Treatment of Staphylococcus aureus infections: new issues, emerging therapies and future directions

Review

10.1517/14728214.12.1.1 © 2007 Informa UK Ltd ISSN 1472-8214 1

Anti-infectives

Treatment of Staphylococcus aureus infections: new issues, emerging therapies and future directions Emma J Bishop & Benjamin P Howden†

Austin Health, Infectious Diseases Department, Studley Road, Heidelberg, 3084, Victoria, Australia

Infections due to Staphylococcus aureus are a major cause of morbidity andmortality worldwide. Antimicrobial resistance in strains of S. aureus is acontinually evolving problem, including widespread methicillin resistance inhospitals, increasing methicillin resistance in community strains, and therecent acquisition of glycopeptide resistance. New antimicrobials withactivity against S. aureus have recently entered the market or are in the latestages of development. In addition, there has been significant interest in thedevelopment of novel and immune-based strategies for prevention ortreatment of S. aureus infections. This review describes established andemerging therapies for S. aureus infections, and considers the safety profilesand likely impact on present treatment standards of novel agents eitherundergoing clinical development or emerging onto the market.

Keywords: antibodies, dalbavancin, daptomycin, flucloxacillin, linezolid, methicillin resistance, quinupristin–dalfopristin, Staphylococcus aureus, tigecycline, vaccine, vancomycin resistance

Expert Opin. Emerging Drugs (2007) 12(1):1-22

1. Background

Staphylococcus aureus was first identified by Rosenbach in 1884 as a pathogencausing wound infections and furunculosis [1]. Worldwide, S. aureus commonlycauses skin and soft tissue infections and serious infections such as bacteraemiaand endocarditis, particularly in susceptible populations, such as prematureinfants, haemodialysis or surgical patients and those with prosthetic devices [2].Staphylococcus aureus continues to present a major global health concern, both as aresult of its ubiquity and ability to continue to develop resistance to newantimicrobials. In particular, there has been a recent shift from Gram-negativetowards Gram-positive pathogens (in particular S. aureus) as causes of nosocomialinfections [3], and there has been an increase in community acquisition ofantibiotic-resistant strains of S. aureus [4]. Examples of common infection typesand treatment recommendations for S. aureus infections are presented in Table 1.

Humans provide a natural reservoir for S. aureus and asymptomatic colonisa-tion of the nasopharynx, perineum and axillae is more common than infection.Carriage rates in the community are in the range of 25 – 50% [5]. Recent estimatessuggest that 89.4 million persons in the US are colonised with S. aureus [6] andcolonisation is an important risk factor for disease. In hospitals in the US∼ 500,000 patients/year contract a staphylococcal infection. In the period of1998 – 2002, S. aureus bacteraemia rates ranged from 35 to 56/100,000 in Aus-tralia and the US, respectively [7]. A significant proportion of S. aureus bacteraemiais of endogenous origin, related to nasal colonisation [8], and nasal carriage ofS. aureus is also a risk factor for postoperative infection [9].

1. Background

2. Medical need

3. Existing treatment

4. Therapeutic class review

5. Current research goals

6. Scientific rationale

7. Competitive environment

8. Potential development issues

9. Expert opinion and conclusion

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Treatment of Staphylococcus aureus infections: new issues, emerging therapies and future directions

2 Expert Opin. Emerging Drugs (2007) 12(1)

Table 1. Common infections caused by Staphylococcus aureus and approach to therapy in adults.

Clinical condition/infection Common treatment strategy

Furuncles/carbuncles – deep-seated necrotic infection of hair follicle

Surgical drainage ± oral antibiotics for 5 – 10 days

Cellulitis – often associated with surgical or traumatic wounds IV and oral antibiotics for 7 – 14 days

Soft tissue abscess Surgical drainage, short-course IV or oral antibiotics

Septic thrombophlebitis Removal of IV catheter and 3 – 6 weeks IV antibiotics ± debridement

Bacteraemia – requires exclusion of metastatic infection plus endocarditis

2 weeks IV antibiotics if uncomplicated. Consider 4 – 6 weeks IV antibiotics if associated with soft tissue/visceral focus

Endocarditis Early consideration for valvular replacement and 6 weeks IV antibiotics

Epidural abscess Surgical debulking and 6 weeks IV antibiotics

Osteomyelitis Debridement of sequestrae and 6 weeks IV antibiotics

Prosthetic joint infection 2 – 4 weeks IV antibiotics and indefinite suppressive oral therapy if prosthesis retained. Alternately, two-stage procedure: removal of prosthesis and 6 weeks IV antibiotics before reinsertion

IV: Intravenous.Based on data from the following references [51,168-171].

1.1 Methicillin resistance in Staphylococcus aureusResistance to methicillin emerged in S. aureus in 1961, soonafter the introduction of this antimicrobial in 1960 [10], andhas been the most important antimicrobial resistance problemin S. aureus. Staphylococcal resistance to methicillin and otherβ-lactam antibiotics is usually mediated by a specificpenicillin-binding protein that has a reduced affinity forβ-lactam antibiotics (PBP2a) [11], encoded by the mecA gene,which is carried on a chromosomal genetic elementdesignated SCCmec [12].

Methicillin-resistant staphylococcal (MRSA) infections arenow the aetiological pathogen for the majority ofhealthcare-associated infections [13]. There are an estimated1.5 million cases of hospital-acquired MRSA infection annuallyworldwide. Surveillance of 300 intensive care units throughoutthe US in 2002 demonstrated that 57.1% of all S. aureus isolatesobtained from their patients were methicillin resistant [14]. TheSENTRY data from 2001 reported that methicillin resistanceoccurred in 34% of clinical S. aureus isolates from the US, 26%from Europe and 24% in those from Australia [15]. Conse-quences for healthcare institutions include a higher mortality andcost per patient associated with MRSA infections versus thosedue to methicillin-susceptible S. aureus [16,17]. The burden ofdisease has persisted globally. However, significantly lower ratesof nosocomial MRSA are seen in some countries including Can-ada, Denmark, Sweden and particularly The Netherlands, due inpart to stringent adherence to infection control practices [18,19].

1.2 Financial implicationsStaphylococcal infections are not only responsible for significantmorbidity and mortality, but add a massive burden in terms of

the global health budget. A retrospective analysis of ∼ 14 millionin-patient stays from a stratified sample of 20% of hospitals inthe US in 2000 – 2001 determined that in-patients withS. aureus infection had on average three times the length of hos-pital stay and three times the total charges ($48,824 versus14,141) of patients without such infections [20]. In an Australianstudy, the estimated additional national hospital costs for theyear of 1998 resulting from S. aureus bacteraemia were$150 million [7]. Hospital-acquired infections (a significantproportion being MRSA) have been estimated to cost theNational Health Service in England £1 billion [21]. There is alsoa cost increment depending on the type of staphylococcalinfection. A study from the US in 2003 assessed patients withsurgical site infections and found that median hospital chargeswere $52,791 for those with methicillin-susceptible S. aureus(MSSA) infections, $92,363 for patients with MRSA infectionsand $29,455 for control subjects [22]. Similar findings have beendemonstrated for MRSA versus MSSA bacteraemia [23]. There-fore, control of endemic MRSA is likely to provide financialbenefits. One cost–benefit analysis demonstrated that an infec-tion control programme involving selective screening andisolation of carriers on intensive care unit admission costing$340 – 1480/patient became cost effective when the programmereached a 14% reduction in MRSA infection rate [24].

1.3 Community-associated MRSACommunity-associated MRSA (CA-MRSA) refers to isolatesof MRSA from patients who have not had significant contactwith the healthcare system in the prior 12 months, suggestingacquisition within the community [25]. The emergence ofCA-MRSA has serious implications for the empiric

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Expert Opin. Emerging Drugs (2007) 12(1) 3

management of patients with presumptive staphylococcalinfections in whom first-line therapy with β-lactams has beenstandard therapy, but may now lead to treatment failure.Although these MRSA strains were initially isolated frompatients with skin and soft tissue infection from thecommunity, nosocomial acquisition has now been reported inthe US [26]. Transmission and infection have been reported inthe context of adults and children subjected to crowding, suchas prison inmates, competitive athletes and military recruits,and in association with childcare and indigenous communities,generating a significant public health problem [27-30].

