Alternatives to Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections
- Reprints or correspondence: Dr. Scott T. Micek, Dept. of Pharmacy, Barnes-Jewish Hospital, Mailstop 90-52-411, 216 S. Kingshighway Blvd., St. Louis, MO (stm8241{at}bjc.org)
Abstract
Vancomycin remains the reference standard for the treatment of systemic infection caused by methicillin-resistant Staphylococcus aureus (MRSA). However, as a result of limited tissue distribution, as well as the emergence of isolates with reduced susceptibility and in vitro resistance to vancomycin, the need for alternative therapies that target MRSA has become apparent. New treatment options for invasive MRSA infections include linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. Additionally, a number of new anti-MRSA compounds are in development, including novel glycopeptides (dalbavancin, telavancin, and oritavancin), ceftobiprole, and iclaprim. The present article will review clinical issues surrounding the newly marketed and investigational agents with activity against MRSA.
Vancomycin has been considered to be the reference standard for the treatment of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, as a result of its relatively clean safety profile, its durability against the development of resistance, and, for many years, the lack of other approved alternatives. However, the advent and testing of new compounds with anti-MRSA activity, for comparison with vancomycin, have rendered results that call into question the efficacy of vancomycin in the treatment of many serious infections. The reasons for clinical failure of vancomycin are many and have been hypothesized to include poor penetration of the drug to certain tissues [1–3], loss of accessory gene—regulator function in MRSA [4], and potential escalation of vancomycin MICs for MRSA [5]. Additionally, an increasing number of reports of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) have populated the literature dating back to 1999. Many alternatives for the treatment of MRSA infections, including linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin, are currently approved by the US Food and Drug Administration (FDA). Additionally, there are several investigational compounds with demonstrated in vitro activity against MRSA. The chemical structures of these agents are shown in figure 1.
Figure 1
Molecular structures of novel antibiotics for methicillin-resistant Staphylococcus aureus infections
Linezolid
Linezolid is a synthetic oxazolidinone that inhibits the initiation of protein synthesis at the 50S ribosome [6]. It is currently approved by the FDA for the treatment of complicated skin and skin-structure infections (SSSIs) and nosocomial pneumonia caused by susceptible pathogens, including MRSA. Several retrospective analyses of pooled data from randomized trials have compared linezolid with vancomycin in patients with proven MRSA infection. An analysis of 2 double-blind studies of patients with MRSA nosocomial pneumonia found that 75 patients treated with linezolid had survival rates that were significantly higher than those of 85 patients treated with vancomycin (80% vs. 64%; P = .03) [7]. The authors hypothesized that a possible explanation for the finding was vancomycin's poor penetration of the lung, particularly when the standard dosage is 1 g administered every 12 h. However, aggressive dosing strategies for vancomycin (goal trough concentrations of <15 μg/mL, or 4–5× the MIC value) may not offer an advantage over traditional dosing strategies [8, 9]. A follow-up, randomized, double-blind trial is under way that compares these 2 agents in hospitalized patients with nosocomial pneumonia due to MRSA. Similarly, retrospective evaluations of complicated skin and soft-tissue infections (SSTIs) caused by MRSA have found that, compared with vancomycin, linezolid is associated with significantly higher clinical cure rates and reduced lengths of hospitalization [6, 10]. A retrospective analysis of pooled data from 5 randomized studies did not find linezolid to be superior to vancomycin in patients with secondary MRSA bacteremia [11].
Linezolid should also be considered for necrotizing infections, including skin lesions [12], fasciitis [13], and pneumonia [14] caused by community-associated MRSA, particularly the USA300 strain. The severity of these infections may be associated with allotypes of mobile genetic elements found in USA300 that code for pathogenic toxins, including Panton-Valentine leukocidin, enterotoxin Q, and enterotoxin K [15]. It has been hypothesized that antibiotics with the ability to inhibit protein synthesis may demonstrate efficacy against susceptible toxin-producing strains. Linezolid, along with clindamycin, has recently been found to reduce production of Panton-Valentine leukocidin, α-hemolysin, and toxic-shock syndrome toxin–1, whereas vancomycin and nafcillin have been found to increase such production in an in vitro model [16].
Despite the apparent advantages of linezolid in the treatment of MRSA infections, concerns about safety often limit its use. of particular concern is the association of linezolid with serotonin toxicity and thrombocytopenia [17, 18]. Linezolid exhibits weak reversible inhibition of monoamine oxidase and can induce toxicity when used in combination with agents that have serotonergic activity, most commonly selective serotonin reuptake inhibitors. Twenty-nine cases of linezolid-associated serotonin toxicity were recently reported. Postmarketing information submitted to the FDA regarding 29 patients with serotonin toxicity showed that 61% had received concomitant treatment with a selective serotonin reuptake inhibitor [17]. Three patients died, possibly because of serotonin toxicity, and another 13 patients required medical treatment [13]. Linezolid used concomitantly with selective serotonin reuptake inhibitors in hospitalized patients has also been evaluated in a retrospective study [19]. This study found a high probability of serotonin toxicity in association with 2 of 72 concomitant uses. The authors suggest that linezolid may be used concomitantly with selective serotonin reuptake inhibitors, with careful monitoring, and they recommend prompt discontinuation of the serotonergic agent if serotonin syndrome is suspected [19]. The occurrence of thrombocytopenia has proven to be not significantly different than that encountered in patients with nosocomial pneumonia or orthopedic infections. of note, patients with renal insufficiency may be at higher risk of developing this toxicity [20, 21]. Finally, there have been sporadic reports of peripheral neuropathy, typically in patients with osteomyelitis or other underlying diseases, and lactic acidosis [22, 23].
