Tobias Welte
email: welte.tobias@mh-hannover.de

Mathias W Pletz

Antimicrobial treatment of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) pneumonia: current and future options

Keywords:

Meticillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of nosocomial pneumonia. Inadequate or inappropriate antimicrobial therapy, often caused by antimicrobial resistance, is associated with increased mortality for these infections. Agents currently recommended for the treatment of MRSA pneumonia include vancomycin and linezolid in the USA, and vancomycin, linezolid, teicoplanin and quinupristin/dalfopristin in Europe.

Antimicrobials such as tigecycline and daptomycin, although approved for the treatment of some MRSA infections, have not demonstrated efficacy equivalent to the approved agents for MRSA pneumonia. Further agents lack data from randomised controlled trials (e.g. fosfomycin, fusidic acid or rifampicin in combination with vancomycin). Antimicrobial agents that have recently been approved or are being investigated as treatments for MRSA infections include the lipoglycopeptides telavancin (approved for the treatment of complicated skin and skin-structure infections in the USA and Canada), dalbavancin and oritavancin, the cephalosporins ceftobiprole and ceftaroline, and the dihydrofolate reductase inhibitor iclaprim. To be an effective treatment for MRSA pneumonia, antimicrobial agents must have activity against antimicrobial-resistant S. aureus, penetrate well into the lung, have a low potential for resistance development and have a good safety profile. Here, the available data for current and potential future MRSA pneumonia antimicrobials are reviewed and discussed.

A c c e p t e d M a n u s c r i p t

Introduction

Pneumonia is a common infection in communities and healthcare facilities, with mortality rates as high as 76% reported under some circumstances in ventilated patients [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF][START_REF] Chastre | Ventilator-associated pneumonia[END_REF]. Currently accepted categories of pneumonia include community-acquired pneumonia (CAP) and nosocomial pneumonia, the latter encompassing healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). CAP is defined as pneumonia occurring outside of the hospital or within 48 h of hospital admission in patients with no prior contact with the healthcare system. HCAP is defined as pneumonia acquired outside of the hospital by patients with certain risk factors for infection with pathogens of nosocomial origin [START_REF] Friedman | Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections[END_REF][START_REF] Kollef | Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia[END_REF]. Patients are required to have at least one of the following risk factors for a diagnosis of HCAP: hospitalisation for >2 days in the previous 90 days in an acute care facility; residence in a nursing home or other long-term care facility; previous antibiotic therapy, chemotherapy or wound care in the previous 30 days; haemodialysis in a hospital or clinic; home infusion therapy or wound care; or a family member infected with a multidrug-resistant (MDR) pathogen [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF]. HAP is defined as pneumonia occurring after 48 h following hospital admission and, similarly, VAP is defined as pneumonia occurring at least 48 h after endotracheal intubation [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF].

Nosocomial pneumonia is associated with increased disease severity, mortality, length of hospital stay and hospital costs compared with CAP [START_REF] Kollef | Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia[END_REF].

HCAP is more similar to HAP and VAP in terms of causative organisms, A c c e p t e d M a n u s c r i p t 4 treatment requirements and prognosis than it is to CAP [START_REF] Kollef | Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia[END_REF]. A distinction can also be made between early-onset and late-onset nosocomial pneumonia, with late-onset infections (≥5 days of current hospitalisation) more likely to be caused by MDR pathogens [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF]. Additional risk factors for infection with MDR pathogens are antimicrobial therapy in the previous 90 days, current hospitalisation of at least 5 days, high frequency of antibiotic resistance in the community or hospital unit, presence of risk factors for HCAP, or immunosuppressive disease and/or therapy [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF].