These isolates are resistant to β-lactam antibiotics, butcharacteristically retain sensitivity to tetracyclines,fluroquinolones, clindamycin and trimethoprim–sulfa-methoxazole (TMP–SMZ) [31]. First reported in the late1970s, when an epidemic occurred among intravenousdrug users in Detroit [32], CA-MRSA infections were laterreported in the early 1990s from Canada and WesternAustralia and subsequently from the eastern states ofAustralia, North America and Europe [4,33]. These strainsfrequently produce the virulence factor Panton–Valentineleukocidin (PVL) [33], which has been reported inassociation with necrotising pneumonia and severe skininfections, even in previously healthy persons [34].However, a recent study found that isogenic PVL-negativeCA-MRSA clinical strains (USA-300 and -400) were aslethal as wild-type strains in a mouse model of sepsis andthey caused comparable skin disease to PVL-positivestrains, thus suggesting this may not be as important avirulence determinant as previously suspected [35].

1.4 Other antimicrobial resistance in Staphylococcus aureusThe growing proportion of clinical isolates of S. aureusdisplaying multi-drug resistance not only against β-lactams,aminoglycosides and fluoroquinolones, but now alsoglycopeptides, has enhanced the need for development ofnovel antimicrobials, with activity against these strains.S. aureus harbours a number of resistance mechanisms thatgenerate this multi-resistance phenotype (Table 2). Strains thatare either heteroresistant (hVISA), intermediately resistant(VISA) or fully resistant to vancomycin have been described,which poses a significant clinical problem in the healthcaresetting [36-39]. hVISA or VISA strains have a thickened cellwall [40], although the underlying molecular mechanismsinvolved have not yet been clearly defined.Vancomycin-resistant S. aureus (VRSA) isolates have beenidentified in only six cases in the US so far, and have occurredafter transfer of the Tn1546 sequence from vanAvancomycin-resistant enterococcus to MRSA [41,42].

1.5 Prevention of infectionEarly studies of an S. aureus capsular vaccine bound torecombinant Pseudomonas aeruginosa exotoxin A werepromising, showing high levels of type-specific opsonising

antibodies in healthy adults [43]. Although there was a 64%decrease in bacteraemia seen in the first Phase III trial in endstage renal failure (ESRF) patients, the primary end pointwas not met, and no statistically significant difference wasseen in protection against infection during weeks 3 – 54 [44].A Phase III confirmatory trial was disappointing and failedto prevent S. aureus infections in haemodialysis patients,leading to vaccine development being halted [201].Encouragingly, other potential vaccine candidates are in theearly stages of development, ranging from preclinical studiesto Phase II trials.

1.6 Novel strategies for treating infectionNew strategies include the development of novelantimicrobial agents such as dalbavancin and televancin, andalternative approaches such as antistaphylococcalimmunoglobulins and antimicrobial peptides. For example,a recent Phase II trial of a humanised monoclonal antibody,tefibazumab, showed a trend to better outcomes in patientswith staphylococcal bacteraemia who received standardtreatment and tefibazumab versus standard care alone [45].Peptides derived from both insects and humans exert theireffect by interacting with bacterial cell membranes, andshow promise in animal studies [46,47]. The cathelicidinfamily of host defence peptides are associated with the sec-ondary granules of neutrophils, and in the laboratory canrapidly kill a broad range of microorganisms with a mecha-nism that appears to be mediated by recognition of mole-cular patterns at the microbial surface and subsequent stepsleading to loss of integrity of the microbial membranes. Aswith other host defence peptides such as defensins, whichhave been demonstrated to enhance cellular and humoralcytokine production and immune responses in mice, thisfamily of molecules provide a template for the developmentof novel therapeutic agents [48-50].

2. Medical need

There are several areas that need to be addressed in terms ofoptimisation of therapies for staphylococcal infections. Betterstrategies are needed for treatment of severe S. aureus infectionssuch as endocarditis [51], and those associated with prostheticmaterials and subsequent biofilm formation, which oftenrequire both prolonged therapy and removal of prostheticmaterial for cure [52]. Optimisation of approaches todecolonisation and development of effective immunotherapyand vaccination are further vital areas of need.

2.1 Novel antimicrobialsGlycopeptide resistance in MRSA isolates, which has beendriven by increased use of glycopeptides in line with rising ratesof nosocomial MRSA, has led to the need for newerantimicrobials that have activity against these strains. As it islikely that CA-MRSA will disseminate further worldwide, thismay potentially further increase the usage of vancomycin as

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Table 2. Antibiotic resistance in Staphylococcus aureus.

Antimicrobial[reference]

Resistance gene Resistance mechanism Epidemiology Implications

Methicillin[12]

mecA Altered penicillin-binding protein, PBP2a, with reduced affinity for β-lactams

Ubiquitous Widespread use of vancomycin

Cephalosporins mecA-

Altered penicillin-binding protein, PBP2a, with reduced affinity for β-lactams.Hydrolysis by type A β-lactamases

Ubiquitous Widespread use of vancomycin.Failure of cephalosporins in severe infections

Clindamycin[98]

erm Enzymes that methylate23S rRNA

Ubiquitous Failure of therapy if D-test is not performed on erythromycin-resistant isolates

Rifampicin[99]

Missense point mutations in rpoB

Encodes the bacterial DNA-dependent RNA polymerase inhibited by rifampicin

Ubiquitous Monotherapy should be avoided

Fusidate sodium[102]

fusA mutationsfusB acquisition (plasmid mediated)

Alter elongation factor G, preventing fusidate affecting its dissociation from the ribosome.Poorly characterised resistance mechanism

SporadicEpidemic

Monotherapy and topical use should be avoided

Ciprofloxacin[172]

gyrA mutationsnorA

Affects ciprofloxacin-mediated inhibition of bacterial DNA gyrase.Encodes membrane-associated active efflux pump

Widespread Diminished role in adjunctive treatment of S. aureus

Mupirocin[173]

mupA (ileS2) Modifies target enzyme isoleucyl-tRNA synthetase

Sporadic Failure to clear colonisation

Vancomycin -vanA

Thickened cell wall VISA, hVISA widespreadVRSA 6 cases

Clinical failures with serious infections

Linezolid G2576T/G2576U mutations in domain V 23S rRNA gene

Prevents inhibition of bacterial protein synthesis

10 cases reported May impact on treatment of hVISA

Quinupristin–dalfopristin[59]

ermvgbA + vgbBvatA, vatB, vatCvgaA + vgaB

Methylation of 23S rRNA.Hydrolysis of streptogramin B by lactonase.Acetyltransferase inactivation of streptogramin A.Efflux of streptogramin A

35 isolates in European SENTRY surveillanceNo clinical cases

Daptomycin[64]

- Thickened cell wall 8 clinical case reports6 resistant isolates in bacteraemia trial

High MIC values seen in MRSA with reduced susceptibility to vancomycin

D-test: Double-disk diffusion test; hVISA: Heteroresistant vancomycin-intermediate S. aureus; MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant S. aureus; VISA: Vancomycin-intermediate S. aureus; VRSA: Vancomycin-resistant S. aureus.

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empiric therapy in the treatment of staphylococcal infections innewly arrived hospital patients, and thus increase selective pres-sure for resistance. It is important to note, novel agents haveemerged that allow a therapeutic option for patients withglycopeptide-resistant isolates. Linezolid and quinupristin–dal-fopristin have been demonstrated to have microbiological andclinical efficacy against such strains, and have been used suc-cessfully both for targeted therapy in such cases, as well as inroutine treatment of MRSA infections [36,53-56]. However, thesafety profile of linezolid, particularly with prolonged therapy[57], and side effects of quinupristin–dalfopristin, as well as thedemonstrated emergence of resistance to these agents, meanother agents will be required in future [58,59]. For this reason,the judicious use of these agents should be practised. The neweragents, daptomycin and tigecyline, also add to the armamentar-ian, and have efficacy in certain clinical situations [60-63], but anoral formulation is not available, and concerns regarding earlyresistance in the former and high rates of nausea in the lattermay complicate their use [62-66]. Therefore, although we are notwithout options for difficult-to-treat infections at this stage,new antistaphylococcal agents must still be developed.

