data to support this approach.
This retrospective case-control study evaluated the effectiveness and safety of vancomycin, compared with that of daptomycin, in the treatment of MRSA BSIs with a high vancomycin MIC (ie, >1 μg/mL).
A total of 118 vancomycin-treated subjects were compared with 59 daptomycin-treated subjects. Clinical failure, defined compositely as mortality, microbiologic failure, and/or recurrence of infection, was numerically lower in daptomycin-treated subjects (31% vs 17%; P = .084) and was mainly driven by a lower incidence of mortality in the daptomycin group (20% vs 9%; P = .046). Factors independently associated with clinical failure included acute renal failure (odds ratio [OR], 3.91 [95% confidence interval {CI}, 1.05-14.56]) and vancomycin treatment group (OR, 3.13 [95%, CI, 1.00-9.76]). Right-sided endocarditis was independently associated with clinical success (OR, 0.07 [95% CI, .01-.83]). A comparison of 60-day mortality between vancomycin- and daptomycin-treated subjects found a higher probability of survival in the daptomycin-treated group (P = .022).
The results demonstrated that daptomycin was associated with a better outcome compared with vancomycin for the treatment of BSIs due to MRSA with higher vancomycin MICs. These findings support the recommendations of recent guidelines, which suggest consideration of the switch to alternative agents when the isolate has a high vancomycin MIC or when patients are not improving during receipt of therapy.
Therapeutic use of vancomycin is characterized by decreased susceptibilities and increasing reports of clinical failures. Few studies have examined the clinical outcomes of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia treated with vancomycin. The primary objective was to compare clinical outcomes of patients with MRSA bacteraemia treated according to standard of care practices.
Patients were included if: (i) admitted to University of New Mexico Hospital between 2002 and 2009; (ii) ≥18 years of age; (iii) had one blood culture positive for MRSA; and (iv) received vancomycin. Clinical outcomes were defined as cure, failure (relapse of infection 30 days after completion of therapy, death or change in therapy) or unevaluable. Patient demographics, source of bacteraemia, treatment regimen, and microbiological characteristics were determined.
Two hundred patients with MRSA bacteraemia were included. Sixty-one patients were unevaluable, leaving 139 patients for the final analysis. Seventy-two (51.8%) patients were cured and 67 (48.2%) experienced vancomycin failure. Vancomycin MIC(90) was 2 mg/L for both groups by Etest. Patients with endocarditis (P = 0.02) or pneumonia (P = 0.02) were more likely to fail therapy. Panton-Valentine leucocidin, loss of agr functionality and strain type were not predictors of outcomes in this study.
High failure rates were observed in patients with MRSA bacteraemia treated with vancomycin, despite high vancomycin troughs and low rates of nephrotoxicity. Predictors of vancomycin failure included endocarditis and pneumonia. In these situations, vancomycin provides suboptimal therapy.
We conducted a retrospective study of 99 patients with methicillin-suseptible Staphylococcus aureus catheter-related bacteremia in which vancomycin MIC was determined by Etest. High vancomycin MIC (>1.5 ug/mL) was the only independent risk factor for development of complicated bacteremia caused by methicillin-susceptible S. aureus (odds ratio 22.9, 95% confidence interval 6.7-78.1).
There are concerns about reduced efficacy of vancomycin in patients with Staphylococcus aureus bacteremia (SAB), especially when the minimum inhibitory concentration (MIC) nears the upper limit of the susceptible range.
We examined the relationship between antibiotic treatment, 30-day mortality, and microbiologic parameters in a large Australasian cohort of patients with SAB.
We assessed 532 patients with SAB from 8 hospitals. All patients with methicillin-resistant S. aureus (MRSA) bacteremia were treated with vancomycin, and patients with methicillin-susceptible S. aureus (MSSA) bacteremia received either flucloxacillin or vancomycin. Increasing vancomycin MIC was associated with increased mortality in vancomycin-treated patients. However, even in patients with MSSA bacteremia treated with flucloxacillin, mortality was also higher if the vancomycin Etest MIC of their isolate was >1.5 μg/mL, compared with those with lower MIC isolates (26.8% vs 12.2%; P < .001). After adjustment in a multivariate model, age, hospital-onset SAB and vancomycin MIC were independently associated with mortality, but methicillin resistance and antibiotic choice were not.
We have confirmed an association between higher vancomycin MIC and increased mortality in patients with SAB, but surprisingly this relationship was not related to the antibiotic treatment received, suggesting that the use of vancomycin per se is not responsible for the poorer outcome.
Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are
intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss
the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections
(SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations
are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility
to vancomycin, and vancomycin treatment failures.
