Newer Antistaphylococcal Agents:
In-Vitro Studies and Emerging Trends in Staphylococcus aureus Resistance
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Abstract: Although remarkable advances in the development of antibacterial agents for infections caused by Staphylococcus aureus began in the 1940s, treatment of this pathogen is still a challenge for clinicians. The emergence of S aureus strains with resistance to penicillin and methicillin in 1948 and 1961 and the recent reports of vancomycin-resistant strains indicate that the battle against this versatile pathogen is not yet over. This review discusses the newly developed antimicrobial agents, mechanisms of action, in-vitro studies, and emerging trends in S aureus resistance to these antibacterial agents. The availability of linezolid in intravenous and oral form is an advantage for the treatment of pneumonia and skin and soft tissue infection. Daptomycin is recommended for the treatment of deep-seated infections, such as endocarditis or osteomyelitis caused by methicillin-resistant S aureus. Tigecycline is a promising antibacterial agent in cases of complicated intra-abdominal infections and complicated skin infections in adults. Novel cephalosporins, quinolones, and conjugate vaccines are currently being developed. Rational antimicrobial usage along with effective infection control measures are required to avert the rapid emergence of resistant strains of S aureus to these new agents.
Staphylococcus aureus became known as a causative agent of infection when Alexander Ogston identified its role in sepsis and abscess formation.1 It continues to be one of the commonest human pathogens and is most frequently isolated in community and hospital-acquired infections. S aureus causes a broad spectrum of diseases, including superficial lesions, such as wound infections; systemic and life-threatening conditions, such as endocarditis, osteomyelitis, pneumonia, brain abscesses, meningitis, and bacteremia; and toxinoses, such as food poisoning, scalded skin syndrome, and toxic shock syndrome.2
The discovery of penicillin in the 1940s and many antibiotics in the 1950s to the 1970s (known as the “Golden Age of Antibiotics”) created a sense of euphoria in the medical community, as it perceived that bacterial infections were curable. However, the bright prospect of antimicrobial therapy began to dim when it became obvious that disease-causing bacteria possess a repertoire of strategies against antimicrobial agents. The emergence of S aureus strains with resistance to penicillin and methicillin was reported in 1948 and 1961, respectively.3,4 In both cases, resistance developed within a few years of the introduction of the antibiotics into clinical medicine. For many years, methicillin-resistant S aureus (MRSA) was considered a multi-drug- resistant pathogen that has been historically associated with hospitals and healthcare facilities.5 However, in addition to having established itself as a major hospital pathogen, MRSA has now been documented in the healthy community affecting persons without established risk factors for MRSA acquisition.6 Following the spread of MRSA, parenteral glycopeptides (vancomycin and teicoplanin) became the mainstay of therapy for MRSA infections. However, the first vancomycin-intermediately resistant S aureus (VISA) isolate was identified in Japan in 1997, and these strains have been reported worldwide.7–10 VISA strains were found to adapt and develop intermediate resistance by thickening of their cell walls. To date, 4 vancomycin-resistant S aureus (VRSA) isolates have been identified in the United States—2 from Michigan and 1 each from Pennsylvania and New York.11–14 Vancomycin-resistant enterococci were isolated from 3 of the 4 patients with VRSA, and it is postulated that in-vivo transfer of the vanA gene could have occurred.15 The authors have observed 4 major trends in the epidemiology of S aureus, especially MRSA. In many countries, infections caused by multiresistant strains (especially MRSA) are of great concern. In other countries, the frequency of MRSA is low. The third trend is the emergence of MRSA in the community, and the final trend is the recent reporting of vancomycin-intermediate and -resistant S aureus.
Over the years, there has been growing concern surrounding the increased prevalence of antimicrobial resistance in S aureus, especially hospital-associated MRSA (HA-MRSA), which limits drug options. This has led to the development of new drugs targeted against this pathogen. However, S aureus continues to demonstrate resistance to a wide range of antimicrobial agents. This review describes the newly developed drugs, their mechanism of action, in-vitro effectiveness based on recent studies conducted in various countries, and emerging trends in S aureus resistance (especially HA-MRSA) to new antibacterial agents.