2.2 EndocarditisS. aureus endocarditis is a serious disease with a mortality of20 – 65% [51], which is on the increase worldwide [67]. Bothflucloxacillin and cephazolin have been used for cases causedby methicillin-susceptible strains, although clinical failures ofcephazolin treatment have been reported, associated withenzymatic hydrolysis of the antimicrobial by type Aβ-lactamases produced by some strains of S. aureus [68]. MRSAinfection was also one of a number of risk factors for death inpatients with endocarditis [69]. This is compounded by the factthat vancomycin has been the agent of choice for therapy, butin line with its demonstrable slower killing of S. aureus thanβ-lactams, significant clinical failure rates have beendocumented [70,71]. Therapeutic failures in MRSA infectionsand endocarditis have also been seen with newer agents such asteicoplanin, quinupristin–dalfopristin and linezolid [56,72,73].However, a recent review of all published case reports andseries also documented some success with linezolid in treatingendocarditis, although the length of follow up in many caseswas relatively short [53]. New bactericidal agents with theability to penetrate vegetations and biofilms, considering theassociation of implantable devices and prosthetic lines withendocarditis, are clearly needed.

2.3 BiofilmsBiofilm-associated infections are becoming more commonand occur because of the increasing use of indwelling andimplanted medical devices, including central venouscatheters. They are associated with serious infections such asendocarditis, osteomyelitis and septic arthritis, andparticularly with implanted devices such as prostheticjoints [74,75]. Once established, biofilm-related infections ofprosthetic devices are almost impossible to eradicate without

removal of the device [76]. In cases in which the infecteddevice cannot be removed, long-term antimicrobial therapyis often required to ‘suppress’ recurrent infection [77].Although active against free-living bacteria, vancomycindisplays poor activity against organisms embedded withinthe biofilm surrounding implanted devices [78]. Someantistaphylococcal agents, such as rifampicin, have activityagainst biofilm-associated organisms. However, resistancewill develop rapidly if it is not used in combination withother active agents. Drugs that could eradicatebiofilm-associated infections on prosthetic devices would bea significant advance in the treatment of S. aureus infectionsassociated with prosthetic material.

2.4 Prevention of infectionPrevention of infection in high-risk patients is a vital part of acommunity and hospital strategy to reduce the burden ofstaphylococcal infection. Clearance of colonisation whencarriage is identified is important in many situations: to preventstaphylococcal transmission; to prevent recurrent infection,such as repeated episodes of boils; or to prevent infections inhigh-risk situations, such as patients undergoing coronaryartery bypass grafts. Many healthcare institutions now usescreening for MRSA and decolonisation as part of their routineapproach to combating S. aureus infections [79-81]. Mupirocinremains the only topical agent used for clearance of MRSAcarriage, and the occurrence of mupirocin resistanceparticularly in outbreak situations is problematic, withinadequate clearance of colonisation reducing the efficacy ofother infection control strategies in preventing cross-trans-mission. [82]. Putative alternatives for clearance of colonisationinclude tea tree oil (Melaleuca alternifolia) and lysostaphin. Teatree oil has shown in vitro efficacy against MRSA andMSSA [83], but in a randomised, controlled trial versusmupirocin in 224 hospital in-patients [84], and in a secondsmaller study [85], no increased eradication of S. aureus versustraditional treatment was demonstrated. Thus, there is littleevidence for the first-line use of tea tree oil, although it mayhave a role in cases in which there is mupirocin resistance.Therefore, new agents are much needed, and those indevelopment include lysostaphin, a recombinant biologicalprotein cell-wall-synthesis inhibitor that has an intranasal andtopical formulation. In Phase II clinical trials, this agent met theend points for safety and microbiological activity.

2.5 ImmunotherapyThe final important area of medical need for S. aureusinfections is that of immunotherapy, for both prevention and,possibly, treatment of active staphylococcal disease.Development of an effective S. aureus vaccine is a goal thatcould substantially reduce the overall burden of staphylococcaldisease. Monoclonal and polyclonal humanised antibodiesagainst S. aureus are being investigated for use in the preventionof infection in high-risk patients and as adjuncts to antibiotictherapy for treating active infection. At present, four

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antistaphylococcal antibodies are under investigation, and onehas reached Phase III trials. The most promising vaccinecandidate so far, Staphvax® (Nabi Biopharmaceuticals), haddisappointing results in the Phase III trial stage, as previouslymentioned [44], which further delays the application ofvaccination as a strategy for the global prevention of S. aureusdisease. At this stage, the authors are aware of five vaccinecandidates being under development, ranging from preclinicalstudies to Phase II trials.

3. Existing treatment

Although the requirement for novel agents to treat resistantinfections has been partly met by the recent introduction ofnew drug classes such as oxazolidinones [86] andlipopetides [87], and modification of existing classes such asthe glycylcylines [88], better use of older antimicrobials mayalso assist in improving management of common conditionsand reserving newer drugs for severe infections. Preservationof the use of older antimicrobials can be assisted also by opti-mal dosing of existing agents, such as vancomycin. Usingalternative therapy to vancomycin where appropriate is alsoimportant, and the increase in CA-MRSA provides thisopportunity. When considering alternatives to glycopeptidetherapy in non-multi-resistant CA-MRSA, there is thepotential to use less complex, conventional antimicrobials,such as TMP–SMZ and clindamycin. However, this may bemost appropriate for skin and soft tissue infections [89], asthere has been has been very few series reporting treatmentoutcomes using these agents and no randomised clinical trialsconsidering their use in serious staphylococcal infections, suchas bacteraemia and pneumonia. One retrospective studydocumented clindamycin to be effective in 20 children withinvasive infections who had received this agent alone and 26who were initially treated with vancomycin or a β-lactamantibiotic [90]. However, increasing constitutive and inducibleclindamycin resistance in CA-MRSA means this agent shouldnot be used for therapy unless appropriate susceptibility test-ing has been performed [91]. Most isolates remain sensitive toTMP–SMZ, and this has been demonstrated to be effective inacute otitis media in children and used in the treatment ofskin and soft tissue infections in children [89,92], but there isno randomised, controlled trial evidence for use of this agentin invasive disease.

4. Therapeutic class review

Available antistaphylococcal agents are summarised in Table 3.

4.1 PenicillinsPenicillin and antistaphylococcal penicillin (cloxacillin, nafcillinand flucloxacillin) are bactericidal and exert theirantistaphylococcal effect by the inhibition of cell-wall synthesis.Few methicillin-sensitive S. aureus strains remain sensitive topenicillin. However, this remains the treatment of choice for

patients with disease caused by such isolates. For all othermethicillin-susceptible isolates an antistaphylococcal penicillin isthe antimicrobial of choice, although other agents including thecarboxypenicillins and ureidopenicillins have activity againstthese strains. Penicillins are more active against susceptiblestaphylococci than other cell-wall-active agents, such ascephalosporins and glycopeptides [51]. There is some evidencethat continuous infusion flucloxacillin is as effective asintermittent therapy, based on the principle that efficacy ofβ-lactams against pathogens such as MSSA is related to the timefor which serum drug concentration exceeds the minimuminhibitory concentration (MIC) for the pathogens [93].Flucloxacillin is occasionally associated with cholestatic jaundiceand can present up to 6 weeks after treatment [94].

4.2 CephalosporinsCephalosporins also inhibit cell-wall synthesis, and haveactivity against MSSA, with first- and fourth-generationcephalosporins being the most active. As discussed previously,cephalosporins, in particular cephazolin, can be hydrolysed bytype A β-lactamases produced by some strains of S. aureus [68]

and are not as bactericidal as penicillins against staphylo-coccus in vitro. These agents are not recommended asfirst-line treatment for severe infections, but may be used inless serious conditions such as skin and soft tissue infections;cephazolin twice daily with the addition of probenecid is aneffective parenteral regimen in this instance [95,96].

4.3 LincosamidesClindamycin exerts a bacteriostatic effect by inhibiting proteinsynthesis in S. aureus. It is useful in skin and soft tissue infec-tions caused by MSSA and CA-MRSA, and it has been used forthe treatment of invasive infections in the latter in children [90].However, CA-MRSA may demonstrate resistance to this agent,with a recent study from 11 US emergency departments dem-onstrating overall resistance in 5% of isolates (3% constitutive,2% inducible), although resistance rates of 60% were seen insome regions [97]. Inducible resistance is caused by the presenceof the erm gene (erythromycin resistance methylase), whichencodes enzymes that methylate the 23S rRNA. This isexpressed in the presence of strong inducers of methylase syn-thesis such as erythromycin and azithromycin. Lincosamidesare only weak inducers of methylase synthesis, so inducibleresistance is not detected by routine susceptibility testing andrequires the use of the double-disk diffusion test (D-test) [98].An advantage is that clindamycin has also been shown to havesome ability to disrupt biofilms. Unfortunately, clindamycin isnotable for causing antimicrobial associated diarrhoea,particularly with longer-term therapy.