Tigecycline
Tigecycline is the first drug approved in the class of glycylcyclines, a derivative of minocycline. A modified side chain on tigecycline enhances binding to the 30S ribosomal subunit, inhibiting protein synthesis and bacterial growth across a broad spectrum of pathogens, including MRSA [24]. In addition, this structural modification circumvents resistance mechanisms that plague tetracycline and other antibiotics in this class. Tigecycline is approved in the United States for the treatment of complicated SSSIs due to MRSA. The drug is also approved for the treatment of complicated intra-abdominal infections but only for those caused by methicillin-susceptible S. aureus. At this time, the published experience with tigecycline for the treatment of MRSA infections is limited to 2 double-blind comparison studies of vancomycin and aztreonam in patients with complicated SSSIs and case reports [25, 26]. Tigecycline has a large volume of distribution and produces high concentrations in tissues outside of the bloodstream, including bile, the colon, and the lung. Conversely, serum concentrations of tigecycline rapidly decrease after infusion, and the area under the concentration-time curve (AUC) after administration of multiple 50-mg doses every 12 h is ∼3 μg∙h/mL [27]. On the basis of studies of the pharmacodynamic properties of tetracycline, the target AUC for tigecycline should be 2–4 times the MIC, in an effort to optimize efficacy in the treatment of MRSA infections. Given a tigecycline MIC90 range of 0.25–0.5 μg/mL for MRSA, caution should be used when using tigecycline for the treatment of patients with suspected or proven bacteremia [27]. The results of further clinical evaluation should be cumulated and assessed to determine whether to accept or refute this potential limitation. The approved dose is a 100-mg intravenous loading dose followed by 50 mg given every 12 h. Nausea and vomiting are the predominant adverse events, and they increase in frequency with dose escalation.
Daptomycin
Daptomycin is a cyclic lipopeptide that causes depolarization of the bacterial cell membrane. The indicated dose for MRSA-associated complicated SSTIs is 4 mg/kg once daily, and that for bloodstream infections, including right-side endocarditis, is 6 mg/kg once daily [28]. of note, daptomycin should not be used in the treatment of MRSA pneumonia, because the activity of the drug is inhibited by pulmonary surfactant. The results of daptomycin trials in patients with complicated SSTIs and bacteremia/endocarditis are shown in table 1 [28, 29]. In brief, of the patients who had MRSA isolated, 20 (44%) of 45 were successfully treated with daptomycin, and, of the patients in the bacteremia/endocarditis trial, 14 (32%) of 44 patients were successfully treated with vancomycin. The difference between daptomycin and standard therapy in the treatment of MRSA infections was not statistically significant. Significantly, for 6 patients who experienced microbiological failure while receiving daptomycin, it was reported that, during therapy, the MICs for the isolated pathogen increased from 0.25 or 0.5 μg/mL to 2 or 4 μg/mL [29]. The mechanism for resistance development while receiving therapy is, at present, not understood, but it is likely to be a consequence and a concern in patients who require prolonged courses of daptomycin therapy.
Table 1
Overview of novel antimicrobial agents available to treat methicillin-resistant Staphylococcus aureus (MRSA).
Glycopeptides
Dalbavancin. Dalbavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis and has in vitro activity against MRSA [34]. The unique feature of this investigational agent is its long half-life (6–10 days), which allows for once-weekly dosing. In a randomized, double-blind trial, dalbavancin (1000 mg given intravenously on day 1 and 500 mg given intravenously on day 8) has been compared with linezolid in the treatment of SSSIs [30]. Overall clinical success rates are presented in table 1. In this trial, 51% of the isolates were found to be MRSA. In a phase 2, open-label study of the treatment of catheter-related bloodstream infections, once-weekly treatment with dalbavancin was compared with treatment with vancomycin [31]. MRSA was identified at baseline in 5 patients who received dalbavancin, and, in the overall intention-to-treat analysis, dalbavancin was found to result in a success rate significantly higher than that noted with vancomycin (87% vs. 50%; P < .05). The most common adverse events included nausea and diarrhea or constipation; however, dalbavancin may also be associated with hypotension, hypokalemia, and increases in alanine aminotransferase and aspartate aminotransferase levels measured in liver function tests, although, to date, the reports of these adverse events are conflicting [34].