Approved Antimicrobial Agents with Activity Against S aureusTable 1
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Quinupristin-dalfopristin. The streptogramins are a series of antibiotic derivatives of natural Streptomyces pristinaespiralis products.16 Discovered in the 1960s, quinupristin-dalfopristin is a derivative of pristinamycin, an agent widely used in animal feed as a growth promoter.17 Quinupristin-dalfopristin consists of mixtures of 2 structurally distinct cyclic peptide antibiotics, type A and type B, which are separately bacteriostatic but bactericidal in appropriate ratio.18 Approved in September 1999 by the US Food and Drug Administration (FDA), dalfopristin and quinupristin are streptogramin A and B, respectively, and in a 70:30 ratio yield a water-soluble drug suitable for intravenous (IV) administration.19,20 Both compounds enter bacterial cells by diffusion and to different sites on the 50S ribosomal subunit, resulting in an irreversible inhibition of bacterial protein synthesis.21 Binding of group A streptogramin (dalfopristin) to the ribosome causes a conformational change that increases the binding affinity for group B streptogramin (quinupristin). The synergistic effect of the combination appears to result in these compounds targeting early and late steps of protein synthesis.22 The FDA has approved quinuprisitin-dalfopristin for the treatment of serious and life-threatening infections associated with vancomycin-resistant Enterococcus faecium (VRE) and for complicated skin and skin structure infections caused by methicillin susceptible S aureus (MSSA) or Streptococcus pyogenes.18,23 The FDA-approved dosing for complicated skin and skin structure infections is 7.5 mg/kg IV for 12 hours in adults.16 The combination loses bactericidal activity in vitro against S aureus isolates with constitutive resistance to the macrolide-lincosamide-streptogramin B (MLSB) class of antibiotics, which is seen frequently in MRSA and less commonly in MSSA.24,25 This is because such isolates are resistant to quinupristin, which is a streptogramin B antibiotic. Resistance to quinupristin is plasmid mediated and controlled by a specific hydrolase.26 Resistance to dalfopristin can occur secondary to an efflux pump or more commonly due to virginiamycin acetyltransferase-induced acetylation.27 As long as strains remain susceptible to dalfopristin, however, the combination retains inhibitory activity. In preregistration clinical studies, quinupristin-dalfopristin has been shown to have similar success rates to comparators (cefazolin, oxacillin, or vancomycin) in complicated skin and skin structure infections, catheter-related bacteraemia caused by staphylococci (including MRSA), and hospital-acquired pneumonia caused by staphylococci and Streptococcus pneumoniae.28–30 In a multicenter study on the treatment of a variety of infections due to MRSA in patients either intolerant of or failing prior therapy, > 70% of patients had successful outcomes following treatment with quinupristin-dalfopristin.31 Recent in-vitro studies of quinupristin-dalfopristin have indicated that the antibiotic showed excellent activity against S aureus isolates investigated in Turkey,32 Norway,33 South Korea,34 North America,35,36 and Spain.37 Unpublished data from the authors’ investigation have also indicated that this agent is effective against MRSA isolates in South Africa.38 However, multicenter studies conducted in Germany and Russia indicated that 0.6% and 1.8% of S aureus strains were resistant to quinupristin-dalfopristin.39,40 The prevalence of MSSA resistance to quinupristin-dalfopristin ranged from 0.1% in Taiwan,41 1.53% and 2.5% in Spain,42 to 39.2% in Spain.43 In addition, the frequency of MRSA resistance to quinupristin-dalfopristin has been reported to be 19.3% in Turkey43 and 31% in Taiwan.44 However, quinupristin-dalfopristin has been reported to be active against vancomycin-intermediate and resistant S aureus strains.45
Quinupristin-dalfopristin’s clinical utility has been limited by its intravenous-only formulation, high cost, and adverse effect profile (eg, myalgias, arthalgias, and thrombophlebitis). An oral streptogramin antimicrobial, XRP2868, which is made up of a streptogramin B component RPR202868 and a streptogramin A component RPR132552 in a 30:70 ratio, has recently been developed. It is as potent as quinupristin-dalfopristin against oxacillin-susceptible and -resistant S aureus strains and 4-fold more potent than the oral streptogramin pristinamycin against these organisms.46 Figure 1 illustrates the structure of quinupristin-dalfopristin.47Figure 1