Potential pathogens and recommended empirical antimicrobial therapies for nosocomial pneumonia, according to the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) 2005 guidelines [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF], are shown in Table 1. Other more recent guidance includes the 2008 UK HAP treatment guidelines [START_REF] Masterton | Guidelines for the management of hospital-acquired pneumonia in the UK: report of the Working Party on Hospital-Acquired Pneumonia of the British Society for Antimicrobial Chemotherapy[END_REF] and the wider European perspective of HAP published in 2009 [START_REF] Torres | Defining, treating and preventing hospital acquired pneumonia: European perspective[END_REF]. As the ATS/IDSA guidelines are the most widely accepted worldwide, these guidelines have been selected as the basis for further discussion. An update of the ATS/IDSA 2005 guidelines is expected in 2010. As the causative pathogen is rarely identified before antimicrobial therapy is initiated, the relevance of the categorisation of pneumonia is to guide prompt administration of an appropriate (pathogen is susceptible) and adequate (high enough level of drug at the site of infection) empirical antimicrobial treatment [START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF].

Inadequate (insufficient level of agent at the site of infection), inappropriate (pathogen resistant to agent) or delayed antimicrobial therapy is associated A c c e p t e d M a n u s c r i p t 5 with increased pneumonia mortality [START_REF] Iregui | Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilatorassociated pneumonia[END_REF][START_REF] Kollef | Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients[END_REF][START_REF] Luna | Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia[END_REF] as well as increased length of hospital stay and costs [START_REF] Shorr | Inappropriate therapy for methicillinresistant Staphylococcus aureus: resource utilization and cost implications[END_REF]. Antimicrobial resistance is thought to be an important determinant of inadequate or inappropriate antimicrobial administration. Kollef et al. [8] demonstrated by multiple logistic regression analysis that inappropriate antimicrobial therapy was independently associated with prior administration of antibiotics (thought to result in subsequent infection with drug-resistant pathogens) in Intensive Care Unit (ICU) patients. Furthermore, this same study demonstrated that patients infected with meticillin-resistant Staphylococcus aureus (MRSA) were more likely to receive inappropriate antimicrobial therapy [START_REF] Kollef | Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients[END_REF]. Similarly, increasing vancomycin minimum inhibitory concentrations (MICs) have been associated with administration of inadequate antimicrobial therapy and increased mortality due to MRSA bacteraemia [START_REF] Lodise | Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin[END_REF][START_REF] Soriano | Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia[END_REF].

Staphylococcus aureus is a major cause of HCAP, HAP and VAP, and increasingly CAP in some countries, particularly the USA [START_REF] Hidron | NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 20062007[END_REF]. Staphylococcus aureus is uniquely problematic due to its ubiquity, expression of virulence factors and high frequency of resistance to many antimicrobial agents [START_REF] Styers | Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States[END_REF].

Staphylococcus aureus was the only pathogen that correlated with mortality in a multiple logistic regression analysis carried out in a large retrospective cohort study of inpatients with culture-positive pneumonia in the USA [START_REF] Kollef | Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia[END_REF].

MRSA is growing in prevalence and is now endemic in many healthcare facilities and communities [START_REF] Klein | Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 19992005[END_REF]. In 2003, >60% of S. aureus isolates from US ICUs were meticillin-resistant [START_REF] Klevens | Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 19922003[END_REF]. In Europe, there is a North to South trend in the proportion of S. aureus that is meticillin-resistant, ranging from 0% in A c c e p t e d M a n u s c r i p t 6 northern European countries to >50% in more southern countries [START_REF]European Antimicrobial Resistance Surveillance System[END_REF]. Some strains of MRSA, particularly those of community origin [community-acquired MRSA (CA-MRSA)], produce the Panton-Valentine leukocidin (PVL) toxin, which is associated with necrotizing infections, often in previously healthy individuals [START_REF] Hidron | Emergence of community-acquired meticillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia[END_REF]. PVL-producing strains may become of increasing importance if CA-MRSA strains continue to invade the hospital setting but they will not be discussed further in this article in order to maintain a focus on nosocomial pneumonia in which PVL-producing strains are much less prevalent.