4.4 Rifamycins and fusidate sodiumRifampicin inhibits nucleic acid synthesis in MSSA andMRSA and has the advantage of being bactericidal with goodintracellular penetration. It should be used in combinationwith other agents to prevent the development of resistance,

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which occurs through the selection of resistant mutants fromS. aureus strains [99]. Importantly, vancomycin does notprevent emergence of rifampicin resistance when used incombination [100]. Its major role is in prolonged combinationtherapy for osteomyelitis and as adjunctive therapy forendocarditis. The major disadvantage of rifampicin is that it isan inducer of CYP enzymatic activity, which may lowerplasma concentrations of other drugs to subtherapeutic levels.Liver dysfunction and thrombocytopenia are common and,therefore, baseline full blood count and liver function testsshould be taken and repeated during therapy.

Fusidate sodium is very active against both MSSA andMRSA isolates. Resistance develops quickly when this is used asa sole agent [101,102], so it is recommended for use systemically,in combination with other agents, usually with rifampicin inthe context of prolonged therapy for osteomyelitis or prostheticjoint or material infections [102]. Topical use has resulted infusidic acid resistant MSSA [102,103].

4.5 FluoroquinolonesCiprofloxacin is the fluoroquinolone traditionally used as anadjunctive treatment with other agents for S. aureus infection,and gains its activity from inhibiting nucleic acid productionin the bacterium. It is active against MSSA and MRSA, butsusceptibility testing must be performed before it is used foreither community-acquired or hospital-acquired MRSA,particularly as resistance is widespread in the latter. Newerfluoroquinolones such as gatifloxacin and moxifloxacin withC8 substitutions appear to be more potent against S. aureusthan are older agents of this class [104]. Of note, there isepidemiological data demonstrating that exposure toquinolones is a risk factor for the isolation of MRSA [105].

4.6 Trimethoprim–sulfamethoxazole Sulfamethoxazole is combined with the dihydofolate reductaseinhibitor trimethoprim, and is active against both MSSA andsusceptible isolates of MRSA, but is not bactericidal against all

Table 3. Presently available antistaphylococcal agents.

Antimicrobial Market share ($) Notable adverse effects

Advantages Disadvantages

Antistaphylococcoal penicillins (e.g., flucloxacillin)

> 4 billion RashJaundice

Greater efficacy than other cell-wall-active agents

Widespread resistance

Cephalosporins > 4 billion Rash Alternative to flucloxacillin when non-immediate hypersenitivity reported

Clinical failures reported in severe infections

Clindamycin Diarrhoea Use for MSSA and CA-MRSA

Inducible resistance

Rifampicin Abnormal LFTs Bactericidal Rapid resistance with monotherapy

Fusidic acid Nausea Role in combination therapy

Rapid resistance with monotherapy

Fluoroquinolones > 4 billion – Newer agents active – role in adjunctive therapy

Widespread resistance to ciprofloxacin

Trimethoprim–sulfamethoxazole

RashBlood dyscrasias

Role in skin and soft tissue CA-MRSA

Lack of evidence in invasive infections

Vancomycin Red man syndrome Not bactericidal – increasing resistance

Linezolid Blood dyscrasiasPeripheral neuropathySerotonin syndrome

Active againstglycopeptides-resistant isolatesIV + oral

Toxicity with prolonged use

Quinupristin–dalfopristin - Active againstglycopeptide-resistant isolates

IV formulation onlyInhibits CYP3A4 enzyme system

Daptomycin Myopathy BactericidalActive against linezolid-resistant strains

Inhibited by pulmonary surfactant

Tigecycline Nausea Broad spectrum Lack of antipseudomonal activity

CA-MRSA: Community-associated methicillin-resistant Staphylococcus aureus; IV: Intravenous; LFT: Liver function test; MSSA: Methicillin-susceptible S. aureus.

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strains. It has a newly appealing niche in the treatment of skinand soft tissue infections associated with community-onsetMRSA [89], but its role as a sole agent for invasive infectionremains to be determined. Results from an older randomisedcomparative trial of treatment with vancomycin versusTMP–SMZ for treatment of S. aureus infections are of con-cern in reference to this point. The study was conducted in101 intravenous drug users, of whom 65% of patients werebacteraemic. The results were not definitive, with vancomycinsuperior in efficacy in the patients with MSSA, but not MRSAinfections, and this agent had a lower rate of adverse eventsthan TMP–SMZ [106]. Significant adverse effects, especiallyrashes and blood dyscrasias, can limit the use of TMP–SMZ,particularly in the elderly.

4.7 MupirocinMupirocin is the only presently available topical anti-staphylococcal agent indicated for clearance of nasal colonisa-tion, and should be used for this indication in combinationwith an antiseptic wash containing triclosan 1%. It has provedefficacy for this indication [107], and long-term intranasalmupirocin in MRSA carrier patients with long hospital stayhas recently been shown to decrease acquired carriage andMRSA infections [108]. Mupirocin resistance has remaineduncommon worldwide, but outbreaks of clonal andplasmid-mediated spread of high-level mupirocin resistancehave been documented [82,109]. Mupirocin is generally welltolerated. Local reactions are uncommon and systemichypersensitivity is extremely rare.

4.8 GlycopeptidesVancomycin is active against S. aureus through inhibition ofpeptidoglycan synthesis. In clinical use it has been associatedwith a slower clinical response and longer duration of MSSAbacteraemia than β-lactam therapy [110]. Failure of therapy hasbeen noted as a predictor of heterogenous vancomycinresistance, and VISA and vancomycin-resistant S. aureus haveemerged, particularly during failed antibiotic therapy[41,42,111,112]. The newer glycopeptide teicoplanin has a similarspectrum of activity to vancomycin, but has not been widelyevaluated in comparative trials. It may have a role in patientswho have mild reactions to vancomycin and causes less redman syndrome, but should not be used in patients with severevancomycin reactions, due to crossreactivity. Recently,semisynthetic glycopeptides including dalbavancin andtelevancin have been developed that appear to have greaterefficacy than conventional glycopeptides [113].

4.9 OxazolidinonesLinezolid was the first oxazolidinone antibiotic approved forclinical use and has activity against glycopeptide-resistantMRSA and vancomycin-resistant enterococci (VRE). It inhibitsbacterial protein synthesis by preventing the formation of the70S initiation complex by binding to the 50S ribosomalsubunit [86]. It has the advantage of 100% oral bioavailability

and although bacteriostatic, has demonstrated efficacy incommunity and nosocomially acquired pneumonia and skinand soft tissue infections [55,114]. Linezolid appears to be the bestalternative to vancomycin in treating nosocomial pneumoniacaused by MRSA, compared with quinupristin–dalfopristin,where the efficacy is modest, and daptomycin, which isinactivated by pulmonary surfactant and has reducedpenetration into lung tissue [115,116]. A recent trial foundnon-inferiority of linezolid when compared with vancomycinfor treatment of neutropenic sepsis, although this was not anintention-to-treat analysis [117]. In terms of adverse reactions,duration-dependent thrombocytopenia and anaemia wereidentified, initially at low rates from the Phase III trials, andsubsequently at higher rates in several case series [57].Postmarketing surveillance has revealed the potential forperipheral neuropathy to develop with prolonged use oflinezolid and, rarely, serotonin syndrome when linezolid is usedin combination with serotonergic agents [118]. Of concern,linezolid resistance has been reported in MRSA, albeit rarely,from as early as 2001, and recently was identified in 4% of 1680coagulase-negative staphylococcal isolates surveyed at a singleinstitution [58].

4.10 StreptograminsQuinupristin–dalfopristin, the first streptogramminantibiotic, has a similar spectrum of activity to linezolid, and isbacteriostatic against staphylococci. The formulation acts toinhibit protein synthesis at the bacterial 50S ribosome [119].Quinupristin–dalfopristin was approved by the FDA in 1999for use in the treatment of serious or life-threatening infectionsassociated with vancomycin-resistant Enterococcus faecium andcomplicated skin and skin structure infections caused byMSSA and group A streptococcus. It has been demonstratedto have comparable clinical success to cephazolin, oxacillinand vancomycin, in the management of hospitalised patientswith complicated Gram-positive skin and skin structure infec-tions in two randomised, open-label clinical trials, although ahigher frequency of adverse events often necessitated prema-ture discontinuation [120]. Comparable outcomes versusvancomycin in S. aureus or coagulase-negative staphylococcalbacteraemia were found in one very small study of infectionsrelated to intravascular catheter-related infections [121].Equivalence to vancomycin in the treatment of nosocomialpneumonia was suggested in a Phase III, prospective, ran-domised study [122]. Two disadvantages of quinupristin–dalfo-pristin are that first, this agent significantly inhibits theCYP3A4 enzyme system, and will increase plasma concentra-tions of drugs metabolised by this system, and second, only anintravenous formulation of the drug is available. An advantageis that the dosage does not need to be modified in patientswith renal impairment.