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Linezolid. The oxazolidinones48 are a novel class of antibiotics discovered in 1987. In April 2000, linezolid became the first oxazolidinone with a novel mechanism of action to obtain FDA approval in 35 years. Other members of this class of antibacterial agents, such as ranbezolid (RBX 7644),49,50 DA 7867,51 and AZD-2563,52 are currently being developed. Linezolid reversibly blocks the formation of protein synthesis initiation complexes by binding to the 23S ribosomal subunit, near the interface formed with the 30S ribosomal subunit (Figure 2).47,53 Figure 2
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Although the binding site of linezolid is near that of chloramphenicol and lincomycin, these antibiotics differ in the mechanism by which they act, with chloramphenicol inhibiting peptide bond formation and linezolid inhibiting initiation complex formation.54,55 The result of this mechanistic difference is that there is only infrequent cross-resistance between linezolid and chloramphenicol or lincomycin.18 Linezolid has a broad spectrum of activity against gram-positive bacteria, and the FDA-approved indications for linezolid use are relatively broad.56,57 They include the treatment of uncomplicated skin and soft tissue infections (SSTIs) caused by MSSA or Streptococcus pyogenes and complicated SSTI caused by MSSA, MRSA, S pyogenes, and S agalactiae in addition to other indications (eg, nosocomial and community-acquired pneumonia and for vancomycin-resistant E faecium infection).58,59 An additional indication was approved in 2003 for treatment of diabetic foot infections caused by S aureus (MSSA and MRSA).60 The action of linezolid against S aureus is best described as bacteriostatic; therefore, its utility is limited for several indications, such as enterococcal endocarditis or staphylococcal osteomyelitis.61 A major advantage of this agent is that it is available for IV and oral use. This flexibility of administration route may translate to a significant advantage for linezolid use in terms of health-economic outcomes compared with other standard intravenous antibiotics, such as vancomycin.62 The FDA-approved dosing for complicated skin and skin-structure infections (cSSSIs) is 600 mg/kg IV for 12 hours in adults, 10 mg/kg IV for 8 hours in children, and 10 mg/kg IV for 12 hours for neonates less than 7 days old.16 However, overuse in the community is a concern, as resistance may limit the drug’s usefulness.61
Linezolid has exhibited excellent activity against S aureus isolates (including MRSA), according to recent studies conducted in Taiwan,41,63,64 Turkey,32,65 United Kingdom and Ireland,66 Germany,67 France,68 Poland,69 Norway,33 Israel,70 South Korea,34 North America,35 and Spain.37 The authors’ survey has also indicated full susceptibility of MRSA isolates to linezolid in South Africa.38 Moreover, vancomycin intermediate strains, as well as 2 vancomycin-resistant S aureus (VRSA) strains isolated in Michigan and Hershey Medical Center (Hershey, Pa), were susceptible to linezolid.71 Several studies have also indicated that linezolid therapy has clear advantages to vancomycin in the treatment of skin and soft tissue infections72–75 and nosocomial pneumonia76–78 caused by MRSA. Linezolid recipients also experienced shorter hospital length of stay (LOS), more discharges in the first week of treatment, fewer days of IV therapy, and less cost of treatment than the vancomycin group in multinational trials.72,79 Despite its excellent activity, reports on the emergence of S aureus resistance to linezolid have been described.80–87 Furthermore, the report by Wilson et al82 on linezolid-resistant EMRSA-15 is also a worrying development given the ability of this clone for nosocomial spread. Resistance arises not from the acquisition of genes but from a G2576T and T2500A mutation in chromosomal genes encoding 23S rRNA.80,83,88 Like quinupristin-dalfopristin, linezolid is substantially more expensive than conventional therapy. The daily cost of IV or oral linezolid is 7-fold that of IV vancomycin.89 Myelosuppression due to prolonged linezolid therapy has been reported, though it is reversible on cessation of the antibiotic.62,90