Telavancin. Telavancin is another semisynthetic lipoglycopeptide that has a dual mechanism of action, including inhibition of cell wall synthesis and disruption of membrane barrier function [35]. It has a half-life of 7–9 h, which allows once-daily dosing (7.5–10 mg/kg/day). The disruption of membrane barrier function translates to rapid bactericidal activity against pathogens, including MRSA. It is currently under investigation for the treatment of SSTIs, nosocomial pneumonia, and uncomplicated bacteremia due to S. aureus [35]. As shown in table 1, the efficacy of telavancin was similar to that of standard therapy in early trials [32, 36]. Preliminary, unpublished phase 3 results indicate that the clinical cure and eradication rates associated with telavancin were higher than those associated with vancomycin, particularly in patients infected with MRSA [37]. Adverse events reported to date include nausea, taste disturbance, and insomnia.
Oritavancin. Oritavancin is also a semisynthetic glycopeptide that is in development. The mechanism of action of this drug involves disruption of transmembrane potential, and it has demonstrated activity against vancomycin-resistant strains of staphylococci and enterococci [38]. Oritavancin has a very long half-life of ∼100 h, and dosing once daily or every other day is likely to be recommended. The percentage of time above the MIC of the free drug was found to be the determinant of microbiological and clinical response in bacteremia [39]. Studies of oritavancin are being conducted in patients with complicated SSTIs, catheter-related bloodstream infections, and nosocomial pneumonia [38]. Preliminary results of studies of SSTIs showed noninferiority of oritavancin to vancomycin and cephalexin. Adverse events associated with oritavantin include headache, nausea, and sleep disorders.
Ceftobiprole and Ceftaroline
Ceftobiprole is an investigational cephalosporin engineered to bind tightly to penicillin-binding protein 2a, a peptidoglycan transpeptidase that confers β-lactam resistance in S. aureus isolates harboring the mecA gene [40, 41]. This compound is the first of the β-lactam antibiotics to have activity against MRSA as well as penicillin-resistant streptococci. Importantly, in preclinical, multipassage resistance-selection studies, ceftobiprole demonstrated a low potential to select for resistance; the highest MIC found in the presence of prolonged serial passages with ceftobiprole at subinhibitory concentrations was 8 μg/mL in 1 of 10 strains after 50 passages [42]. Ceftobiprole is administered twice daily by the intravenous route and has been granted fast-track status by the FDA for the indications of complicated SSSIs and health care—associated pneumonia [41]. Two phase 3 trials for complicated SSSIs have been completed (STRAUSS and STRAUSS II), with preliminary results reportedly demonstrating noninferiority of ceftobiprole to comparators overall and in patients with MRSA [40, 33]. The most common adverse effects were nausea and taste disturbances.
Ceftaroline is another broad-spectrum cephalosporin with gram-positive and gram-negative bactericidal activity. Early testing indicates that MRSA and vancomycin-resistant staphylococci are susceptible to ceftaroline [43]. Phase 2 studies of this agent in patients with SSTIs are under way.
Iclaprim
Iclaprim is a diaminopyrimidine that inhibits the enzyme dihydrofolate reductase. Data on iclaprim are limited. However, it has activity against MRSA, and preliminary results from a phase 3 trial in patients with complicated SSTIs showed noninferiority of iclaprim to linezolid at the test of cure [44]. In this study, ∼25% of the infections were due to MRSA.
Conclusions
Several antibiotics with anti-MRSA activity, including linezolid, tigecycline, and daptomycin, have been approved by the FDA. Additionally, there are a number of compounds in development that will likely provide a broader armamentarium for clinicians in the management of infections due to MRSA. The emergence of vancomycin-intermediate and vancomycin-resistant strains of S. aureus has also created a need for agents with expanded coverage. The in vitro activity of new and investigational agents against VISA and VRSA has recently been reviewed elsewhere [45]. In brief, linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin, as well as the new investigational compounds dalbavancin, telavancin, oritavancin, ceftobiprole, and iclaprim, have demonstrated in vitro activity against VISA and VRSA.
Acknowledgments
Supplement sponsorship. This article was published as part of a supplement entitled “Bugging the Bugs: Novel Approaches in the Strategic Management of Resistant Staphylococcus aureus Infections”, jointly sponsored by the Dannemiller Memorial Educational Foundation and Emeritus Educational Sciences and supported by an educational grant from Ortho-McNeil, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.
Potential conflicts of interest. S.T.M. has received research/grant support from Ortho-McNeil.
- © 2007 by the Infectious Diseases Society of America
References
This Article
- AbstractFree
- » Full Text (HTML)Free
- Full Text (PDF)Free
Classifications
Services
Citing Articles
Google Scholar
PubMed
Related Content
Share
- Email this article
-
CiteULike
Connotea
Delicious
Facebook
Google+
Mendeley
Twitter
Published on behalf of
IDSA Members: For your free access to this journal, log in via the IDSA members area.
The Journal
Impact Factor: 8.186
5-Yr impact factor: 7.898
For The Media
For Authors
- Services for authors
- Self-archiving Policy
- IDSA Conflict of Interest policy
- Instructions for Authors
- ICMJE Form
- Submit Now!
Open access options for authors visit Oxford Open
This journal enables compliance with the NIH Public Access Policy
Corporate Services
Alerting Services
Related IDSA Publications