4.11 DaptomycinDaptomycin is a novel semisynthetic cyclic lipopeptide that isbactericidal against Gram-positive bacteria, through causing

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alterations in cell-membrane electrical charge and transport[87]. It has the advantages of an oral and intravenous formula-tion and its spectrum includes activity against Gram-positiveaerobes and anaerobes, including vancomycin- and line-zolid-resistant strains, and in vitro has synergy with rifampicin[123,124]. However, S. aureus strains with reduced susceptibilityto vancomycin (MIC: 4 – 16 µg/ml) have been noted to alsohave high MIC values to daptomycin and documented treat-ment failures, including two cases of daptomycin-resistantMRSA bacteraemia, have occurred [65,66]. In clinical trials,daptomycin has been shown to have efficacy in skin and skinstructure infections with susceptible pathogens [60], but not incommunity-acquired or animal models of Gram-positivepneumonia, and has been shown to be inhibited bypulmonary surfactant in vitro [115]. A retrospective case seriesoutlined clinical success with the use of daptomycin inendocarditis, for pathogens including MSSA, MRSA andVRE [125]. A recent large trial reported non-inferiority ofdaptomycin versus low-dose gentamicin and anantistaphylococcal penicillin or vancomycin, when used forthe treatment of both MSSA and MRSA bacteraemia andendocarditis [61]. However, as noted by Grayson [126], thestudy contained a heterogenous population, despite beingrandomised, was open-label, did not meet its enrolmentcriteria and found 6 of 19 daptomycin microbiologicalfailures had developed resistance. This suggests caution mustbe exercised with the use of this antimicrobial for severeinfections. Again, despite promising in vitro work showingthat as well as being bactericidal, daptomycin is active againststationary-phase bacteria in biofilms present on implants,authors of one series described concern regarding its efficacyin prosthetic joint infections, particularly when hardware isretained [127]. Notably, severe myopathy with hepaticimpairment and rhabdomyolysis during therapy has beendescribed in case reports [128,129].

4.12 GlycylcyclinesTigecycline is a novel, bacteriostatic glycylcycline approved bythe FDA in June 2005 for complicated skin and soft tissueinfections and intra-abdominal infections. It is structurallyrelated to minocycline and binds to the bacterial 30Sribosome, blocking the entry of transfer RNA [130]. Itsspectrum includes most Gram-positive pathogens includinghVISA and VRE and importantly, extended-spectrum β-lacta-mase-producing enterobacteriaceae [88]. Intravenous tigecylinewas demonstrated to be equivalent to a combination of vanco-mycin and aztreonam for complicated skin and skin structureinfection in a recent study [62]. Tigecycline was also found tobe non-inferior to imipenem/cilastin in terms of safety andefficacy for the treatment of complicated intra-abdominalinfections in a pooled analysis of Phase II and III double-blindtrials, and may potentially be considered an alternative toimipenem/cilastin and timentin in this clinical context [63].Unfortunately, in both of these major trials, tigecycline causedsignificantly higher rates of nausea and vomiting than the

comparator drugs, which may be a disadvantage for itstherapeutic use.

5. Current research goals

A number of strategies and research directions are required toaddress the ongoing issue of S. aureus infections on a globalscale. S. aureus still causes serious and often fatal infections,causes persistent colonisation and infection of biomedicaldevices, and is a continually moving target in terms ofdevelopment of antimicrobial resistance. Despite the recentrelease of a number of new antimicrobials onto the market thathave activity against S. aureus, including multi-resistant strains,resistance in clinical isolates has already been reported to theseagents. The major research goals at present, therefore, include:

• development of new antibiotics and other antimicrobialproducts to treat S. aureus infections, in particular seriousinfections such as bacteraemia and endocarditis

• more vigorous evaluation of the role of older antimicrobialagents for the treatment of some S. aureus infections(e.g., the role of cotrimoxazole and clindamycin, orcombinations of doxycycline, rifampicin and fusidic acid inthe treatment of non-multi-resistant CA-MRSA)

• improved use of existing agents to prevent further spreadand development of antimicrobial resistance

• improved strategies for S. aureus decolonisation• new agents or approaches to the management of prosthetic

device-related infections, in particular development ofagents with activity against S. aureus present in biofilms

• continuing development and evaluation of immune-basedapproaches to the prevention and management of S. aureusinfections

• further exploration of the potential role of novel agents(e.g., phage therapy, antimicrobial peptides) for treatmentof staphylococcal infections

6. Scientific rationale

6.1 Novel antimicrobialsThe availability of a number of S. aureus complete genomesequences has allowed new approaches to drug discovery anddevelopment for S. aureus, by defining novel drug targets forsmall molecules, and immunologicals [131]. The developmentof novel agents to treat S. aureus infections is required toaddress the issue of continued development of antimicrobialresistance, and because many available agents have side effectsthat may limit their use. In addition, a number of availableagents, although active, are not ideal for treating seriousS. aureus infections. For example, vancomycin, which hasbeen the mainstay of treatment for MRSA infections, is lessactive than β-lactams and has some limitations in themanagement of MRSA bacteraemia and endocarditis [70,71].The development of novel agents by modifying existing drugclasses has produced antimicrobials such as the semisynthetic

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glycopeptides, dalbavancin and televancin, which appear tohave improved efficacy and more convenient deliverycompared with conventional glycopeptides [113]. Newcephalosporins with broad-spectrum activity, includingagainst MRSA, are also under evaluation [132]. Developingeffective agents to facilitate decolonisation is also animportant area of research, as only one antibiotic (mupirocin)is marketed for this purpose. As discussed above, colonisationwith S. aureus is common, carries a risk of invasive infectionand can be associated with recurrent skin infections, whereeradication of colonisation is often difficult [133]. Improvedstrategies for decolonisation would aid infection controlinterventions to prevent infections and cross-transmission inhospitals, and help management of community patients withrecurrent staphylococcal infections. Present research effortsare focusing on agents inhibiting protein and cell-wallsynthesis that have topical and mucosal activity.

6.2 Evaluation of older antimicrobialsA number of effective antistaphylococcal antibiotics are alreadyavailable for which limited clinical trial data are available fortheir use in treating significant staphylococcal infections. Withthe recent global epidemic of CA-MRSA, with many strainsdemonstrating a non-multi-resistant phenotype, the role oforal antistaphylococcal agents such as clindamycin andcotrimoxazole in treating infections caused by these strains isbeing investigated as single agents in skin and soft tissueinfection and perhaps as adjunctive therapy in invasive disease.Evaluation of optimal dosing for many existing and newerantistaphylococcal agents is already underway and likely toprovide information to increase use and help prevent furtheremergence of resistance to these agents. For example, studieslinking the use of topical fusidate sodium monotherapy to theemergence of resistance in S. aureus help to provide evidence toreduce such use [102]. The use of mathematical models topredict optimal dosing with different antibiotics againstS. aureus is also being increasingly used [134].

6.3 Antimicrobial peptidesAntimicrobial peptides are part of the innate immune systemand are found on epithelial surfaces, in secretion fluids and inneutrophils, and thus form a first-line in host defence [135].The antibacterial effect of peptide analogues is due to theirinteraction with bacterial membranes, evidenced by theleakage of liposome-entrapped glucose [136]. The syntheticpeptide Dhvar-5, like most antimicrobial peptides, has a netpositive charge that allows it to disrupt and penetrate thenegatively charged target of bacterial cell walls, which differfrom the neutral cell membranes of animals, then attackintracellular organelles [137]. Antibacterial peptides have thebenefit of a low tendency to induce resistance because of theevolutionary difficulty in changing bacterial membranestructure [138], and can also target multi-resistant strains ofS. aureus. Different targets and delivery systems for thesepeptides are being explored.

