Advances in MRSA drug discovery: where are we and where do we need to be?

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multidrug-resistant (MDR) bacterial strains. Although there are a limited number of anti-MRSA drugs available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, the addition of several new antistaphylococcal drugs into clinical practice should broaden clinician's therapeutic options. As MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts for the discovery of lead compounds as well as development of alternative therapies and faster diagnostics are required.

Areas covered: This article summarizes the FDA-approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the article discusses the mode of action of antistaphylococcal molecules and the resistant mechanisms of some molecules.

Expert opinion: The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for MRSA infections in the critically ill. Further research efforts are required for effective phage therapy on MRSA infections in clinical use, which seem to be attractive therapeutic options for the future.     

Ceftaroline for complicated skin and skin-structure infections

Importance of the field: A dramatic increase in infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been observed, in part as a result of the epidemic of community-associated MRSA skin and skin-structure infections (SSSIs). Simultaneously, decreasing sensitivities of S. aureus to vancomycin have been reported and invasive infections caused by these strains have been associated with worse clinical outcomes. Clearly, new agents active against MRSA are needed. Ceftaroline is a new cephalosporin active against MRSA and many Gram-negative bacteria, though it is not active against Pseudomonas spp. and extended spectrum β-lactamase producers (ESBL).

Areas covered in this review: In this review we focus on the properties of ceftaroline such as in vitro activity, the pharmacokinetic and pharmacodynamic characteristics, and its efficacy and safety observed in the clinical trials of patients with SSSI. Finally, we provide an overview of the possible future role of ceftaroline and other compounds in development for the treatment of SSSIs. The literature search was based on PubMed articles plus review of the abstracts presented in the most important international conferences in the field.

What the reader will gain: The reader will gain clear concepts to understand the value that ceftaroline might have in the treatment of SSSIs, including those caused by MRSA.

Take home message: Ceftaroline has shown bactericidal activity against common pathogens associated with SSSIs including MRSA, noninferiority in clinical trials of patients with complicated SSSI (cSSSI), and a favorable safety profile.     

Invasive community-associated MRSA infections: epidemiology and antimicrobial management

Importance of the field: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is now a predominant cause of infections in the community and is adding to the overwhelming MRSA burden in the hospital setting. CA-MRSA is most commonly noted as a prominent pathogen in skin and soft tissue infections (SSTI) but has been increasingly described in more invasive disease. New developments in the epidemiology and treatment of CA-MRSA have emerged to improve the understanding of this disease.

Areas covered in this review: We present the latest epidemiologic and clinical treatment studies of CA-MRSA in a variety of infection types. The methods used involve a comprehensive literature search of the previous 10 years, including a detailed focus on new literature in the last 5 years. The search terms used were ‘CA-MRSA epidemiology’, ‘S. aureus resistance’, ‘CA-MRSA treatment’, and ‘S. aureus virulence’.

What the reader will gain: An in-depth understanding of the changing epidemiology of CA-MRSA and management of SSTI and more invasive infections with this pathogen. Adjunctive and alternative therapies are also reviewed.

Take home message: The epidemiology of CA-MRSA is rapidly evolving. Increasing multi-drug resistance along with virulence factors associated with this serious disease complicate its treatment. Additional clinical trials are needed to select optimal regimens in the treatment of invasive CA-MRSA infections.     

Investigational therapies targeting quorum-sensing for the treatment of Staphylococcus aureus infections

Introduction: Antibiotic resistance is a serious global health concern for developed and developing nations. MRSA represents a particularly severe public health threat that is associated with high morbidity and mortality. The lack of novel antibiotics has led scientists to explore therapies targeting bacterial virulence mechanisms and virulence regulators, including those controlling cell–cell communication.

Areas covered: The authors discuss the role of quorum-sensing in Staphylococcus aureus infections and components of the system that are being targeted using novel investigational drugs. In particular, the authors examine the role of the accessory gene regulator (Agr) system in virulence regulation of S. aureus pathogenesis. Finally, the authors present and compare natural and synthetic compounds that have been found to interfere with Agr functionality.

Expert opinion: There is a great need to develop new therapeutic methods to combat S. aureus infections. These include anti-virulence therapies that target key global regulators involved with the establishment and propagation of infection. Several molecules have been found to interfere with S. aureus virulence regulation, especially those targeting the Agr quorum-sensing signaling molecule. These preliminary findings warrant further investigation and validation, with the goal of refining a compound that has broad-spectrum inhibitory effects on most S. aureus strains and Agr subtypes.     