The aim of this study was to compare the efficacy and safety of tigecycline, a newly developed glycylcycline antibiotic, with those of empirical antibiotic regimens which have been reported to possess good efficacy for complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), community-acquired pneumonia (CAP), and other infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE). A meta-analysis of randomized controlled trials (RCTs) identified in PubMed, the Cochrane Library, and Embase was performed. Eight RCTs involving 4,651 patients were included in the meta-analysis. Compared with therapy with empirical antibiotic regimens, tigecycline monotherapy was associated with similar clinical treatment success rates (for the clinically evaluable [CE] population, odds ratio [OR] = 0.92, 95% confidence interval [CI] = 0.76 to 1.12, P = 0.42; for the clinical modified intent-to-treat [c-mITT] population, OR = 0.86, 95% CI = 0.74 to 1.01, P = 0.06) and similar microbiological treatment success rates (for the microbiologically evaluable [ME] population, OR = 0.86, 95% CI = 0.69 to 1.07, P = 0.19). The incidence of adverse events in the tigecycline group was significantly higher than that in the other therapy groups with a statistical margin (for the modified intent-to-treat [mITT] population, OR = 1.33, 95% CI = 1.17 to 1.52, P < 0.0001), especially in the digestive system (mITT population, OR = 2.41, 95% CI = 1.67 to 3.46, P < 0.00001). No difference regarding all-cause mortality and drug-related mortality between tigecycline and the other regimens was found, although numerically higher mortality was found in the tigecycline group. This meta-analysis provides evidence that tigecycline monotherapy may be used as effectively as the comparison therapy for cSSSI, cIAIs, CAP, and infections caused by MRSA/VRE. However, because of the high risk of mortality, AEs, and emergence of resistant isolates, prudence with the clinical use of tigecycline monotherapy in infections is required.
Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens.
Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7-21 days. The primary end point was clinical response at follow-up/test-of-cure visit.
A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, -5.6% to 4.3%). In the pooled clinically evaluable population (n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, -4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, -0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, -7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%).
The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens.
Linezolid resistance is extremely uncommon in Staphylococcus aureus.
To report an outbreak with linezolid and methicillin-resistant S. aureus (LRSA) in an intensive care department and the effective control measures taken.
Outbreak study of consecutive critically ill patients colonized and/or infected with LRSA at an intensive care department of a 1000-bed tertiary care university teaching hospital in Madrid, Spain. Patients were placed under strict contact isolation. Daily updates of outbreak data and recommendations for the use of linezolid were issued. Extensive environmental sampling and screening of the hands of health care workers were performed.
Linezolid use and clinical and epidemiological characteristics and outcomes using minimal inhibitory concentrations, pulsed-field gel electrophoresis, and polymerase chain reaction of LRSA isolates.
Between April 13 and June 26, 2008, 12 patients with LRSA were identified. In 6 patients, LRSA caused ventilator-associated pneumonia and in 3 patients it caused bacteremia. Isolates were susceptible to trimethoprim-sulfamethoxazole, glycopeptides, tigecycline, and daptomycin. Genotyping identified 1 predominant clone and 3 other types. Cfr-mediated linezolid resistance was demonstrated in all isolates. Potential hospital staff carriers and environmental samples were negative except for one. Six patients died, 5 of them in the intensive care unit, with 1 death attributed to LRSA infection. Linezolid use decreased from 202 defined daily doses in April 2008 to 25 defined daily doses in July 2008. Between July 2008 and April 2010, no new cases have been identified in the weekly surveillance cultures or diagnostic samples.
The first clinical outbreak, to our knowledge, with LRSA mediated by the cfr gene developed at our center, was associated with nosocomial transmission and extensive usage of linezolid. Reduction of linezolid use and infection-control measures were associated with the termination of the outbreak.
To evaluate the efficacy and safety of co-trimoxazole versus that of vancomycin in adults with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia.
Retrospective matched cohort study. Thirty-eight patients with MRSA bacteraemia, treated with co-trimoxazole as the main therapeutic agent, were matched with 76 patients treated with vancomycin as the main agent. The groups were matched for age, sex, functional status, endovascular source of infection, appropriateness of empirical antibiotic therapy, presence of a foreign body, sepsis severity and Charlson score. The outcomes collected were 30 day mortality, persistent bacteraemia [defined as positive blood culture (BC) >14 days after the first positive BC, but within 30 days], relapse (defined as recurrence of the same phenotype >30 days after the first positive BC within 12 months) and adverse events.
The groups were well matched. Thirty day mortality was not significantly different between the groups [co-trimoxazole 13/38 (34.2%); vancomycin 31/76 (40.8%); odds ratio 0.76, 95% confidence interval 0.34-1.7]. There was only one case of relapse in the co-trimoxazole group (2.6%) compared with nine cases in the vancomycin group (11.8%). Incidence of relapse or persistent bacteraemia was lower in the co-trimoxazole group (3/38, 7.9%) than in the vancomycin group (13/76, 17.1%), although the difference was not statistically significant (P = 0.182). Development of renal failure was similar [co-trimoxazole 11/38 (28.9%); vancomycin 21/76 (27.6%)].
Within the limitations of a small retrospective study, co-trimoxazole had a safety and efficacy profile similar to that of vancomycin and may offer an attractive additional therapeutic option for MRSA bacteraemia. A prospective, randomized controlled trial is warranted.
The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, "CPK elevation") in patients with Staphylococcus aureus bacteremia with or without infective endocarditis.
Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression.
Significant relationships between the minimum concentration of drug (C(min)) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. C(min) (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a C(min) 24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in C(min), evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated C(min) to be a significant predictor of time to a CPK elevation (P .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a C(min) 24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively.
This analysis demonstrated that a daptomycin C(min) 24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067 .
Invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA), particularly those involving persistent bacteraemia, necrotizing pneumonia, osteomyelitis and other deep-seated sites
of infections, are associated with high mortality and are often difficult to treat. The response to treatment of severe MRSA
infection with currently available antibiotics active against MRSA is often unsatisfactory, leading some physicians to resort
to combination antibiotic therapy. Now, with the emergence of community-associated MRSA (CA-MRSA) clones that display enhanced
virulence potentially related to up-regulated toxin production, the use of adjuvant protein synthesis-inhibiting antibiotics
to reduce toxin production also has been advocated by some experts. In this review, we discuss the limitations of antibiotics
currently available for the treatment of serious invasive MRSA infections and review the existing literature that examines
the potential role of combination therapy in these infections.
Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed.
We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy.
Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, and methicillin-resistant S. aureus. Daptomycin therapy was associated with a higher rate of microbiologic failure than was standard therapy (19 vs. 11 patients, P=0.17). In 6 of the 19 patients with microbiologic failure in the daptomycin group, isolates with reduced susceptibility to daptomycin emerged; similarly, a reduced susceptibility to vancomycin was noted in isolates from patients treated with vancomycin. As compared with daptomycin therapy, standard therapy was associated with a nonsignificantly higher rate of adverse events that led to treatment failure due to the discontinuation of therapy (17 vs. 8, P=0.06). Clinically significant renal dysfunction occurred in 11.0 percent of patients who received daptomycin and in 26.3 percent of patients who received standard therapy (P=0.004).
Daptomycin (6 mg per kilogram daily) is not inferior to standard therapy for S. aureus bacteremia and right-sided endocarditis. (ClinicalTrials.gov number, NCT00093067 [ClinicalTrials.gov].).
The purpose of this study was to determine the tissue and corresponding serum concentration of tigecycline at selected time points in gall bladder, bile, colon, bone, synovial fluid (SF), lung and CSF in subjects undergoing surgical or medical procedures.
One hundred and four adult subjects (aged 24-83 years; 64 women, 40 men) received a single intravenous (i.v.) dose of tigecycline (100 mg infused over 30 min). Subjects were randomly assigned to one of four collection times at 4, 8, 12 and 24 h after the start of the infusion. For CSF, samples were collected at approximately 1.5 and 24 h after the start of the infusion. All subjects had serum samples collected before the administration of tigecycline, at the end of the infusion and at the time corresponding to tissue or body fluid collection. Drug concentrations in serum, tissues and body fluids were determined by LC/MS/MS. The area under the mean concentration-time curve from 0 to 24 h (AUC(0-24)) was determined for the comparison of systemic exposure between tissue or body fluid to serum.
The mean serum concentrations of tigecycline were similar to those previously published. Tissue penetration, expressed as the ratio of AUC(0-24) in tissue or body fluid to serum, was 537 for bile, 23 for gall bladder, 2.6 for colon, 2.0 for lung, 0.41 for bone, 0.31 for SF and 0.11 for CSF.
A single 100 mg dose of intravenous tigecycline produced considerably higher tissue/fluid concentrations in bile, gall bladder, colon and lung compared with simultaneous serum concentrations. On average, the systemic exposure of tigecycline in bone, SF and CSF ranged from 11% to 41% of serum concentrations. The results in bone are inconsistent with previous radiolabelled studies in animals and it is unclear if tight binding to bone (versus low bone uptake) or poor extraction of tigecycline for LC/MS/MS detection or both may have contributed to the differences we observed in humans.
Safety and efficacy of quinupristin-dalfopristin (an injectable streptogramin antibiotic) were evaluated in the treatment of a variety of infections due to methicillin-resistant Staphylococcus aureus (MRSA) in patients either intolerant of or failing prior therapy. The influence of resistance phenotypes on treatment outcome was also assessed. This worldwide, multicentre, open-label, non-comparative, emergency-use clinical study enrolled patients with one or more of nine predefined, culture-confirmed infections with MRSA, who had no clinically appropriate alternative antibiotic therapy. The recommended quinupristin-dalfopristin dose was 7.5 mg/kg administered iv every 8 h for a duration judged appropriate by the investigator. There were no restrictions on prior or concomitant treatment with other antibiotics. Clinical, microbiological and laboratory assessments were performed at baseline, during study drug treatment, within 24 h after the last dose, and 7-21 days post-therapy. Ninety patients [age (mean ± S.D.) 57.4 ± 18.5 years] with significant underlying medical illnesses were treated at 63 centres in five countries. The most common indications were bone and joint infection (44.4% of patients) and skin and skin structure infection (16.7%). The mean (± S.D.) daily dose and treatment duration was 20.2 ± 2.9 mg/kg/day for 28.5 ± 22.3 days, most frequently administered every 8 h. The overall success rate (defined as a clinical outcome of either cure or improvement and a bacteriological outcome of eradication or presumed eradication) was 71.1% in the all-treated population (n = 90) and 66.7% in patients who were both clinically and bacteriologically evaluable (n = 27). Success rates for endocarditis, respiratory tract infection and bacteraemia of unknown source were below the population mean. The macrolide-lincosamide-streptogramin type B resistance phenotype did not appear to alter the response rate. The most common non-venous adverse events related to study medication were arthralgias (10.8%), myalgias (8.6%) and nausea (8.6%). Quinupristin-dalfopristin should be considered as a treatment option for infections caused by MRSA, especially in patients intolerant of or failing alternate therapy.
In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.
Ceftaroline fosamil is a cephalosporin antibacterial approved by the US Food and Drug Administration (FDA) for use in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). After intravenous administration, ceftaroline fosamil is rapidly converted to its bioactive metabolite, ceftaroline. Ceftaroline has broad-spectrum in vitro activity against Gram-positive and Gram-negative bacteria, including contemporary resistant Gram-positive phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae. Because of its unique spectrum of activity, the Clinical and Laboratory Standards Institute (CLSI) designated ceftaroline as a member of a new subclass of β-lactam antimicrobials, cephalosporins with anti-MRSA activity.
