Update on prevalence and treatment of methicillin-resistant Staphylococcus aureus infections

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) is characterized by variations (sometimes extreme) by country and geographic region. The conventional association of MRSA with healthcare settings has been upset by the emergence of community-associated MRSA infections in many areas. With this surge in MRSA comes a renewed interest in alternative agents to vancomycin for treatment of MRSA infections, including older drugs, such as clindamycin, doxycycline and trimethoprim- sulfamethoxazole. Newer agents, such as linezolid and daptomycin, are aiming to improve on the poor cure rates found with vancomycin in serious MRSA infections, but definitive studies showing superiority of these drugs are not yet available. Finally, the drug-development pipeline contains a number of agents for the treatment of MRSA infections, including enhanced glycopeptides (dalbavancin, oritavancin and telavancin) and anti-MRSA cephalosporins (ceftobiprole). As MRSA becomes the 'new normal' in many areas, clinicians will have to sort out the proper role of a dozen or more anti-MRSA drugs.     

Role of linezolid in the treatment of complicated skin and soft tissue infections

Staphylococcus aureus is the most common cause of complicated skin and soft tissue infections (cSSTIs). Antibiotic choices for these infections continue to evolve. History has seen penicillin progress to antistaphylococcal penicillins and cephalosporins, but these drugs are now giving way to drugs that are effective against methicillin-resistant S. aureus (MRSA). While vancomycin has been the gold standard to treat MRSA infections, newer therapeutic options have been developed over the last 5 years. These include quinupristin-dalfopristin, daptomycin, tigecycline and linezolid, which is the focus for this review. Linezolid is efficacious in the treatment of cSSTIs (including diabetic foot infections) caused by Gram-positive organisms (including MRSA), with a well-defined safety profile and straightforward dosing. It is also approved for nosocomial pneumonia, community-acquired pneumonia and uncomplicated skin and skin structure infections. Linezolid has an oral and parenteral formulation, which are equivalent. The oral formulation has the potential to offer economic benefits as compared with other therapies. Currently, there are only a few new antibiotics in development with MRSA activity. The proper use of all antibiotics, including these newer agents, is increasingly important if we are to slow the evolution of microbial resistance.     

Bactericidal agents in the treatment of MRSA infections--the potential role of daptomycin

Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens. These strains are often multiresistant to several antibiotic classes and are a major cause of serious hospital- and now community-acquired infections and associated morbidity and mortality. As a result of increasing antimicrobial resistance, glycopeptides, such as vancomycin, are widely used as first-line therapy for serious MRSA infections. However, the emergence of glycopeptide tolerance and resistance has complicated treatment and there remains a clinical need for new antibiotics with suitable pharmacokinetic properties with activity against MRSA and other gram-positive pathogens. Infections caused by MRSA and other bacteria usually respond as well to bacteriostatic agents as to bactericidal ones. Nevertheless, there is evidence that rapid bacterial killing has potential clinical advantages over bacteriostatic therapy in certain infections. Daptomycin, the first of the cyclic lipopeptides, shows rapid bactericidal activity against S. aureus, including strains tolerant or resistant to other agents. This review outlines the methods by which bactericidal and bacteriostatic properties are defined and tested, discusses the potential importance of bactericidal therapy in MRSA and other infections and examines the potential role of daptomycin in treatment.     

Vancomycin: understanding its past and preserving its future

The increase in vancomycin use in the 1980s to treat antibiotic-associated colitis and methicillin-resistant Staphylococcus aureus (MRSA) is largely responsible for the appearance of vancomycin-resistant enterococcus, which in turn spawned isolated cases of vancomycin-resistant S. aureus. Perhaps most worrisome to clinicians are strains of MRSA that are heteroresistant to vancomycin; these isolates are difficult to detect. Appropriate use of vancomycin coupled with awareness of infection control measures is paramount to abrogating the emergence of new vancomycin-resistant MRSA organisms and preserving its future efficacy. The continued reliance on vancomycin for the treatment of MRSA infections will depend on whether vancomycin resistance can be minimized. Newer antibacterial agents, particularly those with activity toward MRSA and vancomycin-resistant enterococcus, such as linezolid, quinupristin/dalfopristin, daptomycin, and tigecycline, may take a more prominent clinical role when gram-positive bacteria resistance to vancomycin further escalate.     