A summary of the antimicrobial agents currently approved for the treatment of MRSA pneumonia in the USA and Europe as well as those that may provide treatment options in the future can be found in Table 2 and are discussed further hereafter.

Antimicrobial agents approved for the treatment of MRSA pneumonia

Only vancomycin and linezolid are currently approved in the USA for the treatment of MRSA pneumonia. In some European countries, teicoplanin and quinupristin/dalfopristin (Q/D) are available in addition to vancomycin and linezolid for this indication.

Vancomycin

Vancomycin is a glycopeptide antibiotic that disrupts cell wall synthesis in Gram-positive bacteria by inhibiting peptidoglycan biosynthesis (Fig. 1). It is A c c e p t e d M a n u s c r i p t 7 generally considered slowly bactericidal. Although currently the treatment of choice, there are limitations of vancomycin for the treatment of pneumonia and other serious infections caused by MRSA [START_REF] Kollef | Limitations of vancomycin in the management of resistant staphylococcal infections[END_REF]. Vancomycin has been shown to be less effective than -lactams for the treatment of meticillinsusceptible S. aureus infections [START_REF] Chang | Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study[END_REF][START_REF] González | Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms[END_REF][START_REF] Lodise | Impact of empirical-therapy selection on outcomes of intravenous drug users with infective endocarditis caused by methicillin-susceptible Staphylococcus aureus[END_REF][START_REF] Tice | Risk factors and treatment outcomes in osteomyelitis[END_REF]. In addition, vancomycin penetrates poorly into the lung at therapeutic doses, which is associated with pneumonia treatment failure despite in vitro susceptibility of the bacterial isolates [START_REF] González | Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms[END_REF][START_REF] Cruciani | Penetration of vancomycin into human lung tissue[END_REF][START_REF] Scheetz | Potential impact of vancomycin pulmonary distribution on treatment outcomes in patients with methicillin-resistant Staphylococcus aureus pneumonia[END_REF].

Combining vancomycin with rifampicin, fusidic acid or fosfomycin is theoretically effective for the treatment of MRSA pneumonia although data from randomised controlled (RCTs) trials are lacking. A recent study of 93 patients in South Korea demonstrated that vancomycin plus rifampicin was more effective in the treatment of MRSA nosocomial pneumonia than vancomycin alone [START_REF] Jung | Effect of vancomycin plus rifampicin in the treatment of nosocomial methicillinresistant Staphylococcus aureus pneumonia[END_REF]. Further clinical data are required to assess whether such therapy has clinical utility.

Vancomycin resistance is currently uncommon but seems likely to increase as use of this agent for the treatment of ever more frequent MRSA infections becomes more commonplace [START_REF] Appelbaum | The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus[END_REF]. Since the first documented clinical infection with vancomycin-intermediate S. aureus (VISA) in 1996 in Japan (Mu50) [START_REF] Hiramatsu | Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility[END_REF], clinical isolates have been observed throughout the world.

Vancomycin MICs have been observed to be increasing over time ('MIC creep') [START_REF] Steinkraus | Vancomycin MIC creep in nonvancomycin-intermediate Staphylococcus aureus (VISA), vancomycinsusceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 200105[END_REF][START_REF] Wang | Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period[END_REF], with increased rates of mortality and treatment failure seen in patients with bacteraemia caused by S. aureus with increased vancomycin A c c e p t e d M a n u s c r i p t 8 MIC values [START_REF] Lodise | Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin[END_REF][START_REF] Soriano | Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia[END_REF]. Staphylococcus aureus strains may also be 'tolerant' to vancomycin, defined as a MIC/minimum bactericidal concentration ratio of ≥32. This takes into account susceptible strains that show increased resistance to killing, potentially resulting in treatment failures [START_REF] May | Glycopeptide tolerance in Staphylococcus aureus[END_REF].