Antimicrobial therapy of Staphylococcus aureus bloodstream infection

Staphylococcus aureus bloodstream infection (BSI) contributes significantly to the morbidity and mortality of in-patients. The optimal therapy for methicillin-susceptible S. aureus BSI consists of penicillins. The efficacy of these drugs is well documented from several published data and supported from a long clinical experience. Methicillin-resistant S. aureus (MRSA) strains are responsible for the majority of nosocomial BSI and are recovered with increasing frequency at hospital admission. Although glycopeptides still represent the drugs of choice, there are several concerns on the treatment of MRSA BSI: reports of clinical failure with vancomycin treatment, regardless of the in vitro susceptibility; increasing reports of MRSA strains with reduced vancomycin susceptibility; difficulty in therapeutic dosage monitoring of teicoplanin; lack of evidence on the efficacy of combination therapy. Recently, new drugs have been introduced in the therapeutic arsenal for MRSA infections, but their clinical use is not yet clearly established for BSI. The review summarises evidence on present therapeutic options for the treatment of S. aureus BSI.     

The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract

Background:

The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 1: IV options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a predominant pathogen resulting in significant morbidity and mortality. Optimal dosing of anti-MRSA agents is needed to help prevent the development of antimicrobial resistance and to increase the likelihood of a favorable clinical outcome.

Areas covered: This review summarizes the available data for antimicrobials routinely used for MRSA infections that are not administered orally or topically. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: Improvements in MIC determination and therapeutic drug monitoring are needed to fully implement individualized dosing that optimizes antimicrobial pharmacodynamics.Additional data will become available for these agents in regards to effectiveness for severe MRSA infections and pharmacokinetic data for special patient populations.     

Inhibition of methicillin-resistant Staphylococcus aureus (MRSA) by antimicrobial peptides (AMPs) and plant essential oils

Context: Drug-resistant bacterial infections cause considerable patient mortality and morbidity. The annual frequency of deaths from methicillin-resistant Staphylococcus aureus (MRSA) has surpassed those caused by human immunodeficiency virus/acquired immune deficiency syndrome. The antimicrobial peptides (AMPs), plant essential oils (EOs) and their combinations have proven to be quite effective in killing a wide selection of bacterial pathogens including MRSA.

Objectives: This review summarizes the studies in the use of AMPs, plant EOs and their combinations for coping with MRSA bacteria, and to formulate new prospects for future studies on this topic.

Methods: The sources of scientific literature such as PubMed, library search, Google Scholar, Science Direct and electronic databases such as ‘The Antimicrobial Peptide Database’, ‘Collection of Anti-Microbial Peptides’ and ‘YADAMP’. Physicochemical data of anti-MRSA peptides were determined by Scientific DataBase Maker software.

Results: Of the 118 peptides, 88 exhibited an activity against MRSA with the highest activity of minimum inhibitory concentration values. Various plant EOs have been effective against MRSA. Remarkably, lemongrass EOs completely inhibited all MRSA growth on the plate. Lemon myrtle, Mountain savory, Cinnamon bark and Melissa EOs showed a significant inhibition.

Conclusion: Several of these AMPs, EOs and their combinations were effective against MRSA. Their activities have implications for the development of new drugs for medical use.     

The potential use of toxin antibodies as a strategy for controlling acute Staphylococcus aureus infections

Introduction: The pandemic human pathogen, Staphylococcus aureus, displays high levels of antibiotic resistance and is a major cause of hospital- and community-associated infections. S. aureus disease manifestation is to a great extent due to the production of a large arsenal of virulence factors, which include a series of secreted toxins. Antibodies to S. aureus toxins are found in people who are infected or asymptomatically colonized with S. aureus. Immunotherapies consisting of neutralizing anti-toxin antibodies could provide immediate aid to patients with impaired immune systems or in advanced stages of disease.

Areas covered: Important S. aureus toxins, their roles in pathogenesis, rationales for selecting S. aureus toxins for immunization efforts, and caveats associated with monoclonal antibody-based passive immunization are discussed. This review will focus on hyper-virulent community-associated methicillin-resistant S. aureus because of their recent surge and clinical importance.

Expert opinion: Antibodies against genome-encoded toxins may be more broadly applicable than those directed against toxins found only in a sub-population of S. aureus isolates. Furthermore, there is substantial functional redundancy among S. aureus toxins. Thus, an optimal anti-S. aureus formulation may consist of multiple antibodies directed against a series of key S. aureus genome-encoded toxins.     

Safety profiles of old and new antimicrobials for the treatment of MRSA infections

ABSTRACT

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA.

Areas covered: Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials.

Expert opinion: Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.     

Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants,children and adults

Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline and ceftaroline). The use of the majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety and efficacy data of these drugs with a specific focus in infants.     