Daptomycin. Daptomycin is a novel lipopeptide antibiotic derived from the fermentation of a strain of Streptomyces roseosporus. Eli Lilly and Company (Indianapolis, Ind) discovered this antibacterial agent in the 1980s.91 The original generic name was deptomycin, but it was changed to daptomycin to avoid possible confusion with agents like streptomycin.92 However, concerns on skeletal muscle toxicity and treatment failures in patients with S aureus endocarditis led to a halt in the development of daptomycin.20 Following the increased resistance rates of gram-positive infections, Cubist Pharmaceutical (Lexington, Mass) obtained worldwide rights from Lilly in 1997 to develop, manufacture, and market daptomycin.93,94 In September 2003, daptomycin became the first FDA-approved cyclic lipopeptide for the treatment of cSSSIs caused by S aureus (including MRSA), S pyogenes, S agalactiae, S dysgalactiae subsp. equisimilis, and E faecalis (vancomycin susceptible only).95 The unique structure of daptomycin, which is made up of a 13-member amino acid cyclic lipopeptide with a decanoyl side-chain, confers a novel mechanism of action (Figure 3)Figure 3
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.47,96 The mechanism of action involves the calcium dependent insertion of the compound into the bacterial cytoplasmic membrane.18 Currently, the mode of action is believed to involve a multistep process in which cell membrane depolarization and not inhibition of lipoteichoic acid is the major event.96–98 With this unique mode of action, there is no cross-resistance between daptomycin and other antimicrobials.99 An interesting property of daptomycin that seems to arise from its unique action is that, unlike most antibiotics that target only growing cells, daptomycin is effective at all growth phases, including the stationary phase. This property has been suggested to be particularly useful in the treatment of indolent, deep-seated infections, such as endocarditis and osteomyelitis.18 Of particular clinical importance is the fact that daptomycin was active against S aureus isolates resistant to linezolid, quinupristin-dalfopristin, and teicoplanin.100 Furthermore, the prolonged half-life of 8 to 9 hours in adults allows for once-daily dosing—the FDA-approved dosing for cSSSIs is 4 mg/kg IV for 24 hours in adults.16 Clinical trials using a higher dose (6 mg/kg) for treatment of staphylococcal bacteremia are ongoing.61
The bactericidal effect of daptomycin is rapid—greater than 99.9% of MRSA and MSSA bacteria die in less than 1 hour post treatment.101,102 The minimum inhibitory concentration (MIC90) values for daptomycin against MSSA range from 0.5–1.0 mg/L100,103 and 0.25–1.5 mg/L for MRSA isolates.63,100,103–106 Daptomycin also has been shown to have excellent in-vitro activity against VRSA.16 The synergy of daptomycin, oxacillin, and other beta-lactams against MRSA has been proposed for the treatment of MRSA infection, although further studies are needed to determine the in-vivo efficacy of the combination.107 Resistance to daptomycin has been difficult to generate in the laboratory in single passage and serial passage experiments.98 The emergence of resistance was < 0.2% across the entire set of Phase II and III clinical trials with more than 1,000 daptomycin-treated patients. However, 2 reports of daptomycin resistance in S aureus have been described.108,109 Drawbacks of daptomycin include its high cost, lack of an oral formulation, poor penetration to pulmonary tissue, and possible rhabdomylosis.99 The drug has the potential to cause a reversible myopathy, which is evident when high doses were given twice daily; however, it appears to be an infrequent event with new dosing regimens.110
Telithromycin. Telithromycin was the first ketolide belonging to the macrolide-lincosamide-streptogramin B (MLSB) family to become available for clinical use in 2004. Telithromycin differs from the MLSB family in that it has a carbonyl group in the C-3 position instead of a cladinose sugar.111 This modification leads to a more stable compound in an acidic environment and enhances activity against macrolide-resistant isolates.112 Although the mechanisms of action of ketolides and macrolides are similar and bind strongly to a region of domain V in the 23S rRNA of the ribosome, telithromycin has additional strong binding to a region in domain II to which macrolides bind weakly.113,114 The mechanism of telithromycin may contribute to the efficacy of the antibacterial agent against various macrolide-resistant bacteria.115 Due to its activity against many gram-positive and -negative respiratory pathogens, it