Susceptibility to vancomycin decreases under persistent exposure and improves upon removal of the selection pressure [START_REF] Aeschlimann | Analysis of vancomycin population susceptibility profiles, killing activity, and postantibiotic effect against vancomycin-intermediate Staphylococcus aureus[END_REF][START_REF] Boyle-Vavra | Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates[END_REF], such that increased use of vancomycin to treat escalating MRSA infections will intuitively lead to more resistance.

Complete resistance to vancomycin is conferred by the vanA determinant, first detected in 1988 in a vancomycin-resistant enterococci (VRE) isolate [START_REF] Leclercq | Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium[END_REF]. In vitro studies have shown that vanA has the capacity to be transferred from VRE to S. aureus by naturally occurring horizontal gene transfer, thus creating a vancomycin-resistant S. aureus (VRSA) [START_REF] Noble | Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus[END_REF]. In 2002, the first vanAcontaining VRSA was isolated from a dialysis patient in Michigan, USA [START_REF] Chang | Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene[END_REF]; such isolates have since been detected throughout the world although the incidence remains low.

Vancomycin is frequently combined with -lactam antimicrobials. In 2002, a class of MRSA strains that developed vancomycin resistance in the presence of -lactam antibiotics [-lactam-induced vancomycin-resistant meticillinresistant S. aureus (BIVR)] were reported in Japan [START_REF] Haraga | Emergence of vancomycin resistance during therapy against methicillin-resistant Staphylococcus aureus in a burn patient-importance of low-level resistance to vancomycin[END_REF]. Although defined phenotypically, the mechanism of this acquired resistance is not yet understood. Up to 20% of MRSA strains in a further Japanese study exhibited A c c e p t e d M a n u s c r i p t 9 the BIVR phenotype [START_REF] Hanaki | Improved method of detection of -lactam antibiotic-induced VCM-resistant MRSA (BIVR)[END_REF]. Recent results indicate that BIVR may be associated with increased mortality in patients with MRSA bacteraemia [START_REF] Takata | Relationship between heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), -lactam induced vancomycin-resistance (BIVR), and outcome in MRSA bacteremia[END_REF].

Vancomycin is associated with nephrotoxicity and ototoxicity, although the frequency of these adverse reactions was higher in early reports and is attributed to the low purity of early formulations [START_REF] Levine | Vancomycin: a history[END_REF]. Nephrotoxicity due to vancomycin is of great concern owing to the contribution of acute kidney injury to poor clinical outcome in critically ill patients in the ICU, a population particularly vulnerable to MRSA infection [START_REF] Kielstein | Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study[END_REF][START_REF] Metnitz | Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients[END_REF][START_REF] Sesso | Prognosis of ARF in hospitalized elderly patients[END_REF][START_REF] Vinsonneau | Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial[END_REF]. Concurrent aminoglycosides and other known nephrotoxic agents are thought to increase the risk of nephrotoxicity during vancomycin therapy, in addition to medical conditions including sepsis, liver disease, obstructive uropathy and pancreatitis [START_REF] Rybak | Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists[END_REF]. Monitoring of trough serum vancomycin concentrations is recommended to reduce vancomycin nephrotoxicity in patients with unstable renal function or in those receiving aggressive or prolonged vancomycin therapy or concomitant nephrotoxic agents [START_REF] Rybak | Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists[END_REF].