The activity of ceftaroline against S. aureus extends to heteroresistant vancomycin-intermediate, vancomycin-intermediate, vancomycin-resistant and daptomycin-nonsusceptible isolates. Ceftaroline has low minimum inhibitory concentrations (MICs) for all tested species of streptococci, and has potent activity against S. pneumoniae isolates with varying degrees of penicillin resistance. The activity of ceftaroline is limited against Enterococcus faecalis and Enterococcus faecium and against anaerobes such as Bacteroides fragilis. The in vitro activity of ceftaroline includes many Gram-negative pathogens, but does not extend to bacteria that produce extended-spectrum β-lactamases, class B metallo-β-lactamases or AmpC cephalosporinases, or to most nonfermentative Gram-negative bacilli.
Ceftaroline fosamil has been studied for the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired pneumonia (CAP) in phase III randomized, double-blind, international, multicentre noninferiority clinical trials. Two identical trials (CANVAS 1 and CANVAS 2) compared the efficacy of ceftaroline fosamil with that of vancomycin plus aztreonam in 1378 adults with cSSSI. Results demonstrated that ceftaroline was noninferior to vancomycin plus aztreonam, with 91.6% in the ceftaroline fosamil group (pooled analysis) achieving clinical response compared with 92.7% in the vancomycin plus aztreonam group (difference −1.1%, 95% CI −4.2, 2.0). An additional analysis evaluated clinical cure in a subgroup of patients who met the FDA guidance definition of ABSSSI at treatment day 3. Clinical response, defined as cessation of lesion spread and absence of fever, was 74.0% in the ceftaroline fosamil group compared with 66.2% in the vancomycin plus aztreonam group (treatment difference 7.8%, 95% CI 1.3, 14.0).
Clinical efficacy of ceftaroline fosamil in 1240 hospitalized adults with CAP was compared with that of ceftriaxone in two additional phase III trials (FOCUS 1 and FOCUS 2). Of note, because ceftriaxone does not have activity against MRSA, patients with confirmed or suspected MRSA CAP were excluded from the FOCUS trials. Results demonstrated that ceftaroline was noninferior to ceftriaxone, with 84.3% in the ceftaroline fosamil group achieving clinical cure compared with 77.7% in the ceftriaxone group (difference 6.7%, 95% CI 1.6, 11.8). An additional analysis of the trials was conducted in patients with moderate to severe CAP and at least one proven typical bacterial pathogen at baseline (i.e. CABP). Day 4 clinical response rates were 69.5% for ceftaroline and 59.4% for ceftriaxone (difference 10.1%, 95% CI −0.6, 20.6).
In the phase III trials, adverse event rates were similar between groups. Overall, ceftaroline is well tolerated, which is consistent with the good safety and tolerability profile of the cephalosporin class.
In summary, ceftaroline fosamil is a broad-spectrum parenteral cephalosporin with excellent in vitro activity against resistant Gram-positive pathogens, including MRSA, as well as many common Gram-negative organisms. It is a welcome treatment option for ABSSSI and CABP.
To study the effectiveness and safety of vancomycin compared with that of other antibiotics for the treatment of gram-positive infections.
Major electronic databases were searched. Data from published randomized controlled trials (January 1, 1950, to September 15, 2011) were pooled using a meta-analytic method.
Fifty-three trials comparing vancomycin with linezolid, daptomycin, quinupristin-dalfopristin, tigecycline, ceftaroline, ceftobiprole, telavancin, teicoplanin, iclaprim, and dalbavancin were included in the meta-analysis. Individual antibiotics were as effective as vancomycin, except for linezolid, which was more effective than vancomycin for the treatment of skin and soft tissue infections (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.07-2.43). Comparators were as effective as vancomycin in the intent-to-treat population (OR, 1.08; 95% CI, 0.98-1.18) but were more effective in the clinically evaluable population (OR, 1.14; 95% CI, 1.02-1.27) when all infections were pooled. When available data from all trials were pooled, no differences were noted when patients with febrile neutropenia (OR, 1.07; 95% CI, 0.82-1.39), pneumonia (OR, 1.10; 95% CI, 0.87-1.37), bacteremia (OR, 1.05; 95% CI, 0.76-1.45), and skin and soft tissue infections (OR, 1.11; 95% CI, 0.89-1.39) were studied. Comparators were more effective in open-label (OR, 1.28; 95% CI, 1.08-1.50) but not in double-blind trials (OR, 1.04; 95% CI, 0.90-1.20). Total adverse events attributed to studied antibiotics (OR, 1.07; 95% CI, 0.90-1.28) and patients withdrawn from trials (OR, 0.86; 95% CI, 0.68-1.09) were similar in the compared groups. Mortality was not different between vancomycin and comparator antibiotics when all trials were included in the analysis (OR, 1.09; 95% CI, 0.96-1.23). Comparators were associated with higher mortality in open-label (OR, 1.27; 95% CI, 1.05-1.54) but not double-blind trials (OR, 0.96; 95% CI, 0.80-1.14).
On the basis mainly of data from open-label trials, vancomycin is a treatment choice that is as effective as other available antibiotics for patients with gram-positive infections. Study design seems to make a major contribution to the outcome.
On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death.
PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms "tigecycline" and "randomized controlled trial (RCT)" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis.
Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I(2 )= 0%; P = .99) or noncure rates (I(2 )= 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I(2 )= 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I(2 )= 0%; RD, 0.7%; P = .06).
Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections.
Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.
