Combating the growing problem of methicillin-resistant Staphylococcus aureus: do the newer antibiotics represent a better alternative to vancomycin?

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious nosocomial infections, and the emergence of virulent strains of this organism in community-dwelling patients lacking traditional risk factors for MRSA is particularly concerning [1,2]. Overall, rates of MRSA infection observed in US clinical laboratory surveillance have been increasing steadily since 1998, accounting for 53% of all S. aureus infections in 2005 [3], and community-acquired MRSA is now the most common recognizable cause of skin and skin-structure infections [4,5]. One particular clone, designated USA300, is the predominant one causing skin and skin-structure infections and may be more virulent than hospital-associated strains [6].

Vancomycin, a glycopeptide that has been in clinical use for more than 50 years, still serves as the cornerstone of the treatment of drug-resistant Gram-positive infections [7]. However, there are significant concerns owing to decreasing susceptibility to this agent among Enterococcus spp. and S. aureus[8–10]. Furthermore, vancomycin is slowly bactericidal, which may be partly responsible for reported clinical failures using this drug [11,12]. The growing awareness of the limitations of vancomycin has served as an impetus for the development of newer agents [13]. Quinupristin–dalfopristin, linezolid, daptomycin and tigecycline are four drugs that have received regulatory approval in the last decade for the treatment of infections caused by drug-resistant Gram-positive pathogens. Although these drugs do have certain differentiating attributes and may offer some advantages over vancomycin, they also have significant limitations. More importantly, as discussed below, there are limited data from well-controlled double-blind studies supporting greater therapeutic efficacy of the newer agents, compared with vancomycin, in the treatment of MRSA infections.

Quinupristin–dalfopristin is a streptogramin combination antibiotic whose activity against Gram-positive pathogens demonstrates the concept of antimicrobial synergy. However, infusion-related side effects contribute to the poor tolerability profile of this drug and there are issues of drug–drug interaction, both of which have limited the usefulness of this antibiotic [14]. Furthermore, clinical efficacy data for this agent, specifically against MRSA infections, are limited and, as such, it has not gained regulatory approval for this indication.

Linezolid is unique in that it is available in both intravenous and oral dosage forms, which have equivalent bioavailability. Its bacteriostatic properties and potential to cause bone marrow toxicity and neuropathies during longer courses of therapy are a concern [15]. In the only reported double-blind study in complicated skin and skin-structure infections (cSSSIs) comparing linezolid with oxacillin–dicloxacillin, patients with MRSA at baseline were excluded from the study [16]. The efficacy of linezolid against MRSA cSSSI was demonstrated in a subsequent open-label study in which 285 patients had MRSA as the baseline pathogen [17]. With respect to clinical cures, linezolid and vancomycin were not statistically different in efficacy. In subgroup analyses, linezolid was marginally but statistically superior to vancomycin in patients with MRSA, but this outcome should be weighed against the fact that the study was open label and the incidence of certain adverse effects (thrombocytopenia, diarrhea and nausea) was statistically significantly higher in the linezolid arm [17]. The efficacy of linezolid in nosocomial pneumonia was assessed using vancomycin as the comparator in two separate prospective, double-blind studies in which 74 patients had MRSA as the documented pathogen in the microbiologically evaluable population [18,19]. In one study, microbiological eradication rates were numerically lower in the linezolid arm (15 out of 23; 65.2%) compared with vancomycin (seven out of nine; 77.8%), whereas the reverse trend was observed in the second study (eradication rates of 12 out of 19; 63.2% and ten out of 23; 43.5%, respectively) [18,19]. Clinical cure rates in the MRSA subset were not reported for the two studies, although superiority of linezolid was claimed in a retrospective MRSA subset analysis of the two pooled studies [20]. Although reports to date of S. aureus resistance to linezolid are rare, the first such case was reported in 2001, in which the minimum inhibitory concentration (MIC) increased from 2 to 32 µg/ml after 4 weeks of linezolid treatment in a patient with end-stage renal failure [21]. Since that time, at least seven additional cases of linezolid resistance in S. aureus isolates have accumulated [22]. Thus, an increasing frequency of resistance may potentially accompany more widespread use of this drug.

Tigecycline’s distinctive feature is that it confers broad antibiotic coverage of drug-resistant Gram-positive bacteria and certain, but not all, species of multidrug-resistant Gram-negative bacteria, although it is a bacteriostatic agent [23]. The safety and efficacy of tigecycline versus that of vancomycin–aztreonam was studied in two Phase III, double-blind studies in hospitalized adults with cSSSI [24]. Only 50 patients had MRSA as the baseline pathogen and, in these subjects, the eradication rate in the tigecycline group (29 out of 37; 78.4%) was similar to that in the vancomycin–aztreonam group (26 out of 34; 76.5%).

Daptomycin has the advantage of being a once-daily dosed, rapidly bactericidal agent. However, it lacks efficacy in pneumonia owing to its inactivation by pulmonary surfactant and it can cause muscle toxicity [25]. An analysis of two randomized, double-blind studies comparing daptomycin with an antistaphylococcal penicillin or vancomycin for the treatment of cSSSI suggested equivalence with respect to outcomes in patients with MRSA infection (cure rates of 21 out of 28; 75% and 25 out of 36; 69%, respectively) [26]. Notably, the proportion of MRSA patients in the microbiologically evaluable population in these studies was small (64 out of 761) [26]. A more recent study comparing daptomycin versus initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin in 124 patients with S. aureus bacteremia and endocarditis (of whom 89 had MRSA as baseline pathogen) demonstrated that daptomycin was not inferior to standard therapy [27]. Clinical success was low in the MRSA subset of patients but favored daptomycin (20 out of 45; 44.4%) over standard therapy (14 out of 44; 31.8%). Of concern, however, was the observation that, in five MRSA patients in the daptomycin group who had microbiological failure, isolates with reduced daptomycin susceptibility emerged (MIC increased from 0.25–0.5 to 2–4 µg/ml).

In summary, MRSA represents a growing threat to public health and the need for antibiotics that are more efficacious than vancomycin has never been greater. Compelling evidence of the improved efficacy of the newer agents against MRSA infections in prospective, randomized, double-blind studies is generally lacking and, in many of the trials, the total number of MRSA patients enrolled is relatively small. In order to justify the significantly greater costs of these newer agents, data are needed that demonstrate more favorable outcomes in larger studies enrolling a greater proportion of MRSA patients. One or more of the newer agents and those currently in development may eventually prove to be more efficacious than vancomycin, but these may not ultimately provide a sufficient repertoire with which to address the growing problem of bacterial resistance among Gram-positive pathogens.

Conflict of interest

Hegde is an employee of Theravance, Inc. Chambers has served as a consultant for Theravance, Inc.