Linezolid

Linezolid is approved for the treatment of nosocomial pneumonia in the USA and Europe, including cases caused by MRSA. In the USA it represents the only alternative to vancomycin for this indication. Linezolid is a synthetic oxazolidinone that prevents binding of the 30S and 50S ribosomal subunits, thus inhibiting the initiation of protein synthesis (Fig. 1 Two retrospective subgroup analyses of ventilated and non-ventilated patients with MRSA [START_REF] Kollef | Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin[END_REF][START_REF] Wunderink | Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia[END_REF] from nosocomial pneumonia clinical trials [START_REF] Rubinstein | Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study[END_REF][START_REF] Wunderink | Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia[END_REF] showed that linezolid-treated patients had higher survival and clinical cure rates than vancomycin-treated patients. It has been suggested that this may be due to the favourable intrapulmonary distribution of linezolid [START_REF] Conte | Intrapulmonary pharmacokinetics of linezolid[END_REF]. However, the viability and validity of these subset analyses has been questioned [START_REF] Powers | FDA evaluation of antimicrobials: subgroup analysis[END_REF][START_REF] Powers | Linezolid and vancomycin for methicillin-resistant Staphylococcus aureus nosocomial pneumonia: the subtleties of subgroup analyses[END_REF] such that further trials are required before linezolid can be recommended to be used preferentially over vancomycin for the treatment of MRSA pneumonia. A recent trial of patients with MRSA VAP failed to show statistical superiority of linezolid over vancomycin, although linezolid-treated patients had numerically better values compared with vancomycin-treated patients with respect to microbiological eradication (56.5% and 47.4%, respectively), clinical cure (66.7% and 52.9%, respectively), survival rate (86.7% and 70.0%, respectively), length of hospitalisation (18.8 days and 20.1 days, respectively), duration of ventilation (10.4 days and 14.3 days, respectively) and length of ICU stay (12.2 and 16.2 days, respectively) [START_REF] Wunderink | Early microbiological response to linezolid vs vancomycin in ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus[END_REF].

Resistance was first observed in a clinical S. aureus isolate in 2001 [START_REF] Tsiodras | Linezolid resistance in a clinical isolate of Staphylococcus aureus[END_REF], although the LEADER surveillance programme has shown that 99.55% of isolates remained susceptible to linezolid in the USA in 2006 [START_REF] Jones | LEADER surveillance program results for 2006: an activity and spectrum analysis of linezolid using clinical isolates from the United States (50 medical centers)[END_REF].

A c c e p t e d M a n u s c r i p t 11 Thrombocytopenia is a commonly observed adverse reaction to linezolid therapy, with occurrence rates of ca. 30% [START_REF] Attassi | Thrombocytopenia associated with linezolid therapy[END_REF][START_REF] Bishop | Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients[END_REF][START_REF] Orrick | Thrombocytopenia secondary to linezolid administration: what is the risk?[END_REF], a rate much higher than that reported in phase 3 trials [46]. Thrombocytopenia is more common following prolonged treatment (>14 days) and in patients with renal insufficiency [START_REF] Bishop | Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients[END_REF][START_REF] Lin | High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency[END_REF]. The inhibition of mitochondrial protein synthesis by linezolid can result in potentially severe clinical effects, including optic/peripheral neuropathy and lactic acidosis [START_REF] Vriese | Linezolid-induced inhibition of mitochondrial protein synthesis[END_REF]. These events are not frequently observed and are mostly reversible following termination of linezolid treatment, but there are reports of severe irreversible effects such as permanent blindness in patients treated for only a short time [START_REF] Azamfirei | Complete blindness after optic neuropathy induced by shortterm linezolid treatment in a patient suffering from muscle dystrophy[END_REF]. As a reversible, non-selective monoamine oxidase inhibitor, linezolid in combination with serotonergic agents has been associated with serotonin syndrome [START_REF] Lawrence | Serotonin toxicity associated with the use of linezolid: a review of postmarketing data[END_REF]. The linezolid licence recommends that treatment be restricted to a maximum of 28 days [46].

Teicoplanin

Teicoplanin is a glycopeptide with bactericidal activity against many Grampositive pathogens, including MRSA. It is approved for the treatment of lower respiratory tract infections, including those caused by MRSA, in some parts of Europe but not in the USA.