The antibiotic telithromycin (Ketek, Sanofi-aventis) had two of three treatment indications withdrawn after postmarketing reports of serious and fatal adverse events. The rationale for the withdrawal of specific indications (acute bacterial sinusitis and acute exacerbations of chronic bronchitis), while permitting the drug to remain available for the treatment of community-acquired pneumonia, focused on the lack of demonstrated efficacy from clinical trials that included an active control to which the investigational drug, telethromycin, was determined to be statistically noninferior. This action regarding telithromycin represents a reversal of previous FDA guidelines for the conduct of clinical trials for antibacterial treatment indications and has increased the regulatory risk for future drug development. New clinical trial guidelines have been published that will increase the time and resources required to achieve regulatory marketing approval. This paper reviews recent regulatory actions and discusses the impact these new guidelines will have on future antibacterial clinical trial designs and challenges.
The resolution of antibiotic-ribosomal subunit complexes and antibacterial-protein complexes at the atomic level has provided new insights into modifications of clinically relevant antimicrobials and provided new classes that target the protein cellular apparatus. New chemistry platforms that use fragment-based drug design or allow novel modifications in known structural classes are being used to design new antibiotics that overcome known resistance mechanisms and extend spectrum and potency by circumventing ubiquitous efflux pumps. This review provides details on seven antibiotics in development for treatment of moderate-to-severe community-acquired bacterial pneumonia and/or acute bacterial skin and skin structure infections: solithromycin, cethromycin, omadacycline, CEM-102, GSK1322322, radezolid, and tedizolid. Two antibiotics of the oxazolidinone class, PF-02341272 and AZD5847, are being developed as antituberculosis agents. Only three antibiotics that target the protein cellular machinery, TP-434, GSK2251052, and plazomicin, have a spectrum that encompasses multidrug-resistant Gram-negative pathogens. These compounds provide hope for treating key pathogens that cause serious disease in both the community and the hospital.
The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.
Fifty years ago methicillin-resistant Staphylococcus aureus (MRSA) first revealed themselves to the medical community, having been described in a landmark article published in the British Medical Journal. Among other things, their discovery set off a major response from the scientific and medical professions to control or even
eliminate them as major human pathogens. Despite these efforts, however, MRSA have spread throughout the world and a half
century after they burst upon the scene they continue to pose major challenges to research scientists and clinicians alike.
In a very real sense, this year marks the ‘birthday’ of a remarkably successful pathogen. The major reasons for the ability
of MRSA to prosper and cause disease in settings inimical to its survival form the basis of this article.
There is an urgent need for new antibacterials to target emerging multidrug-resistant bacteria. The need for such agents is rising while the efforts in antibacterial research have declined dramatically in the past few decades with the result of only four compounds belonging to new chemical classes being approved for clinical use. The main reasons that led to this critical situation are shortly described. A renewed interest in the research of new effective antimicrobials is nonetheless delivering compounds deriving mainly from modification of existing drugs, yet new chemical classes are appearing. Because many of these activities have started relatively recently, we should expect a long period before new antibiotics are added to the medical armamentarium.
Multidrug resistance among bacteria increases the need for new antimicrobial drugs with high potency and stability. Tigecycline is one candidate drug, and a previous meta-analysis of only published randomised controlled trials suggested that it might as effective as comparator treatments; we did a meta-analysis to include new and unpublished trials to assess its efficacy for the treatment of adult patients with serious bacterial infection.
We searched PubMed, Cochrane Central Register, and Embase up to March 30, 2011, to identify published studies, and we searched clinical trial registries to identify completed unpublished studies, the results of which were obtained through the manufacturer. Eligible studies were randomised trials assessing the clinical efficacy, safety, and eradication efficiency of tigecycline versus other antimicrobial agents for any bacterial infection. The primary outcome was treatment success in patients who received at least one dose of the study drug, had clinical evidence of disease, and had complete follow-up (the clinically assessable population). Meta-analysis was done with random-effects models because of heterogeneity across the trials.
14 randomised trials, comprising about 7400 patients, were included. Treatment success was lower with tigecycline than with control antibiotic agents, but the difference was not significant (odds ratio 0·87, 95% CI 0·74-1·02). Adverse events were more frequent in the tigecycline group than in the control groups (1·45, 1·11-1·88), with significantly more vomiting and nausea. All-cause mortality was higher in the tigecycline group than in the comparator groups, but the difference was not significant (1·28, 0·97-1·69). Eradication efficiency did not differ between tigecycline and control regimens, but the sample size for these comparisons was small.
Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections. Our findings show that assessment with unpublished studies is needed to make appropriate decisions about new agents.
None.
Because a significant proportion of Staphylococcus aureus strains as well as most coagulase-negative staphylococci are resistant to penicillin and semisynthetic beta-lactam drugs, the need for vancomycin and related antibiotics has never been greater. Effective use of vancomycin requires knowledge of dosing parameters and selection of target trough levels appropriate to the specific infection and to the pathogen being treated. For clinicians, it is vital to remain up-to-date with evolving definitions for vancomycin susceptibility, with new interpretations of efficacy, and with information on toxicity.
Tigecycline is a novel glycylcycline that exhibits broad-spectrum antibacterial activity. Recently, the US FDA issued a warning concerning increased mortality with tigecycline in randomized controlled trials (RCTs).