Significance of antibiotic resistance in treatment of soft tissue infections

Soft tissue infections are common. The clinical spectrum includes infections of skin, subcutaneous tissue, and of deeper structures such as fascia and muscles. The pathogenesis of these infections is quite variable. Introduction of microorganisms through skin breaks or through trauma of other soft tissue is usually at the origin of such infections. Staphylococci, especially S. aureus, as well as streptococci, mainly group A streptococci cause most soft tissue infections. In immunocompromised patients or in particuluar circumstances gram-negative bacteria may also be found to cause such infections. Occasionally, infections are polymicrobial. Given the predominance of gram-positive cocci, betalactam antibiotics with good antistaphylococcal activity are the drugs of choice for empiric treatment. Penicillins or cephalosporins that are stable against penicillinase should be chosen, since many staphylococci produce penicillinase. Over the course of the last 40 years staphylococci first became resistant against penicillin, and later developed resistance against methicillin. Methicillin-resistant S. aureus (MRSA) is now a significant problem worldwide. There continue to be major differences in the prevalence of MRSA between geographic regions. In areas with a high prevalence of methicillin resistance among S. aureus, empiric treatment of life-threatening soft tissue infections should include treatment with a glycopeptide (i.e. vancomycin or teicoplanin). New antibiotics such as oxazolidinones (i.e. linezolid) or quinupristin/dalfopristin are interesting alternatives to the glycopeptides in the treatment of soft tissue infections.     

Recent trend and development of novel antimicrobial agents for MRSA infections]

Gram-positive organisms such as Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, Enterococcus spp., and Streptococcus spp. have in recent years emerged as significant pathogens in hospitals and are now being isolated more frequently than gram-negative bacilli. These organisms are often multidrug resistant. Therefore, alternative agents with potent activity against gram-positive organisms are of considerable interest. In addition to the glycopeptide antibiotic vancomycin and the aminoglycoside antibiotic arbekacin, which can be used in MRSA infections, teicoplanin, RP 59500 and daptomycin are now under basic research in Japan. These antimicrobial agents are very active against gram-positive organisms, including MRSA and appear to be potent agents against infections due to gram-positive cocci, particularly MRSA.     

Clinical pharmacological approach for balancing the use of daptomycin and linezolid in comparison with that of vancomycin in the treatment of MRSA-related infections

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most challenging bacterial pathogens responsible for severe infections among hospitalized patients. In recent years there is increasing evidence that the clinical efficacy of vancomycin is progressively decreasing. Although daptomycin and linezolid are valuable alternatives to vancomycin for the treatment of MRSA-related bloodstream infections and pneumonia, respectively, a great deal of debate exists about their role in daily clinical practice due to cost-effectiveness issues. In this article we put into perspective the importance of pharmacokinetic/pharmacodynamic (PK/PD) considerations based on recent experimental and clinical data to argue whether they could be helpful in identifying clinical conditions in which these agents could be advantageous as compared to vancomycin.     

Can clinical and molecular epidemiologic parameters guide empiric treatment with vancomycin for methicillin-resistant Staphylococcus aureus infections?

Reports of vancomycin treatment failure for infections caused by susceptible methicillin-resistant Staphylococcus aureus (MRSA) strains with elevated minimum inhibitory concentration (MIC) has prompted use of high-dose therapy, but nephrotoxicity is a concern. We determined whether clinical and molecular epidemiologic parameters can be used to guide empiric vancomycin therapy and strain susceptibility to alternative agents. Medical charts of 180 hospitalized adults with MRSA infections were reviewed. MICs of vancomycin, daptomycin, linezolid, and tigecycline were determined by Etest. Patient isolates were assayed for genes encoding Panton-Valentine leukocidin (PVL) and SCCmec type. High vancomycin MIC did not correlate with place of acquisition, invasiveness of infection, or history of health care exposure. High MIC was present in 32% of strains overall and in 23% of PVL+, SCCmec IV strains; all were susceptible to alternative agents. Clinicians should not make empiric treatment decisions related to vancomycin use based on history of healthcare exposure risk or residence at onset of infection for patients hospitalized with MRSA infections.     

Bench-to-bedside review: Understanding the impact of resistance and virulence factors on methicillin-resistant Staphylococcus aureus infections in the intensive care unit

Methicillin-resistant Staphylococcus aureus (MRSA) displays a remarkable array of resistance and virulence factors, which have contributed to its prominent role in infections of the critically ill. We are beginning to understand the function and regulation of some of these factors and efforts are ongoing to better characterize the complex interplay between the microorganism and host response. It is important that clinicians recognize the changing resistance patterns and epidemiology of Staphylococcus spp., as these factors may impact patient outcomes. Community-associated MRSA clones have emerged as an increasingly important subset of Staphyloccocus aureus and MRSA can no longer be considered as solely a nosocomial pathogen. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and appropriate, as delays in treatment are associated with adverse outcomes. Although vancomycin has long been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent have opened the door for existing and investigational agents demonstrating efficacy in this role.     

