Editorial

10.1586/14787210.5.3.333 © 2007 Future Drugs Ltd ISSN 1478-7210 333

Combating the growing problem of methicillin-resistant Staphylococcus aureus: do the newer antibiotics represent a better alternative to vancomycin?‘MRSA represents a growing threat to public health and the need for antibiotics that are more efficacious than vancomycin has never been greater.’

Henry F Chambers and Sharath S Hegde†

†Author for correspondenceTheravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USATel.: +1 650 808 6432Fax: +1 650 808 6441shegde@theravance.com

Expert Rev. Anti Infect. Ther. 5(3), 333–335 (2007)

Methicillin-resistant Staphylococcus aureus(MRSA) is a major cause of serious nosocomialinfections, and the emergence of virulentstrains of this organism in community-dwelling patients lacking traditional risk fac-tors for MRSA is particularly concerning [1,2].Overall, rates of MRSA infection observed inUS clinical laboratory surveillance have beenincreasing steadily since 1998, accounting for53% of all S. aureus infections in 2005 [3], andcommunity-acquired MRSA is now the mostcommon recognizable cause of skin and skin-structure infections [4,5]. One particular clone,designated USA300, is the predominant onecausing skin and skin-structure infections andmay be more virulent than hospital-associatedstrains [6].

Vancomycin, a glycopeptide that has been inclinical use for more than 50 years, still servesas the cornerstone of the treatment of drug-resistant Gram-positive infections [7]. How-ever, there are significant concerns owing todecreasing susceptibility to this agent amongEnterococcus spp. and S. aureus [8–10]. Further-more, vancomycin is slowly bactericidal, whichmay be partly responsible for reported clinicalfailures using this drug [11,12]. The growingawareness of the limitations of vancomycin hasserved as an impetus for the development of

newer agents [13]. Quinupristin–dalfopristin,linezolid, daptomycin and tigecycline are fourdrugs that have received regulatory approval inthe last decade for the treatment of infectionscaused by drug-resistant Gram-positive patho-gens. Although these drugs do have certaindifferentiating attributes and may offer someadvantages over vancomycin, they also havesignificant limitations. More importantly, asdiscussed below, there are limited data fromwell-controlled double-blind studies support-ing greater therapeutic efficacy of the neweragents, compared with vancomycin, in thetreatment of MRSA infections.

Quinupristin–dalfopristin is a streptogramincombination antibiotic whose activity againstGram-positive pathogens demonstrates theconcept of antimicrobial synergy. However,infusion-related side effects contribute to thepoor tolerability profile of this drug and thereare issues of drug–drug interaction, both ofwhich have limited the usefulness of this anti-biotic [14]. Furthermore, clinical efficacy datafor this agent, specifically against MRSA infec-tions, are limited and, as such, it has notgained regulatory approval for this indication.

Linezolid is unique in that it is available inboth intravenous and oral dosage forms,which have equivalent bioavailability. Its

Chambers & Hegde

334 Expert Rev. Anti Infect. Ther. 5(3), (2007)

bacteriostatic properties and potential to cause bone marrowtoxicity and neuropathies during longer courses of therapy area concern [15]. In the only reported double-blind study in com-plicated skin and skin-structure infections (cSSSIs) comparinglinezolid with oxacillin–dicloxacillin, patients with MRSA atbaseline were excluded from the study [16]. The efficacy of line-zolid against MRSA cSSSI was demonstrated in a subsequentopen-label study in which 285 patients had MRSA as the base-line pathogen [17]. With respect to clinical cures, linezolid andvancomycin were not statistically different in efficacy. In sub-group analyses, linezolid was marginally but statistically supe-rior to vancomycin in patients with MRSA, but this outcomeshould be weighed against the fact that the study was openlabel and the incidence of certain adverse effects (thrombo-cytopenia, diarrhea and nausea) was statistically significantlyhigher in the linezolid arm [17]. Theefficacy of linezolid in nosocomialpneumonia was assessed using vanco-mycin as the comparator in two sepa-rate prospective, double-blind studies inwhich 74 patients had MRSA as thedocumented pathogen in the micro-biologically evaluable population [18,19].In one study, microbiological eradication rates were numeri-cally lower in the linezolid arm (15 out of 23; 65.2%) com-pared with vancomycin (seven out of nine; 77.8%), whereasthe reverse trend was observed in the second study (eradicationrates of 12 out of 19; 63.2% and ten out of 23; 43.5%, respec-tively) [18,19]. Clinical cure rates in the MRSA subset were notreported for the two studies, although superiority of linezolidwas claimed in a retrospective MRSA subset analysis of the twopooled studies [20]. Although reports to date of S. aureus resist-ance to linezolid are rare, the first such case was reported in2001, in which the minimum inhibitory concentration (MIC)increased from 2 to 32 µg/ml after 4 weeks of linezolid treat-ment in a patient with end-stage renal failure [21]. Since thattime, at least seven additional cases of linezolid resistance inS. aureus isolates have accumulated [22]. Thus, an increasingfrequency of resistance may potentially accompany morewidespread use of this drug.