We conducted a systematic review and meta-analysis of RCTs that compared tigecycline with any other antibiotic regimen for the treatment of any infection. A comprehensive search, without publication status or other restrictions, was conducted. The primary outcome was overall 30 day mortality. The secondary outcome included clinical and microbiological failure, superinfections and adverse events (AEs). The trials' risks of bias and their effects on results were assessed. Two reviewers independently extracted the data. Individual trials' relative risks (RRs) were pooled using a fixed effect meta-analysis.
Fifteen trials (7654 patients) were included. Overall mortality was higher with tigecycline compared with other regimens [RR 1.29, 95% confidence interval (CI) 1.02-1.64, without heterogeneity]. The type of infection assessed and the trials' reported risks of bias did not affect this result. Clinical failure was significantly higher with tigecycline (RR 1.16, 95% CI 1.06-1.27) and non-statistically significant higher rates of microbiological failure were demonstrated (RR 1.13, 95% CI 0.99-1.30). Development of septic shock was significantly more frequent with tigecycline (RR 7.01, 95% CI 1.27-38.66). Superinfections were significantly more common with tigecycline and so were AEs, including all AEs and AEs requiring discontinuation.
In the light of the increased mortality, probably explained by decreased clinical and microbiological efficacy, clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a last-resort drug.
High rates of vancomycin failure in methicillin-resistant Staphylococcus aureus (MRSA) infections have been increasingly reported over time. The primary objective of our study was to determine the impact of vancomycin exposure and outcomes in patients with MRSA bacteremia initially treated with vancomycin.
This was a single-center retrospective analysis of 320 patients with documented MRSA bacteremia initially treated with vancomycin from January 2005 through April 2010. Two methods of susceptibility, Etest and broth microdilution, were performed for all isolates to determine the correlation of susceptibility testing to patient outcomes.
Among a cohort of 320 patients, more than half (52.5%) experienced vancomycin failure. Independent predictors of vancomycin failure in logistic regression included infective endocarditis (adjusted odds ratio [AOR], 4.55; 95% confidence interval [CI], 2.26-9.15), nosocomial-acquired infection (AOR, 2.19; 95% CI, 1.21-3.97), initial vancomycin trough <15 mg/L (AOR, 2.00; 95% CI, 1.25-3.22), and vancomycin minimum inhibitory concentration (MIC) >1 mg/L by Etest (AOR, 1.52; 95% CI, 1.09-2.49). With use of Classification and Regression Tree (CART) analysis, patients with vancomycin area under the curve at 24 h (AUC(24h)) to MIC ratios <421 were found to have significantly higher rates of failure, compared with patients with AUC(24h) to MIC ratios >421 (61.2% vs 48.6%; P = .038).
In light of the high failure rates associated with this antimicrobial, optimizing the pharmacokinetic/pharmacodynamic properties of vancomycin by targeting higher trough values of 15-20 mg/L and AUC(24h)/MIC ratios ≥400 in selected patients should be considered.
We sought to characterize the pharmacodynamic profile of the more intensive vancomycin dosing regimens currently used in response to the recent vancomycin guidelines.
A series of Monte Carlo simulations was performed for vancomycin regimens ranging from .5 g intravenous (IV) Q12H to 2 g IV Q12H. The probability of achieving an AUC/MIC ratio ≥ 400 for each dosing regimen was calculated for minimum inhibitory concentrations (MICs) from .5 to 2 mg/L. The risk of nephrotoxicity for each regimen was derived from a previously published vancomycin trough-nephrotoxicity logistic regression function. Restricted analyses were performed that only included subjects with troughs between 15 and 20 mg/L.
At a MIC of 2 mg/L, even the most aggressive dosing regimen considered (2 g every 12 h) only yielded a probability of target attainment (PTA) of 57% while generating a nephrotoxicity probability upward of 35%(.) At a MIC of 1 mg/L, ≥3 g per day provided PTA in excess of 80% but were associated with unacceptable risks of nephrotoxicity. In the restricted analyses of subjects with troughs between 15 and 20 mg/L, all regimens produced a PTA of 100% at MICs ≤1 mg/L. The PTA was variable among the regimens at a MIC of 2 mg/L and was highly dependent on the total daily dose administered.
This study indicates that vancomycin may not be useful for treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC values > 1 mg/L where PTA is questionable. Since an AUC/MIC ratio ≥ 400 is target associated with efficacy, one should consider incorporating computation of AUC when monitoring vancomycin.
Linezolid (Zyvox) is the first member of an entirely new class of antibiotics to reach the market in over 35 years; it was approved for use in 2000. A member of the oxazolidinone class of antibiotics, linezolid is highly effective for the treatment of serious Gram-positive infections and has activity that compares favorably with vancomycin for most clinically relevant pathogens. Zyvox is approved for use against serious Gram-positive infections, including those caused by Streptococcus pneumoniae, and the very challenging methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium organisms. Zyvox inhibits bacterial protein synthesis by binding to 23S rRNA in the catalytic site of the 50S ribosome. It can be administered both orally and intravenously and has good tissue distribution. Recent results have demonstrated that oxazolidinone analogs related to linezolid are effective in treating pulmonary tuberculosis caused by resistant Mycobacterium tuberculosis in animal infection models and suggest additional new therapeutic applications for these antibiotics.