6.4 Bacteriophage therapyBacteriophages are viruses that specifically infect and lysebacteria and are effective against multi-drug-resistantpathogenic bacteria, while theoretically having the addedadvantages of being able to mutate to respond tophage-resistant mutants, without affecting eukaryotic cells,so side effects are uncommon [139]. Phage therapy againstS. aureus has been shown to prevent abscess formation in arabbit model of wound infection [140], suppressS. aureus-induced lethality in a mouse model ofbacteraemia [141], and reduce staphylococcal numbers onhuman skin in a handwash solution [142]. Recently, theeffect of targeted drug-carrying phages on the growth ofS. aureus bacteria was evaluated using chloramphenicollinked to filamentous bacteriophages, and found to retardgrowth of the bacteria more than bacteriophages alone, thussuggesting these viruses may have a role in transportingantibiotics [143]. The major issues that need to be resolved atthis stage in order to allow a potential role for phagetherapy in combating human infection include the inactiva-tion of administered phages or lysis by a neutralisingantibody, appearance of resistant bacterial mutants andcapture and transfer of bacterial toxin genes by phages [139].In addition, concerns have been raised about penetration ofphages into tissues, and the fact that the susceptibility todifferent phages differs between different staphylococcalstrains. In fact, differences in phage susceptibility are thebasis of phage-typing systems for S. aureus [144].

6.5 BiofilmsInfections associated with biofilms are a very importantclinical problem, as the number of prosthetic devices (e.g.,joint replacements, cardiac pacemakers) being inserted isincreasing dramatically on a global scale. Research effortsaim to develop strategies and agents that are able toovercome the problem of infected prosthetic devices. Thepathogenesis of implant-associated infection involvesinteraction between the microorganisms (biofilmformation), the implant and the host [74]. These infectionsare difficult to treat due to the inherent antibiotic resistanceof the sessile bacteria, relating to a slow growth rate,production of extracellular polymeric substance, failure ofantimicrobials to penetrate the biofilm and the presence ofbiomaterials [52]. Even if an antimicrobial agent can killbacteria embedded in biofilms, the biofilm is not disruptedunless the extracellular matrix is also destroyed. Whereasdaptomycin has activity against stationary-phase bacteria inbiofilms, lysostaphin, a biological protein cell-wall synthesisinhibitor, has the ability to both disrupt biofilms anddestroy the extracellular matrix, while also being activeagainst planktonic staphylococci [145]. This enzyme isspecifically capable of cleaving the crosslinking pentaglycinebridges in the cell walls of staphylococci, which contain highproportions of pentaglycine. Because of this action, MRSAand VRSA are susceptible to this agent. The novel target of

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this agent is important, as it has been demonstrated thatconventional antimicrobial agents may not adequately killbacteria from disrupted biofilms [146]. For example, onestudy assessed the in vitro susceptibility of intact anddisrupted MRSA- and MSSA-associated biofilms tovancomycin, quinupristin–dalfopristin and linezolid. Theauthors found that bacteria in disrupted biofilms were asresistant as those in intact biofilms, which may help explaindifficulties with conventional treatment. Interestingly,quinuprisin–dalfopristin was more active than the other twoagents against cells of the disrupted biofilms and linezolidwas less active than vancomycin [52]. A new approach is theuse of an RNA III-inhibiting peptide, which interferes withS. aureus quorum-sensing mechanisms. Quorum-sensingsystems in staphylococci enable cell-to-cell communicationand regulation of numerous colonisation and virulence fac-tors based on cell density [147]. A study evaluating thispeptide found that it inhibited bacterial adherence to HaCatand HEP-2 cells and reduced adherence and biofilmformation on dialysis catheters in vitro [148]. Novel deliverysystems of conventional antibiotics such as liposomescontaining ciprofloxacin sequestered within a poly(ethyleneglycol)–gelatin hydrogel have also been shown in vitro toinhibit bacterial adhesion on catheter surfaces [149], but raisethe spectre of resistance emerging when used forprophylaxis. Hence, other compounds such as usnic acid, asecondary lichen metabolite possessing antimicrobialactivity against Gram-positive bacteria, are being trialledin vitro as part of novel delivery systems [74].

6.6 Immunotherapy: monoclonal antibodies and vaccinesAnother major and extremely important area of research focusis that of immunotherapy.

The concept of monoclonal antibodies as adjunctivetherapy to antibiotics in patients with staphylococcal shockhas held up in animal studies and Phase II trials, althoughsuccessful Phase III trials are yet to be completed. Vaccinedevelopment strategies had focused mainly onsurface-expressed polysaccharides, but are now evolving toconsider other staphylococcal targets [150]. Human trials arefocusing on high-risk populations such as dialysis patients,although the prevalence of S. aureus colonisation in thegeneral population supports the argument for universalimmunisation [150].

The virulence factors expressed by S. aureus include surfaceproteins that promote colonisation of host tissues and invasinsand toxins such as leukocidin, hyaluronidase and haemolysins[151]. Phagocytic engulfment is inhibited by the polysaccharidecapsule and protein A, and other important properties of theorganism are the production of coagulase, clotting factor andtoxins that are responsible for manifestations of severe disease.Toxins include superantigens such as toxic shock syndrometoxin and the enteroxins [152]. Viable targets for monoclonalantibodies include clumping factor A, the red blood cell

receptor CR1 and superantigens. Clumping factor is afibrin–fibrinogen binding surface protein expressed by moststrains of S. aureus, which promotes attachment to blood clotsand traumatised tissues, and its antagonism assists theprevention of bacterial adherence in vivo. ETI-211 (ElusysTherapeutics, Inc.) is a monoclonal antibody specific for thered blood cell receptor CR1 that is chemically linked to a sec-ond monoclonal antibody that targets S. aureus. After admin-istration, the heteropolymer rapidly binds organisms to redblood cells and immobilises them on the erythrocyte surfaceand facilitates their clearance and destruction via liver macro-phages. Aurograb is a recombinant antibody fragment thatbinds to the immunodominant cell surface antigen GrfA, astaphylococcal ATP-binding cassette transporter protein [2].

Superantigenic toxins (including SEA, B, C, D, E, G andtoxic shock syndrome toxin) stimulate T cells non-specificallywithout normal antigen recognition by binding directly toMHC class II complexes of antigen-presenting cells outsidethe conventional antigen-binding groove. This produces acytokine storm involving IL-2, IFN-α and TNF, which resultsin toxic shock syndrome [153]. Superantigen toxin antagonistsblock the action of the toxins prior to T-cell activation andhave potential both as monoclonal antibodies and vaccines. Asuperantigen toxin-targeting monoclonal antibody(TSS mAb, Callisto) is undergoing preclinical trials. A broadspectrum, low molecular weight vaccine, which opposed theaction of superantigenic toxins via inhibition of T helper 1cell activation, underwent animal trials in 1999 (YissumProject No. 11649, Yissum), but has not been furtherdeveloped. A newer approach has involved the production ofrecombinant staphylococcal enterotoxin B to form the basis ofa staphylococcal vaccine, which has induced an immuneresponse in mice, in the form of anti-staphylococcalenterotoxin B IgG and IgA antibodies (staphylococcalenterotoxin vaccine, DynPort Vaccine Company). There havebeen other vaccine targets investigated in preclinical studies,which have not reached clinical trials. These include S. aureusRNA III-activating protein, which activates thequorum-sensing molecule, RNA III. RNA III controls severalvirulence genes encoding exoproteins and cell-wall-associatedproteins [154]. Immunisation of mice with RNA III activatingprotein resulted in a significantly reduced mortality in treatedmice versus controls, following a challenge with S. aureus [155].Polysaccharide intracellular adhesin is the product of the icaoperon found in S. aureus and S. epidermidis, and a prepara-tion of this material has been reported to provide infectiousimmunity in mice, although there have been concerns aboutthe reproducibility of this work [150].