Linezolid was shown to be superior to teicoplanin for the treatment of suspected or confirmed Gram-positive infections (skin infections, pneumonia and bacteraemia) [START_REF] Wilcox | Linezolid compared with teicoplanin for the treatment of suspected or proven Gram-positive infections[END_REF] and equivalently effective for the treatment of Grampositive infections in the critically ill [START_REF] Cepeda | Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study[END_REF]. A retrospective analysis comparing A c c e p t e d M a n u s c r i p t 12 the two drugs also indicated the clinical superiority of linezolid over teicoplanin, with numerically better response to therapy (although not statistically significant) for S. aureus infections, including MRSA [START_REF] Tascini | Linezolid treatment for Gram-positive infections: a retrospective comparison with teicoplanin[END_REF].

Although there is evidence to suggest that the tissue penetration of teicoplanin may be better than that of vancomycin [START_REF] Drago | Serum and bone concentrations of teicoplanin and vancomycin: study in an animal model[END_REF], lung penetration may be suboptimal. A study in critically ill patients with VAP indicated that high teicoplanin doses are required to reach adequate trough concentrations in the lung [START_REF] Mimoz | Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia[END_REF]. In addition, owing to a common target in the bacterial cell wall, reduced susceptibility to teicoplanin in S. aureus manifests in the same way as that of vancomycin, and a general term for strains with reduced susceptibility to either agent is glycopeptide-intermediate S. aureus (GISA) [START_REF] Shlaes | Teicoplanin selects for Staphylococcus aureus that is resistant to vancomycin[END_REF].

Teicoplanin is generally considered to have a favourable safety profile compared with vancomycin, with lower risk of nephrotoxicity and reactions resulting from histamine release (such as red man syndrome). However, thrombocytopenia is more commonly observed during teicoplanin than vancomycin therapy, especially when administered at does higher than those normally recommended [START_REF] Svetitsky | Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis[END_REF][START_REF] Wood | Comparative safety of teicoplanin and vancomycin[END_REF].

Quinupristin/dalfopristin

Q/D consists of two streptogramin components; quinupristin inhibits late-stage protein synthesis whilst dalfopristin inhibits early-stage protein synthesis (Fig.

What drug attributes should antimicrobials for MRSA pneumonia possess?

New agents are urgently needed to expand the limited repertoire of available agents approved for the treatment of MRSA pneumonia. To be a useful agent to treat MRSA pneumonia, several characteristics are important. Activity against key pneumonia pathogens, including MRSA and other resistant strains, is essential (Table 1). Bactericidal activity would be preferable, as the rapid resolution of serious infections has many benefits. However, the importance of bactericidal versus bacteriostatic activity is still a matter of debate [START_REF] Finberg | The importance of bactericidal drugs: future directions in infectious disease[END_REF][START_REF] Pankey | Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections[END_REF]. The clinical outcome of respiratory infections is dependent on sustained antimicrobial concentrations at the site of infection [START_REF] Cazzola | Delivering antibacterials to the lungs: considerations for optimizing outcomes[END_REF], therefore it is important that the agent reaches microbiologically active concentrations in the relevant parts of the lung and is not inactivated by pulmonary surfactant.

Low nephrotoxicity is also important; many patients with MRSA pneumonia are critically ill in the ICU with multiple organ dysfunction. Antimicrobial-A c c e p t e d M a n u s c r i p t 14 induced nephrotoxicity resulting in acute kidney injury may contribute to poor clinical outcome in this population [START_REF] Kielstein | Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a randomized controlled study[END_REF][START_REF] Metnitz | Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients[END_REF][START_REF] Sesso | Prognosis of ARF in hospitalized elderly patients[END_REF][START_REF] Vinsonneau | Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial[END_REF]. As the use of agents with activity against MRSA looks certain to increase in the future, an agent with low potential for resistance development would be ideal.

Approved anti-MRSA agents not currently indicated for the treatment of MRSA pneumonia

Agents approved in some countries for the treatment of MRSA infections other than pneumonia that have potential utility for the treatment of MRSA pneumonia include tigecycline and telavancin. Daptomycin will not be discussed as although this agent has demonstrated good activity against MRSA it is inactivated by pulmonary surfactant in animal models [START_REF] Silverman | Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact[END_REF] and did not achieve non-inferiority to vancomycin in clinical trials of pneumonia [START_REF] Pertel | Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia[END_REF]. It is thus unlikely that daptomycin has clinical utility for the treatment of MRSA pneumonia.