Antibiotic therapy of methicillin-resistant Staphylococcus aureus in critical care

The treatment of methicillin-resistant Staphylococcus aureus (MRSA) in the critically ill patient is challenging. Data for treatment of critically ill patients are often lacking because many such patients are excluded from industry-sponsored prospective randomized clinical trials. Infections due to MRSA are common in the critical care setting. Up to 24% of patients in intensive care units are colonized with MRSA, and 20% of all nosocomial bloodstream infections are due to MRSA. It is also one of the leading bacterial causes of ventilator- and hospital-acquired pneumonia. Vancomycin has been the drug of choice for treatment of MRSA in the critical care setting. Recent data showing vancomycin resistance, increasing numbers of MRSA isolates with higher vancomycin minumum inhibitory concentrations, and an apparent increase in vancomycin clinical failures have brought vancomycin's utility into question. A variety of treatment options for MRSA are available. Quinupristin-dalfopristin was the first alternative to vancomycin. However, its safety profile and potential for drug interactions limit its use. Linezolid has been shown to be effective in the treatment of pneumonia and skin and skin-structure infections due to MRSA. The drug's potential to cause bone marrow suppression limits its use, especially in treatment durations extending beyond 14 days. Daptomycin has been shown to be effective for the treatment of MRSA bloodstream and of MRSA skin and skin-structure infections. Tigecycline is the newest available drug with MRSA activity. It has demonstrated noninferiority to vancomycin in skin and skin-structure infections. However, its role in the treatment of ventilator- and hospital-acquired pneumonia is still unclear.     

The bactericidal effects of anti-MRSA agents with rifampicin and sulfamethoxazole-trimethoprim against intracellular phagocytized MRSA

We experienced therapeutic failure with vancomycin in patients with serious methicillin-resistant Staphylococcus aureus (MRSA) infections, in some of whom the bacteria were found to be alive in the leukocytes. We therefore evaluated the antimicrobial activity of several anti-MRSA agents (vancomycin, linezolid, quinupristin/dalfopristin, arbekacin) and co-administered agents (rifampicin, sulfamethoxazole-trimethoprim) against clinically isolated MRSA in phagocytized human polymorphonuclear leukocytes. After allowing the leukocytes to phagocytize the bacteria, the mixture was separated into leukocytes and supernatant, to which MRSA agents were added, and incubated for 24 h. After incubation, the leukocytes were crushed and the intracellular MRSA was cultured quantitatively. Vancomycin resulted in a less than 1% survival ratio of extracellular MRSA, but it was one of the highest ratios of intracellular MRSA with 33.8% compared with other agents. The survival ratios of intracellular MRSA with vancomycin plus rifampicin and with vancomycin plus rifampicin plus sulfamethoxazole-trimethoprim were 0.78% and 1.02%, respectively, which is significantly lower than that of vancomycin. For linezolid, quinupristin/dalfopristin, and arbekacin, there were no significant differences in the survival ratios between monotherapy and combination therapy against either extracellular or intracellular MRSA. The results suggest that the concomitant use of rifampicin or rifampicin plus sulfamethoxazole/trimethoprim with vancomycin is effective for MRSA phagocytized in leukocytes when vancomycin monotherapy is not sufficiently effective. Combination therapy showed no difference in efficacy in the case of linezolid, quinupristin/dalfopristin, and arbekacin.     

Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections

This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets.     

Traitement des infections sévères à staphylocoques dorés résistants à la méticilline : vancomycine ou nouvelles molécules ? Données récentes

Whether vancomycin is still themainstay of therapy for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is currently a matter for debate. Vancomycin resistance among MRSA strains remains extremely rare. However, because of minimum inhibitory concentration (MIC) creep and of the link between vancomycin failure and higher MICs, clinicians should consider using alternative agents either empirically or when vancomycin MIC is > 1 mg/L. Despite intense researches in anti-Gram positive development over the past decade, only few agents have been licensed. Randomized controlled trials and metaanalyses suggest that linezolid is not inferior than glycopeptides for the treatment of hospital-acquired pneumonia and may be even superior in the subset of patients with MRSA infection. Daptomycin, a lipopeptide antibiotic, is extremely bactericidal and is active against biofilm-producing staphylococci. This molecule is an attractive agent for the treatment of bacteremia and endocarditis caused by MRSA. Telavancin, a lipoglycopeptide agent was shown to be non-inferior to vancomycin in the treatment of hospital-acquired pneumonia. Finally, ceftarolin is a broad-spectrum cephalosporin with in vitro activity against methicillin-resistant staphylococci.     