is often used for the treatment of respiratory-tract infections.18 Shortridge et al116 observed that telithromycin exhibited excellent activity against susceptible and inducible-resistant S aureus. However, S aureus isolates with the constitutive MLSB phenotype are less susceptible to telithromycin, demonstrating the important difference in telithromycin activity against inducible- and constitutive-resistant strains.111,117 A recent study in Taiwan indicated that 86% of the MRSA studied were resistant to telithromycin.63 Resistance among inducible-resistant MSSA isolates from Spain has also been described.42 Figure 4 illustrates the structure of telithromycin.118Figure 4
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Tigecycline. Tigecycline (9-t-[butylglycylamido]-minocycline) is a representative glycylcycline agent that was approved on June 16, 2005, by the FDA for the treatment of cSSSIs caused by a wide variety of microorganisms (including MSSA and MRSA) and complicated intra-abdominal infections (MSSA only).119 It is the first glycylcycline to be launched and the first new tetracycline analogue since minocycline was introduced more than 30 years ago.120 The primary receptor site for tigecycline and the tetracycline class is the bacterial ribosome, and compared with tetracycline and minocycline, tigecycline has a considerably stronger binding affinity, making it less likely that strains resistant to tigecycline will emerge rapidly.121,122 The unique attribute of tigecycline is its stability against common mechanisms of tetracycline resistance. Tigecycline has demonstrated activity against strains containing tet genes that code for major forms of tetracycline resistance.121 To date, tigecycline-resistant isolates in the laboratory setting using prolonged exposure to suboptimal concentrations of tigecycline have been unsuccessful.121 An oral formulation of tigecycline is not yet available, and administration is limited to IV. This represents a potential disadvantage compared with current agents that are available in both parenteral and oral formulations.123 Intravenously administered tigecycline (recommended dosage regimen 100 mg initially, followed by 50 mg every 12 hours for 5–14 days) has been FDA approved for the treatment of cSSSIs and complicated intra-abdominal infections (cIAIs).124 Recent studies have indicated that tigecycline showed pronounced activity against S aureus with MIC90 ranging between 0.25–0.5 µg/mL125–130 and S aureus intermediately resistant to glycopeptides (GISA).131–133 Tigecycline also bacteriostatically inhibited the vancomycin-resistant S aureus isolated at the Hershey Medical Center in the United States.71 Figure 5 describes the structure of tigecycline.134Figure 5
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Drugs Being Clinically Investigated Oritavancin. This agent is a glycopeptide antibiotic derived semi-synthetically from a precursor drug closely related to vancomycin. It was discovered by Eli Lilly but is now developed by InterMune (Brisbane, Calif) as an injectable glycopeptide for the treatment of gram-positive infections.135 Oritavancin and related alkyl glycopeptides inhibit bacterial cell-wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis.136 However, unlike vancomycin, this agent dimerises strongly and can anchor to the cytoplasmic membrane by virtue of its alky side-chain (Figure 6)Figure 6
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.18,20 Oritavancin is distinguished from vancomycin by its bactericidal activity against enterococci, S pneumoniae, and staphylococci, including MRSA.137–139 It is not affected by the vanA, vanB, and vanC-encoded alterations in the bacterial cell wall that impart vancomycin resistance.137 It also has in-vitro activity against staphylococci, including MRSA, which is generally comparable with that of vancomycin.140,141 Oritavancin has completed Phase III clinical trials for skin and soft tissue infection, and a Phase II trial for the treatment of bacteremia is currently underway.99 It has a longer half-life (> 10 days) than vancomycin and, thus, can potentially offer a shorter duration of treatment.49 However, the long half-life has also raised concerns with respect to drug accumulation and the potential for organ toxicity.142