The recent emergence of meticillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin has prompted clinicians to prescribe vancomycin therapy targeting high trough concentrations (15-20 mg/L). Relevant studies (n=12) analysing the occurrence of nephrotoxicity with high-dose therapy were reviewed. Most studies were retrospective and the temporal relationship between elevated trough levels and development of nephrotoxicity was unclear, precluding a definitive cause-effect analysis. Available data suggest an association between vancomycin trough level and risk of nephrotoxicity as a function of intensity and duration of therapy (>7 days), compounded by concomitant receipt of nephrotoxins, vasopressor therapy and underlying physiological impairment. In separate studies in which a high trough concentration was measured prior to the onset of nephrotoxicity, the frequency of occurrence was 21-28% in patients with concomitant risks compared with 7% in patients without risks. A similar comparison between risk and no-risk groups who attained a standard trough concentration (10-15 mg/L) indicates the rates of occurrence as 9-21% vs. 2%. Onset of nephrotoxicity ranged from 4 days to 8 days from the start of therapy. The degree of renal dysfunction was modest, with a reported decrease of 35-45% in creatinine clearance from baseline. Resolution occurred in >70% of patients by the time of discharge. Future studies should detail clearly the temporal relationship between drug exposure and onset of nephrotoxicity, confounding risk factors, extent of injury and time course of recovery, and should also determine the relative risk versus benefit of high-dose vancomycin versus alternative agents.
Although there has been a relentless increase in resistance to antimicrobial agents amongst important bacterial pathogens throughout the world, it is well known that the number of new antimicrobial agents being brought to the market has undergone a steady decline in the past several decades. There are a number of reasons for this, which are detailed in this article, but there is also a great deal of continuing research to find new effective antimicrobials, much of it now being carried out in academic centres and especially in small biotechnology companies, rather than by large pharma. Whilst classic screening methods and chemical modification of known antimicrobial agents continue to produce potential leads for new antimicrobial agents, a number of other approaches are being investigated. These include the search for potentiators of the activity of known antimicrobial agents and the development of hybrid agents, novel membrane-active drugs, and inhibitors of bacterial virulence and pathogenesis. A number of new bacterial targets are also being exploited, as are bacteriophages and their lytic enzymes. Given the amount of investigation presently underway, it is clear that although the antibiotic pipeline is not as promising as it was half a century ago, it is far from dry.
The use of policies and practices regarding surveillance, decolonization, and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections and the formulary status of various antimicrobial agents used to treat MRSA were characterized.
A 61-item questionnaire was sent to the director of pharmacy at each of 263 acute care hospitals that were members of a national group purchasing organization.
Responses were received from 102 hospitals (38.8%). Active surveillance culture protocols were in place at 44 hospitals (44%). Nearly 75% engaged in key antimicrobial stewardship activities, while only 18% reported having a formal antimicrobial stewardship team. MRSA decolonization policies existed in approximately 25% of the respondent hospitals. Vancomycin was on the formulary in all hospitals with few restriction policies, while the newer anti-MRSA agents-linezolid, daptomycin, and tigecycline-were on the formulary in most hospitals but with restrictions. Vancomycin was the most commonly used antimicrobial for the treatment of various MRSA infections, followed by linezolid. Nearly 70% of the respondent hospitals reported having a vancomycinspecific dosing or monitoring guideline in place. Most specified the use of actual body weight for dosing and trough serum concentrations at steady state for therapeutic monitoring (84% and 91%, respectively). Most guidelines did not address the use of a loading dose to attain a high target trough or methods for choosing alternative agents.
Acute care hospitals in the United States varied in their policies and practices of surveillance, decolonization, and treatment of MRSA infections, but most were consistent with national guideline recommendations.
Resistance to antibiotics among gram-positive bacteria, especially enterococci and staphylococci, has led to the need to develop new antibiotics. Vancomycin, a glycopeptide antibiotic, has been used for over 3 decades to treat serious methicillin-resistant Staphylococcus aureus infections. The increased frequency of multidrug-resistant bacteria, especially vancomycin-resistant strains, has focused interest on three new lipoglycopeptides for the treatment of infections caused by gram-positive bacteria: oritavancin, dalbavancin, and telavancin. Although oritavancin and dalbavancin are still in development, telavancin received approval from the United States Food and Drug Administration in September 2009 for treatment of complicated skin and skin structure infections. Structurally different from vancomycin and teicoplanin, all three lipoglycopeptides have greater potency and less potential for development of resistant organisms. Of particular importance is the activity of oritavancin, dalbavancin, and telavancin against vancomycin-resistant organisms. In addition, the pharmacokinetic properties of these new antimicrobials substantially differ from those of vancomycin. Both oritavancin and dalbavancin have long terminal half-lives, which may allow for infrequent dosing. In addition, oritavancin is primarily cleared through hepatic pathways, which makes it potentially useful in patients with renal compromise. In animal models, these new lipoglycopeptides were effective in treating serious gram-positive infections, including complicated skin and skin structure infections, endocarditis, bacteremia, and pneumonia; in clinical studies, however, efficacy was shown only in complicated skin and skin structure infections for all three agents. According to preliminary data, the adverse-effect profile of these lipoglycopeptides is generally similar to that of drugs currently used to treat severe gram-positive infections. However, further evaluation and monitoring is necessary as more patients are exposed to these agents. As antimicrobial resistance continues to increase worldwide, the lipoglycopeptides may provide clinicians with a useful antimicrobial in the continued fight against multidrug-resistant gram-positive bacteria.
The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin-resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo. Factors associated with loss of susceptibility and ways to reduce the risk of resistance to daptomycin are reviewed, including the importance of prompt mechanical reduction of bacterial inoculum through surgery or through potent or combination antibiotic therapy, as well as optimisation of daptomycin pharmacodynamic exposure.