A comparison of linezolid with glycopeptides in severe MRSA pneumonia

Evaluation of: Luna CM, Bruno DA, García-Morato J et al. Effect of linezolid compared with glycopeptides in methicillin-resistant Staphylococcus aureus severe pneumonia in piglets. Chest 135(6), 1564–1571 (2009).

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen in nosocomial infections and accounts for a large proportion of nosocomial pneumonia. However, there are limited antibiotics available for the treatment of this serious and potentially lethal infection. Until recently, the only effective antibiotic was vancomycin, but the oxazolidinones, such as linezolid, have been shown to be a valuable addition to the arsenal of antimicrobial agents that can be used for MRSA pneumonia. Clinical trials have been conducted to compare vancomycin and linezolid head-to-head in pneumonia and, in post hoc subgroup analyses, showed that linezolid use was associated with improved survival. The ensuing debate over these results was dominated by two opinions; there were those who speculated on the mechanism by which linezolid achieved this benefit, namely attributing it to pharmacodynamics and pharmacokinetics, and others who criticized the methodology of the studies and questioned the validity of the results altogether. This study by Luna and colleagues was designed with several goals in mind. The first was to attempt to generate an animal model of MRSA pneumonia in piglets by duplicating techniques used in animal models of Gram-negative pneumonia. Then they studied the effect of three antibiotics (vancomycin, linezolid and teicoplanin) on outcomes in the same model, while simultaneously measuring antibiotic levels in the serum, bronchoalveolar lavage fluid and lung tissue, in an attempt to attribute differences in survival to pharmacological properties of the drugs used. Their results showed a survival benefit only for linezolid, despite the fact that all three antibiotics had levels above MIC in all the compartments sampled, leading them to speculate that linezolid may have improved outcomes by mechanisms not directly related to its antimicrobial actions.     

Methicillin-resistantStaphylococcus aureau (MRSA) infection in Japan: Its prophylaxis and treatment based on the mechanisms

Deep infections by methicillin-resistantStaphylococcus aureaus (MRSA) have become a serious problem in clinical fields in Japan since 1980 following the initial development and wide use of so-called third-generation cephem antibiotics. MRSA is a new type of multiple drug resistance byS. aureus. It originated from the multiple antibiotic-resistance byS. aureus due to interbacterial transfer of plasmids in the 1950s. Additionally, this strain ofS. aureus acquired resistance to all β-lactam antibiotics by production of a new fraction of the target enzyme, PBP2' possessing low binding affinity to β-lactams. The PBP2' fraction is controlled by the exogenous and chromosomalmecA gene. Prevention of deep MRSA infections requires both the countermeasures for nosocomial infections and application of β-lactam antibiotics showing strong antistaphylococcal activity such as cefazoline or cefotiam, for postoperative prophylaxis. When deep infections occur due to MRSA, prompt treatment with an adequate antimicrobial agent possessing strong anti-MRSA activity, i.e., vancomycin or arbekacin, is necessary. Delayed trial and error for the treatment of deep MRSA infections may result in refractory diseases.     

Analysis of synergy between beta-lactams and anti-methicillin-resistant Staphylococcus aureus agents from the standpoint of strain characteristics and binding action

In light of the increasing number of clinical cases resistant to traditional monotherapies and the lack of novel antimicrobial agents, combination therapy is an appealing solution for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we evaluated the efficacy of anti-MRSA agents, such as vancomycin (VAN), daptomycin (DAP), and linezolid (LZD), in conjunction with 13 beta-lactams and non-beta-lactams. We assessed the in vitro activities of the various combinations against 40 MRSA strains based on the maximum synergistic effect (MSE), an index calculated from the MIC change with a combination agent. Nearly all the anti-MRSA agents, which were combined with beta-lactams as well as VAN and DAP, showed a synergistic effect with arbekacin. VAN also exhibited varying degrees of synergy depending on the type of beta-lactam, whereas DAP and LZD showed similar synergy with different beta-lactams. These effects were confirmed by antibiotic kill curves, except for the apparent interaction between LZD and beta-lactams. The MSE results were analyzed according to strain characteristics including susceptibility to combination agents, staphylococcal cassette chromosome mec type, and presence of the blaZ gene; however, no obvious correlations were observed. In a fluorescence binding assay, the fluorescence intensity of boron-dipyrromethene (BODIPY)-VAN decreased, whereas that of BODIPY-DAP increased in combination with a beta-lactam agent. These findings suggest that beta-lactam combinations are promising treatment options for MRSA infections and that the type of beta-lactam combined with VAN is important for the synergistic effect.     