Tigecycline’s distinctive feature is that it confers broad anti-biotic coverage of drug-resistant Gram-positive bacteria andcertain, but not all, species of multidrug-resistant Gram-negative bacteria, although it is a bacteriostatic agent [23]. Thesafety and efficacy of tigecycline versus that ofvancomycin–aztreonam was studied in two Phase III, double-blind studies in hospitalized adults with cSSSI [24]. Only50 patients had MRSA as the baseline pathogen and, in these

subjects, the eradication rate in the tigecycline group (29 out of37; 78.4%) was similar to that in the vancomycin–aztreonamgroup (26 out of 34; 76.5%).

Daptomycin has the advantage of being a once-daily dosed,rapidly bactericidal agent. However, it lacks efficacy in pneu-monia owing to its inactivation by pulmonary surfactant and itcan cause muscle toxicity [25]. An analysis of two randomized,double-blind studies comparing daptomycin with an anti-staphylococcal penicillin or vancomycin for the treatment ofcSSSI suggested equivalence with respect to outcomes inpatients with MRSA infection (cure rates of 21 out of 28; 75%and 25 out of 36; 69%, respectively) [26]. Notably, the propor-tion of MRSA patients in the microbiologically evaluable popu-lation in these studies was small (64 out of 761) [26]. A morerecent study comparing daptomycin versus initial low-dose

gentamicin plus either an antistaphylo-coccal penicillin or vancomycin in124 patients with S. aureus bacteremiaand endocarditis (of whom 89 hadMRSA as baseline pathogen) demon-strated that daptomycin was not inferiorto standard therapy [27]. Clinical successwas low in the MRSA subset of patients

but favored daptomycin (20 out of 45; 44.4%) over standardtherapy (14 out of 44; 31.8%). Of concern, however, was theobservation that, in five MRSA patients in the daptomycingroup who had microbiological failure, isolates with reduceddaptomycin susceptibility emerged (MIC increased from0.25–0.5 to 2–4 µg/ml).

In summary, MRSA represents a growing threat to publichealth and the need for antibiotics that are more efficaciousthan vancomycin has never been greater. Compelling evidenceof the improved efficacy of the newer agents against MRSAinfections in prospective, randomized, double-blind studies isgenerally lacking and, in many of the trials, the total number ofMRSA patients enrolled is relatively small. In order to justifythe significantly greater costs of these newer agents, data areneeded that demonstrate more favorable outcomes in largerstudies enrolling a greater proportion of MRSA patients. Oneor more of the newer agents and those currently in develop-ment may eventually prove to be more efficacious than vanco-mycin, but these may not ultimately provide a sufficient reper-toire with which to address the growing problem of bacterialresistance among Gram-positive pathogens.

Conflict of interestHegde is an employee of Theravance, Inc. Chambers has servedas a consultant for Theravance, Inc.

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‘Compelling evidence of improved efficacy of the newer

agents against MRSA infections in prospective,

randomized, double-blind studies is generally lacking.’

Combating MRSA: alternatives to vancomycin

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Affiliations

• Henry F Chambers, MD

Chief, Division of Infectious Diseases, San Francisco General Hospital, Building 30, Room 3400, 1001 Potrero Avenue, San Francisco, CA 94110, USATel.: +1 415 206 5437Fax: +1 415 648 8425hchambers@medsfgh.ucsf.edu

• Sharath S Hegde, PhD

Executive Director, Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USATel.: +1 650 808 6432Fax: +1 650 808 6441shegde@theravance.com