Dalbavancin. Dalbavancin (formerly BI-397) is a bactericidal dimethylaminopropyl amide derivative of the glycopeptide A40926 (Figure 6).18,20,49,143,144 Discovered by Bioresearch Italia, it is presently being developed by Vicuron Pharmaceuticals (now part of Pfizer, New York, NY).145 Its spectrum of activity is similar to oritavancin but with lesser activity against vancomycin-resistant enterococci.136 It has a half-life of 9–12 days, and the developmental program for this agent has exploited this pharmacokinetic feature; once-weekly dosing strategies (1,000 mg on Day 1 and 500 mg on Day 8) have been used in Phase II studies of cSSSIs caused by methicillin-susceptible and -resistant S aureus.146 This agent is up to 16-fold more active than vancomycin against staphylococci tested in vitro.141 In a recent survey of 1,177 MRSA clinical isolates, the MIC90 of dalbavancin was 0.06 mg/L compared with 2 mg/L for vancomycin and teicoplanin, respectively.147 Dalbavancin was also noted as the most potent compound tested against S aureus isolates obtained from medical centers in Latin America.148 It is also active against isolates with reduced susceptibility to vancomycin and teicoplanin (GISA)149 and was active against 1 of the 2 VRSA strains isolated in the United States.71 Like oritavancin, dalbavancin is eliminated slowly from the serum with a half-life of several days, even in individuals with normal renal function. Other glycopeptides being developed for the treatment of gram-positive infections include telavancin developed by Theravance (South San Francisco, Calif)150 and ramoplanin, a lipoglycodepsipetide antibiotic produced by Actinoplanes species ATCC 33076.150,151
Garenoxacin. Garenoxacin (BMS-284756) is a broad-spectrum des-fluoroquinolone6 that was developed by Bristol-Myers Squibb (New York, NY) under license from Toyama Chemical Co. (Toyama, Japan). In September 2003, Bristol-Myers Squibb returned all rights for the antibiotic to Toyama, and an agreement was signed in June 2004.150 Its structure modification is the absence of fluorine at C-6 but has fluorine incorporated through a C-8 difluoromethyl ether linkage.152 However, its mechanism of action is the same as other fluoroquinolones.153 The compound, with oral and injectable formulations, has been evaluated for treatment of respiratory, urinary tract, and skin and soft tissue infections caused by susceptible and resistant organisms.150 This agent is reported to be active against MRSA strains that are resistant to other fluoroquinolones and selects fluoroquinolone-resistant mutants at a lower frequency than older agents.154,155 In-vitro studies have indicated that oxacillin-susceptible and -resistant S aureus were susceptible to garenoxacin at an investigational MIC breakpoint of 0.5 mg/L and 1 mg/L, respectively.156,157 However, a recent study of S aureus isolates in the Asia-Pacific region showed that 1% and 9% of oxacillin-susceptible and -resistant S aureus isolates resistant to ciprofloxacin were also resistant to 4 mg/L garenoxacin, respectively, indicating that it may not be a long-term alternative for the treatment of oxacillin-resistant S aureus infections.152 Other new generation fluoroquinolones approved by the FDA include moxifloxacin (April 2001) and gatifloxacin (October 2002) for use in cSSSIs.20 DW286, a naphthyridone, is among several fluoroquinolones in development that have in-vitro activity against MRSA.158 Others include ABT-492,159 DK-507k,160 and WCK-771.161 Figure 7 describes the structure of ganeroxacin.162Figure 7
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Other Antibacterial Agents Currently Developed Novel β-lactamase-stable cephalosporins with high affinity for PBP2a are in clinical development. They include BMS-247243,163 the zwitterionic cephem RWJ-54428,164 RWJ-442831,165 TAK-599,166 CB-181963,167,168 BAL5788,169 a prodrug of BAL9141,170,171 and S-3578.172 SM-197436, SM-232721, SM-232724, SM-216601, and CS-023 (R-115685) are novel methylcarbapenems that have shown in-vitro activity against MRSA.173–175 Iclaprim, a dihydrofolate reductase inhibitor, currently developed by Arpida, has completed Phase II clinical trials for the treatment of serious gram-positive infections, including MRSA, VRSA, and macrolide-, quinolone-, and trimethoprim-resistant strains. It has been shown to be effective when administered intravenously as a treatment for cSSSIs.150
The lantibiotic nisin, alone and combined with peptidoglycan-modulating antibiotics, has indicated activity against MRSA and vancomycin-resistant enterococci.176,177 The lantibiotic gallidermin is as active as nisin and is currently produced and developed for clinical studies.178 Other antimicrobial agents include REP8839, a novel methionyl-tRNA synthetase (MetS) inhibitor,179 muraymycins,180 mannopeptimycins,181 arylalkylidene rhodanines, and arylalkylidene iminothiazolidin-4-ones.182