Vancomycin: does it still have a role as an antistaphylococcal agent?

The recognition of the shortcomings of vancomycin as an antistaphylococcal agent, together with the burgeoning availability of alternative effective antistaphylococcal antibiotics, has led to a reassessment of the role of this glycopeptide antimicrobial in clinical therapeutics. Evidence indicates that vancomycin is inferior to semisynthetic penicillins in the treatment of infections due to methicillin-susceptible Staphylococcus aureus. Additional evidence suggests that vancomycin may be inferior to some comparator agents in the treatment of infections due to methicillin-resistant S. aureus (MRSA). While high-level resistance remains rare, data from some centers suggest an evolutionary change in S. aureus, evidenced by reduced susceptibility to vancomycin. This, together with the problem of heteroresistance to vancomycin, as well as poor tissue penetration after its systemic administration, presents potential obstacles to the successful therapy of S. aureus infections with this glycopeptide. While it has been suggested that these problems may be overcome by administration of vancomycin in much higher doses, the efficacy and safety of this approach remains to be determined and will require randomized clinical trials for its demonstration. A number of novel agents with activity against MRSA have been introduced to clinical practice in the last 2 years and others are still in the investigational stage. Despite the fact that these newer agents have been compared with vancomycin in trials only designed to demonstrate noninferiority, some potential evidence of superiority over vancomycin has emerged. While the relative roles of each of these newer agents and vancomycin can only be determined definitively by performance of adequately powered randomized clinical trials, current evidence suggests that vancomycin may be an inferior therapeutic agent.     

Antibiotic resistance in Staphylococcus aureus: concerns,causes and cures

Methicillin-resistant Staphylococcus aureus (MRSA) is currently a predominant and dangerous nosocomial pathogen. Unfortunately, infections caused by this organism are becoming more difficult to treat as further evolution of drug resistance occurs within the pathogen. Vancomycin has become the drug of choice for treating MRSA infections. However, treatment failures, adverse side effects and the emergence of vancomycin-resistant MRSA are leading to urgent requirements for alternative antiMRSA therapies. Linezolid is a new agent recently developed for Gram-positive infections, including MRSA. However, resistance to this drug is already developing. The need for superior antiMRSA drugs is therefore highly evident. This article explores some of the opportunities for the development of new treatments for MRSA. These arise principally from extensions of existing drug classes and the discovery of novel agents by genome-driven technologies. Other possibilities concern the re-evaluation of earlier pharmacophores that have not so far been developed as antiMRSA agents.     

Antibiotic resistance in Staphylococcus aureus: concerns, causes and cures

Methicillin-resistant Staphylococcus aureus (MRSA) is currently a predominant and dangerous nosocomial pathogen. Unfortunately, infections caused by this organism are becoming more difficult to treat as further evolution of drug resistance occurs within the pathogen. Vancomycin has become the drug of choice for treating MRSA infections. However, treatment failures, adverse side effects and the emergence of vancomycin-resistant MRSA are leading to urgent requirements for alternative antiMRSA therapies. Linezolid is a new agent recently developed for Gram-positive infections, including MRSA. However, resistance to this drug is already developing. The need for superior antiMRSA drugs is therefore highly evident. This article explores some of the opportunities for the development of new treatments for MRSA. These arise principally from extensions of existing drug classes and the discovery of novel agents by genome-driven technologies. Other possibilities concern the re-evaluation of earlier pharmacophores that have not so far been developed as antiMRSA agents.     

Activism—A Double-Edged Sword

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA), one of the most common causes of infections, has been traditionally recognized as a nosocomial pathogen. However, in recent years, its epidemiology has radically changed, being now observed even more frequently in the community, and accounting for > 50% of staphylococcal infections in the US outpatient setting. Community-acquired (CA)-MRSA strains typically cause infections among otherwise healthy individuals, with risk factors differing from those of nosocomial MRSA. The clinical manifestations may range from a furuncle to life-threatening infections, such as necrotizing fasciitis and pneumonia. The antibiotic treatment of these infections may also differ because CA-MRSA strains often retain susceptibility to antimicrobials other than glycopeptides and newer agents. Moreover, the production of toxins, such as the Panton-Valentine leukocidin (PVL), should influence the antibiotic choice because in these cases the use of a combination therapy with antimicrobial agents able to decrease toxin production is suggested. There are still many unanswered key questions regarding the epidemiology, prevention, and treatment of CA-MRSA infections. This article reviews current knowledge of CA-MRSA.