7. Competitive environment

7.1 Novel intravenous and oral antimicrobialsThe agents with antistaphylococcal activity in development atpresent are summarised in Table 4. Several novel antibiotics areunder development, with dalbavancin (Pfizer) being the closest

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Table 4. Competitive environment table for antistaphylococcal agents awaiting FDA approval or under active investigation

Compound Company Structure Indication Development stage

Mechanism of action

Dalbavancin Pfizer Lipoglycopeptide Catheter-related MRSA bloodstream infectionComplicated skin and skin structure infection

Awaiting FDA approval

Cell-wall-synthesis inhibitor

Televancin Therevance Lipoglycopeptide Complicated skin and skin structure infection

Phase III Pertubation of bacterial cell membrane and cell-wall-synthesis inhibitor

Iclaprim Arpida Diaminopyrimidine In vitro activity against MRSA

Phase III – IVPhase I – oral

Dihydrofolate reductase inhibitor

Oritavancin Targanta Glycopeptide Skin and skin structure infections

Phase III Cell-wall-synthesis inhibitor

PPI-0903 Cerexa Cephalosporin In vitro activity against MRSA

Phase II High affinity for PBP2a

Ceftobiprole Basilea; Johnson & Johnson

Cephalosporin In vitro activity against MRSA

Phase III High affinity for PBP2a

MK-2764/PTK-0796 Paratek Aminomethylcycline Gram-positive organisms including MRSA

Phase I – IVPreclinical – oral

Inhibition of protein synthesis – interacts with ribosome binding sites

DX-619 Daiichi Des-F(6)-quinolone In vitro activity against MRSA and VRSA

Phase I Interacts with type II topoisomerases – DNA gyrase and topoisomerase IV

Pleuromutilin GlaxoSmithKline Topical antistaphylococcal including mupirocin-resistant S. aureus

Phase III Protein synthesis inhibitor

Lysostaphin Biosynexus Recombinant biological protein

Topical antistaphylococcal

Phase II Cell-wall-synthesis inhibitor

REP-8839 Replidyne Synthetic chemical Topical antistaphylococcal agent

Phase II Methionyl tRNA inhibitor

HB-50 Helix Biomedix Antimicrobial peptide

Topical antistaphylococcal, including mupirocin- and vancomycin-resistant S.aureus

Preclinical Interaction with bacterial membrane

Tefibazumab Inhibitex Humanised monoclonal antibody

Staphylococcal bacteraemia

Phase II Binds clumping factor A

Aurograb Neutec Recombinant antibody fragment

Severe deep-seated staphylococcal infections

Phase III Intrinsic activity against staphylococci

ETI-211 Elusys Heteropolymer crosslinked monoclonal antibody

Antibiotic-resistant staphylococcal infections

Preclinical Not stated

MRSA: Methicillin-resistant Staphylococcus aureus; PBP: Penicillin-binding protein; VRSA: Vancomycin-resistant S. aureus.

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to FDA approval for clinical use. Dalbavancin is a new semisyn-thetic lipoglycopeptide, cell-wall-synthesis inhibitor, with anintravenous formulation. It has better activity in vitro than van-comycin and teicoplanin against MRSA, S. pneumoniae, coagu-lase-negative staphylococci and vancomycin-susceptibleenterococci, but no activity against VRE possessing the vanAgene [113]. An advantage is that it has a long eliminationhalf-life, allowing an appealing dosage regimen of once-weeklyadministration [156]. In a rabbit model, there was a trend toimproved efficacy against S. aureus when compared withvancomcyin [78]. In a Phase II open-label clinical trial, dalba-vancin was superior when compared with vancomycin in treat-ing catheter-related bloodstream infection including thosecaused by MRSA, although most of the isolates werecoagulase-negative staphylococci [157]. After a successfulPhase II trial [158], a Phase III clinical study demonstratednon-inferiority of dalbavancin versus linezolid for the treatmentof complicated skin and skin structure infections [159].

Televancin (Theravance, Inc.) is also a novel lipoglycopeptidewith a similar spectrum to dalbavancin and exhibitsconcentration-dependent bactericidal effects. It acts by causingperturbation of the bacterial cell membrane as well as inhibitingcell-wall synthesis. This agent was effective in a Phase II clinicaltrial with complicated skin and soft tissue infection [160], and isin Phase III development.

Other new compounds being investigated include the diami-nopyrimidine, dihydrofolate reductase inhibitor, iclaprim(Arpida, Ltd), which is primarily active in vitro against MRSA.An intravenous formulation is in Phase III development andPhase I work with an oral formulation has begun [2]. Another

glycopeptide with a long half-life in Phase III development isoritavancin (Targanta Therapeutics, Inc.), which demonstratedcomparable results to vancomycin in the treatment of skin andskin structure infections [161]. Two novel cephalosporins withhigh affinity for PBP2a and resulting activity against MRSAin vitro include PPI-0903 (Cerexa, Inc.) and ceftobiprole(Basilea Pharmaceutica AG; Johnson & Johnson Pharmaceu-tical Research & Development), which are in Phase II and IIIstudies, respectively [2]. MK-2764 (formerly PTK-0796), dis-covered by Paratek Pharmaceuticals and now being developed incollaboration with Merck and Co. Inc., is a broad-spectrumintravenous aminomethylcycline antibiotic derived from the tet-racycline family, which has demonstrated good activity in pre-clinical studies against Gram-positive organisms (eg. MRSA),Gram-negative bacteria and anaerobes and is undergoing PhaseI evaluation [162,202]. A potential shortcoming in recent drugdevelopment is the lack of orally bioavailable agents undergoingassessment. MK-2764/PTK-0796 fortunately is orally bioavail-able, and an oral formulation is in Phase I trials. Another poten-tial new oral candidate for MRSA infection is DX-619 (DaiichiSankyo Co. Ltd), which is a new des-F(6)-quinolone under-going Phase I study. This agent has demonstrable activityin vitro against methicillin- and quinolone-resistant S. aureusand, importantly, against VRSA [163].

7.2 Novel topical antimicrobialsNew topical antistaphylococcal agents include the promisingpleuromutilin (SB-275833, GlaxoSmithKline plc), a pro-tein-synthesis inhibitor with a novel mechanism of action,which demonstrated in vitro activity against staphylococci,

Altastaph Nabi Polyclonal antibody Prevention of staphylococcal infection

Phase I Not stated

Intercell vaccine Merck Biological protein Prevention of staphylococcal infection

Phase I Immunostimulant

6343 vaccine Callisto Biological protein Prevention of toxic shock syndrome

Preclinical Targets superantigens

Staphylococcal enterotoxinvaccine

DynPort Vaccine Company

Recombinant biological protein

Prevention of staphylococcal infection

Preclinical Promotes antistaphylococcal enterotoxin antibodies

Staphylococcus vaccine

BioSante Recombinant biological protein


Phase II Immunostimulant

Inh-2 Inhibitex, Wyeth Origin from bacterial cells


Preclinical Immunostimulant

Table 4. Competitive environment table for antistaphylococcal agents awaiting FDA approval or under active investigation (continued)

Compound Company Structure Indication Development stage

Mechanism of action

MRSA: Methicillin-resistant Staphylococcus aureus; PBP: Penicillin-binding protein; VRSA: Vancomycin-resistant S. aureus.

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including mupirocin-resistant strains and is now in Phase IIItrials [2]. Lysostaphin (Biosynexus, Inc.), a recombinant bio-logical protein cell-wall-synthesis inhibitor, met the endpoints for safety and microbiological activity in Phase II clini-cal trials for both intranasal and topical forms of this agent.REP-8839 (Replidyne, Inc.) is a topical methionyl tRNA syn-thetase inhibitor that showed activity in vitro against MSSAand MRSA; Phase II/III trials in MRSA are expected in 2006.

7.3 Antimicrobial peptidesAntimicrobial peptides provide an alternative therapeuticapproach to conventional antibiotics, but have yet to becomecommercially available for clinical use. The synthetic peptideDhvar-5, which is based on histatin-5 found in human saliva,has been investigated as a treatment for osteomyelitis, byincorporating this peptide into polymethylmethacrylate beadsand noting sustained release and retained activity against aclinical isolate of MRSA after 7 days [137]. The increasedsurvival rate of treated versus untreated mice challenged withlethal doses of MRSA demonstrated in vivo efficacy of apeptide based on the cyclin D,L-α peptide architecture [46].Several reports of antibacterial efficacy of insect oligopeptideshave been made based on in vitro assessments [164,165].However, in the first demonstration of in vivo efficacy,modified oligopeptides from the beetle Allomyrina dichotomawere noted to decrease the mortality of mice inoculated withMRSA [47]. HB-50 is a topical gel formulation of anantimicrobial peptide in the preclinical phase of developmentby Helix BioMedix, Inc. for prophylaxis of S. aureus woundinfections. It demonstrated activity against mupirocin- andvancomycin-resistant S. aureus.