Several agents targeting virulence factors have also being investigated. Capsular polysaccharides act as virulence factors by reducing the ability of host polymorphonuclear neutrophils to opsonize the bacteria. Although 12 S aureus capsular polysaccharides have been identified, types 5 and 8 have historically accounted for the majority of S aureus disease. In addition, type 336, a newly identified capsular polysaccharide, is also appearing more frequently.183 Nabi (now Nabi Biopharmaceuticals, Boca Raton, Fla) is developing a bivalent vaccine against S aureus types 5 and 8 (NABI-StaphVAX, StaphVAX) under a CRADA agreement with the US National Institutes of Health. The vaccine contains type 5 and type 8 S aureus capsular polysaccharides conjugated to a protein carrier (recombinant exoprotein A, a genetically detoxified form of Pseudomonas aeruginosa exotoxin A).184 StaphVAX has been demonstrated to provide temporary protection against the occurrence of S aureus bacteremia in patients receiving hemodialysis185,186 and is the only staphylococcal vaccine to date that has been tested in a Phase III clinical trial.185 It has been shown to be safe, immunogenic, and efficacious, as determined by reduction in S aureus bacteremia through up to 10 months post-immunization in end-stage renal disease patients.187 Nabi Pharmaceuticals intends to develop a second-generation version of StaphVAX that will include antigen from Staphylococcus type 336. This would increase the vaccine’s coverage of staphylococcal infection. Nabi also intends to develop 2 combination vaccines. The first, StaphVAX+, will contain the StaphVAX and EpiVAX trademark in a single vial, and the second, CombiVAX, will contain components of StaphVAX, EpiVAX trademark, and EnteroVAX trademark.184 Other vaccines being developed include tefibazumab (Aurexis; Inhibitex), a humanized monoclonal antibody directed at the microbial surface components recognizing adhesive matrix molecule (MSCRAMM) clumping factor A,188 INH-A21 (Veronate; Inhibitex), BYSX-A110,189 and Aurograb (Neu Tec Pharma).190,191
Conclusion Infections caused by S aureus, especially MRSA, continue to be a major challenge to clinicians worldwide. It is evident that the emergence of resistant forms of S aureus seems to coincide with the introduction of new classes of antibiotics. Therefore, the importance of the search for and development of new antimicrobials cannot be over-emphasized. Despite reports of vancomycin- and teicoplanin-resistant S aureus, parenteral glycopeptides remain the mainstay of therapy for systemic infections. For MRSA unresponsive to vancomycin therapy, the choice of a treatment alternative depends on the location of the infection, the activity of the agent, the pharmacokinetics and safety profile, resistance potential, and cost to patient and institution.192 For the treatment of pneumonia and skin and soft tissue infection, linezolid appears to be more effective than vancomycin. The availability of linezolid in intravenous and oral form is also an advantage for long-term outpatient therapy. Oral therapy is usually less expensive than its intravenous counterpart, and provides the clinician and patient with greater flexibility in an effective therapeutic regimen. However, prudent use is necessary to limit the potential for the development of widespread resistance. The effectiveness of a bactericidal agent like daptomycin in all growth phases has been noted to be particularly important for the treatment of deep-seated infections, such as endocarditis or osteomyelitis caused by MRSA. However, daptomycin is not recommended for treatment of pneumonia. Tigecycline appears to be a promising new antibacterial agent in cases of complicated intra-abdominal infections and complicated skin infections in adults. The advent of investigational agents for clinical use could also provide clinicians with a variety of options for the treatment of S aureus infections. Nevertheless, rational antimicrobial usage along with effective infection control measures is required to avert the rapid emergence of resistant strains of S aureus to these new agents.
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| Wounds - ISSN: 1044-7946 - Volume 18 - Issue 5 - May 2006 - Pages: 129 - 146 | |
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