Pharmacokinetic drug evaluation of ceftobiprole for the treatment of MRSA

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA), while decreasing in overall incidence, is still a prominent concern world-wide. New agents coming to market in the last 10 years allow practitioners to optimize treatment for MRSA infections. Ceftobiprole is a cephalosporin agent with MRSA activity, currently approved in selected countries for the treatment of community-acquired pneumonia and hospital-acquired pneumonia.

Areas covered: Relevant literature regarding spectrum of activity, pharmacokinetics, pharmacodynamics, and clinical trials will be discussed.

Expert opinion: Ceftobiprole is an addition to a growing number of antimicrobials with activity against MRSA. Concern for appropriate dosing in critically ill patients remains due to its ineffectiveness for the treatment of ventilator-associated pneumonia (VAP). While ceftobiprole has activity against gram-negative organisms, the allowance for use of an additional agent for gram-negative infections in clinical trials limits recommendations for monotherapy for empirical treatment of HAP. Ceftobiprole’s place in therapy will lie in its activity against gram positive organisms, such as Streptococcus spp. and Staphylococcus spp.     

Emerging drugs on methicillin-resistant Staphylococcus aureus

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) has proven to be a prominent pathogen in hospitals and in the community, which is capable of causing a variety of severe infections. Until now, there has been a limited antimicrobial armamentarium for use against MRSA, of which glycopeptides and linezolid are the main agents used.

Areas covered: This review assesses current treatment and the agents being developed for MRSA infections. A search was conducted in PubMed for English-language references published from 2000 to 2013, using combinations of the following terms: ‘MRSA', ‘MRSA therapy', ‘gram (+) infections therapy', ‘new antibiotics', ‘vancomycin', ‘staphylococcus resistance', ‘oritavancin', ‘ceftaroline', ‘linezolid' and ‘tigecycline'. The clinicalTrials website was also searched with keywords regarding the new antibiotic agents against MRSA infections.

Expert opinion: There are a number of new agents, the place of which in therapeutic regimens is yet to emerge. New glycopeptides, such as dalbavancin and oritavancin, with long half-lives, enabling once-weekly dosing, and oral agents, such as iclaprim, may provide a treatment approach for outpatient therapy. A decision must be made regarding the most suitable agent for an individual patient, the site of infection and the place of therapy.     

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

Introduction: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach.

Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included.

Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.     

Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): a meta-analysis

Abstract

Objective:

To evaluate the clinical and microbiological outcomes of linezolid versus vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) using a meta-analysis.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

Preliminary investigations into developing all‐D Omiganan for treating Mupirocin‐resistant MRSA skin infections

Staphylococcus aureus is the primary pathogen responsible for the majority of human skin infections, and meticillin‐resistant S. aureus (MRSA) currently presents a major clinical concern. The overuse of Mupirocin, the first‐line topical antibacterial drug over 30 years, has led to the emergence of Mupirocin‐resistant MRSA, creating a clinical concern. The antimicrobial peptide Omiganan was touted to be a promising antibacterial drug candidate due to its rapid membrane‐disrupting bactericidal mode of action, entering clinical trials in 2005 as a topical gel to prevent catheter site infections. However, drug development ceased in 2009 due to a lack of efficacy. We postulate this to be due to proteolytic degradation caused by endogenous human skin proteases. Herein, we tested our hypothesis using Omiganan and its all‐D enantiomer in a human skin protease stability assay, followed by anti‐MRSA activity assay against of a panel of clinical MRSA isolates, a bactericidal/static determination and a time‐kill assay to gauge all‐D Omiganan's potential for further topical antibacterial drug development.     

Designing drugs that combat kidney damage

Introduction: Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority.

Areas covered: The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials.

Expert opinion: Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI.     

Antibiotic resistance in Staphylococcus aureus and its relevance in therapy

Staphylococcus aureus is a major cause of infections. Only ～ 20% of the strains remain sensitive to penicillin. β-lactamase stable penicillins such as flucloxacillin form the mainstay of treatment of staphylococcal infection. Meticillin-resistant S. aureus (MRSA) are resistant to all β-lactam antibiotics. Glycopeptide antibiotics are effective against most MRSA strains but, in the last few years, isolates of MRSA that have reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus) have been isolated. Some strains exhibit frank resistance to glycopeptides (vancomycin-resistant S. aureus). Infections due to these strains are difficult to treat. This review summarises the therapeutic options for MRSA, glycopeptide-intermediate S. aureus and vancomycin-resistant S. aureus. Novel therapeutic strategies such as immunotherapy and vaccines are also discussed.