7.4 ImmunomodulatorsA Phase II trial of a humanised monoclonal antibodytefibazumab (Inhibitex, Inc.), which binds clumping factor A,showed a trend to better outcomes in terms of mortality,relapse and sepsis severity progression, in patients withstaphylococcal bacteraemia who received standard treatmentand tefibazumab, versus standard care alone [45]. A largerPhase II trial in S. aureus bloodstream infections is planned.A genetically recombinant antibody fragment Aurograb®

(Neutec Pharma plc) has reached Phase III trials for theadjunctive therapy of staphylococcal infections. This antibodyfragment has intrinsic activity against staphylococci, whichimportantly includes VISA and strains showing high MICvalues to linezolid. It has synergistic activity with vancomycin,and will be assessed in combination with vancomycin versusthis antibiotic with placebo in patients with severe,deep-seated staphylococcal infections [203]. ETI-211 is aheteropolymer crosslinked monoclonal antibody underdevelopment for the treatment of antibiotic-resistant S. aureusinfections. In mice, it was effective as prophylaxis against alethal MRSA challenge. Phase I trials in healthy volunteersand in ESRF patients are expected in 2007. Altastaph® (Nabi)is a polyclonal antibody that showed appropriate safety and

response when trialled in 48 patients at risk of staphylococcalinfection, and a Phase II trial is expected in 2007. Finally,GlaxoSmithKline (anti-infectives, ID) and Callisto(TSS mAb) have monoclonal antibodies in the preclinical trialstage of development.

7.5 VaccinesDespite the setbacks encountered by Staphvax in Phase IIIclinical trials in terms of a decrease in vaccine efficacy after40 weeks, this initially promising agent may still undergofurther investigation by considering booster doses. It is possible,however, that the staphylococcal capsule alone may not be asufficient candidate for a vaccine [150]. It may be necessary toinclude other staphylococcal components in a vaccine for thisreason, and other novel vaccine candidates are being explored.A S. aureus vaccine (Intercell AG) is in Phase I development(Merck). The target is unspecified, but is not based on live orattenuated bacteria, and Phase II trials are expected over2006 – 2007. Another new vaccine candidate 6343 (Callisto),targeting superantigens to prevent toxic shock syndrome due tostaphylococcus, is in the preclinical stage of development. Inaddition, an inhaled recombinant staphylococcal enterotoxinvaccine (DynPort Vaccine Company) is in preclinical studies.A biodefence vaccine targeting S. aureus (BioSante) is in thePhase I/II trials stage. The Inh-2 vaccine (Inhibitex) with anundisclosed target is in preclinical trials. As it is likely thatmultiple virulence determinants are involved in most S. aureusinfections, and the organism does not rely on a single proteinproduct to establish disease manifestations, vaccines relying ona specific cellular component only, may permit organismevasion by modification of target expression [150]. Hopefully,the undisclosed targets of vaccines in development may includemultiple cellular components or those less susceptible tovariation in expression by S. aureus.

8. Potential development issues

The development of new antimicrobials is threatened bythe relatively low financial return on investment seen bylarge pharmaceutical companies with novel anti-infectiveagents [2]. This relates to both the fact that antibacterialsgenerally require short-course therapy versus agents used forchronic disease, and that as ‘life-saving’ medications theyare often subject to intensive price controls by regulatorybodies [166]. However, continued interest from major com-panies is required to ensure an adequate level of researchand development is performed to provide new therapies asresistance continues to emerge to established and newlyintroduced antibiotics. Financial issues can limit theopportunities for ‘in house’ research programmes totranslate promising research in animal models into clinicaltrials. A Harvard Medical School polysaccharide staphy-lococcal vaccine candidate was protective in mice chal-lenged with different strains of S. aureus, but did not reachclinical development.

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The transition from demonstrating in vitro to in vivo effect isnot always smooth and has principally plagued thedevelopment of vaccines and immunomodulators. Unexpectedeffects that are context specific can occur, such as the inhibitionof daptomycin by pulmonary surfactant and its subsequentinadequacy in the treatment of pneumonia [115]. Developmentof an intravenous hyperimmune polyclonal immunoglobulin,SA-IGIV, which prevented bacterial attachment andcolonisation, providing passive immunity, was discontinuedafter it did not meet the primary end point of prevention ofS. aureus infection in premature and low-birth-weight neonates(n = 2000) in a randomised, placebo-controlled, double-blindPhase III trial. This was disappointing as SA-IGIV had beenmore effective in combination with vancomycin thanvancomycin alone in sterilising valvular vegetations and clearingbacteraemia in a rabbit model of catheter-induced aortic valveendocarditis. The capsular vaccine (Staphvax) failed todemonstrate efficacy in its Phase III trial of ESRF patients withS. aureus bacteraemia, despite showing high levels oftype-specific opsonising antibodies in healthy adults [43].Vaccine efficacy may be affected by the complex virulencemechanisms of S. aureus allowing the organism to evade hostimmune responses even when demonstrable pre-existingantibody levels are present.

Unexpected adverse events are an important reason forarrested drug development, although there have beenexamples in which companies have ceased the clinicaldevelopment of an agent, and another company latercompletes clinical trials and receives FDA approval. One suchexample is daptomycin, whose clinical development wasceased by Lilly Research Laboratories in 1991 due to reportsof potential skeletal muscle toxicity, but resumed by CubistPharmaceuticals in 1997, and a safer dosage regimenestablished [167]. However, as previously described, there havebeen two concerning isolated reports of myopathy withclinical use.

9. Expert opinion and conclusion

S. aureus remains a major human pathogen, and continues toevolve and acquire antimicrobial resistance. A number ofolder and new antimicrobials with good activity againstS. aureus are available, but at least some resistance has beendocumented for all agents. We have not reached the stagewhere we are faced with medically untreatable staphylococcalinfections, but this remains a threat in future if developmentsin pharmacotherapy do not precede the development ofresistance to existing drugs. Many of the existingantimicrobials have some limitations, either in terms ofefficacy or side-effect profile.

The use of recently approved antistaphylococcal agents isthreatened by their widespread use, which enhances

selective pressure for resistance to develop. We wouldfavour limiting use of newer agents to situations in whichresistance to older agents is confirmed or suspected, orwhere newer agents are thought to be clinically superior.For example, despite demonstrated equivalence of agentssuch as linezolid and tigecycline with vancomycin in skinand skin structure infections, it may not always be appro-priate to use the new, broad-spectrum agents, when theolder antimicrobial may be adequate. In our institution, wehave reserved the use of linezolid for situations in whichthere is evidence of glycopeptide resistance in MRSAstrains, failure of glycopeptide therapy, or a clear contra-indication to glycopeptide therapy or intravenous anti-microbial administration. This proposed need to limit theuse of new agents and preserve their use is obviously mademore difficult because of pressure from pharmaceuticalcompanies to promote increased use and, therefore, recouptheir significant financial investment.

There remains a medical need for the development of newagents with rapid bactericidal activity against multi-resistantS. aureus strains and good safety profiles, as well as agents withgood oral bioavailability. As always, the role of infectioncontrol measures in preventing avoidable nosocomialinfections remains paramount, to reduce the MRSA diseaseburden. Newer strategies such as peptides and monoclonalantibodies look promising to provide an alternative toconventional pharmacotherapy, but require much more workbefore they are likely to be clinically useful.

The apparent failure of the staphylococcal capsular vaccinewas disappointing, and highlights the difficulties associatedwith developing a S. aureus vaccine. However, new vaccinecandidates are being developed, although further under-standing of the pathogenesis of staphylococcal infections willbe required in order to convert promising results from animalstudies into a successful human vaccine. Despite remainingelusive, the possibility of developing a global vaccinationstrategy against S. aureus is an attractive option for providinga more definitive solution to reducing the burden ofstaphylococcal disease.

Ultimately, in the short to medium term, S. aureus willcontinue to be a significant burden to human health,especially in hospitalised patients and those with prostheticmaterials, but also more commonly in the community withthe spread of virulent, antibiotic-resistant strains. S. aureuswill continue to adapt and persist despite efforts to control it,and further emergence of antimicrobial resistance is likely andwill provide challenges for control and treatment for manyyears to come. Prevention of disease may be achieved byimproved strategies for decolonisation and limitingcross-transmission in a subset of the community. Tosignificantly reduce the burden of S. aureus disease, aneffective vaccine is required.

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Websites

201. http://www.nabi.com/pipeline/clinicaltrials.php

202. http://www.paratekpharm.com

203. http://www.neutecpharma.com

AffiliationEmma J Bishop1 & Benjamin P Howden†2

†Author for correspondence1Austin Health, Infectious Diseases Department, Studley Road, Heidelberg, 3084, Victoria, AustraliaTel: +61 3 9496 6676; Fax: +61 3 9496 6677;E-mail: [email protected] Health, Infectious Diseases Department, Studley Road, Heidelberg, 3084, Victoria, Australia

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Documents

Treatment of Staphylococcus aureus infections: new issues, emerging therapies and future directions