Methicillin-resistant Staphylococcus aureus (MRSA) is a dynamic pathogen. Rates of MRSA are increasing worldwide. In some centers, MRSA is becoming less susceptible to vancomycin, and these strains have been associated with worse clinical outcomes. Intermediate or fully resistant vancomycin strains of MRSA have emerged clinically, whereas MRSA acquired in the community has become epidemic. The purpose of this manuscript is to provide clinicians with an evidence-based review on new treatments for MRSA.
Linezolid, daptomycin and tigecycline have been approved during the last decade to treat infections due to MRSA. Although these agents are extremely valuable in the fight against MRSA, each one has limitations. New lypoglycopeptides (telavancin, dalbavancin and oritavancin) are in advanced phase of clinical development. Similarly, new broad-spectrum cephalosporins active against MRSA (e.g. ceftobiprole and ceftaroline) and a new dihydrofolate reductase inhibitor (iclaprim) are in or have completed phase 3 studies.
Here, we review the most relevant information on new drugs to treat MRSA. New studies with available agents and upcoming studies with investigational drugs will help to better understand the role of each compound in the treatment of patients infected with MRSA and assist the clinician in keeping pace with this challenging pathogen.
The objectives of this study were to examine the predictive value of method-specific vancomycin (VAN) minimum inhibitory concentration (MIC) results on treatment outcomes of meticillin-resistant Staphylococcus aureus (MRSA) infections. VAN MIC values for MRSA strains were determined using Etest, VITEK-1, MicroScan (MScan) and broth microdilution (BMD), with additional screening for heterogeneous glycopeptide-intermediate S. aureus (hGISA) phenotype. Patients' charts were reviewed for outcome correlation. Performance characteristics of method-specific VAN MICs in predicting outcome were compared. Most (76%) of the 92 strains tested caused pneumonia or bacteraemia. The majority of strains tested (>70%) had a VAN MIC >1mg/L by Etest or MScan compared with 41% by Vitek and 7% by BMD. Agreement between test methods for high versus low MICs (>1mg/L vs. < or = 1mg/L) ranged from 36% to 71%. High versus low VAN MICs by Etest differentiated response of invasive strains to VAN. Performance characteristics (sensitivity/specificity/positive predictive value/negative predictive value) were: Etest, 55/81/89/38%; and Vitek, 56/62/81/32/%, respectively. Eight strains (9%) demonstrated a hGISA phenotype; more yielded high MICs by Etest, MScan and Vitek than BMD (87%, 87% and 75% vs. 50%). In conclusion, VAN MIC testing methods produce highly variable results. The Etest method appears to be relatively more reliable in predicting treatment response and yielded higher MICs for strains with a hGISA phenotype.
Safety and efficacy of quinupristin-dalfopristin (an injectable streptogramin antibiotic) were evaluated in the treatment of a variety of infections due to methicillin-resistant Staphylococcus aureus (MRSA) in patients either intolerant of or failing prior therapy. The influence of resistance phenotypes on treatment outcome was also assessed. This worldwide, multicentre, open-label, non-comparative, emergency-use clinical study enrolled patients with one or more of nine predefined, culture-confirmed infections with MRSA, who had no clinically appropriate alternative antibiotic therapy. The recommended quinupristin-dalfopristin dose was 7.5 mg/kg administered iv every 8 h for a duration judged appropriate by the investigator. There were no restrictions on prior or concomitant treatment with other antibiotics. Clinical, microbiological and laboratory assessments were performed at baseline, during study drug treatment, within 24 h after the last dose, and 7-21 days post-therapy. Ninety patients [age (mean +/- S.D.) 57.4 +/- 18.5 years] with significant underlying medical illnesses were treated at 63 centres in five countries. The most common indications were bone and joint infection (44.4% of patients) and skin and skin structure infection (16.7%). The mean (+/- S.D.) daily dose and treatment duration was 20.2 +/- 2.9 mg/kg/day for 28.5 +/- 22.3 days, most frequently administered every 8 h. The overall success rate (defined as a clinical outcome of either cure or improvement and a bacteriological outcome of eradication or presumed eradication) was 71.1% in the all-treated population (n = 90) and 66.7% in patients who were both clinically and bacteriologically evaluable (n = 27). Success rates for endocarditis, respiratory tract infection and bacteraemia of unknown source were below the population mean. The macrolide-lincosamide-streptogramin type B resistance phenotype did not appear to alter the response rate. The most common non-venous adverse events related to study medication were arthralgias (10.8%), myalgias (8.6%) and nausea (8.6%). Quinupristin-dalfopristin should be considered as a treatment option for infections caused by MRSA, especially in patients intolerant of or failing alternate therapy.
The development, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and dosage and administration of daptomycin are reviewed.
Daptomycin, a novel cyclic lipopeptide antimicrobial, is bactericidal against a range of gram-positive bacteria, including many multiple-drug-resistant isolates. It has only minimal activity against anaerobic bacteria and no activity against gram-negative bacteria. Daptomycin exhibits linear pharmacokinetics, and the plasma concentration-versus-time relationship is best described by a two-compartment model with first-order elimination. The initial bactericidal activity is rapid, extensive, and concentration related. In clinical trials, daptomycin has shown efficacy in treating complicated skin and skin-structure infections (CSSSIs); the drug carries FDA-approved labeling for same. The adverse effects of daptomycin appear comparable to those of vancomycin and semisynthetic penicillins. The dosage for CSSSIs is 4 mg/kg by i.v. infusion every 24 hours.
Daptomycin is bactericidal against gram-positive organisms and offers an option in the treatment of CSSSIs.