Tigecycline

Tigecycline is a semisynthetic glycycline with antimicrobial activity (generally bacteriostatic) against a broad range of Gram-positive, Gram-negative and anaerobic pathogens, although it is ineffective against Pseudomonas aeruginosa [79]. Like the tetracyclines, tigecycline inhibits protein translation by binding the 30S ribosomal subunit, preventing peptide elongation (Fig. 1) [START_REF] Olson | Functional, biophysical, and structural bases for antibacterial activity of tigecycline[END_REF]. However, development of resistance in MDR Gram-negative bacilli and subsequent poor outcome has been observed in patients with infections treated with tigecycline [START_REF] Anthony | Clinical and microbiological outcomes of serious infections with multidrug-resistant Gram-negative organisms treated with tigecycline[END_REF]. Furthermore, in a phase 3 study, tigecycline (plus ceftazidime and aminoglycoside for P. aeruginosa coverage, if required) did not achieve non-inferiority to imipenem (plus an aminoglycoside and vancomycin for MRSA coverage, if required) for the treatment of HAP [START_REF] Maroko | Results of phase 3 study comparing a tigecycline regimen with an imipenem/cilastatin regimen in treatment of patients with hospital acquired pneumonia[END_REF]. This reflected the lower clinical cure rates for the subgroup of patients with VAP [47.9% for tigecycline vs. 70.1% for imipenem (per-protocol analysis) and 46.5% for tigecycline vs. 57.8% for imipenem (intent-to-treat analysis)] [START_REF] Maroko | Results of phase 3 study comparing a tigecycline regimen with an imipenem/cilastatin regimen in treatment of patients with hospital acquired pneumonia[END_REF].

Pharmacokinetic/pharmacodynamic studies in humans indicate that tigecycline has good penetration into alveolar cells but achieves only low levels in epithelial lining fluid (ELF) [START_REF] Burkhardt | Tigecycline possibly underdosed for the treatment of pneumonia: a pharmacokinetic viewpoint[END_REF][START_REF] Conte | Steady-state serum and intrapulmonary pharmacokinetics and pharmacodynamics of tigecycline[END_REF]. Such results indicate that tigecycline may potentially be underdosed for the treatment of pneumonia [START_REF] Burkhardt | Tigecycline possibly underdosed for the treatment of pneumonia: a pharmacokinetic viewpoint[END_REF]; effectiveness at higher doses is being investigated in ongoing trials, although the impact of such doses on tolerability needs to be carefully evaluated.

A c c e p t e d

M a n u s c r i p t 16

Telavancin

Telavancin is a bactericidal lipoglycopeptide derivative of vancomycin with a multifunctional mechanism of action, disrupting bacterial cell wall synthesis and membrane integrity (Fig. 1) [START_REF] Higgins | Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus[END_REF]. Telavancin has displayed good activity against clinically important Gram-positive pathogens, including MRSA, and has displayed rapid concentration-dependent bactericidal activity against S. aureus in time-kill studies [START_REF] King | Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with multiple mechanisms of action against Gram-positive bacteria[END_REF][START_REF] Pace | In vitro activity of TD-6424 against Staphylococcus aureus[END_REF]. As with other similar agents, telavancin does not have activity against Gram-negative pathogens and is less active against vanA-expressing strains of VRE [START_REF] Draghi | In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the 200405 Prospective European Surveillance Initiative[END_REF]. Telavancin has demonstrated good penetration into human ELF and alveolar macrophages, being present at concentrations greater than the MIC 90 (MIC for 90% of the organisms) for MRSA (0.5 g/mL) for the entire dosing interval, and Monte Carlo simulation has indicated that the levels of telavancin in ELF are ca. 75% of those in plasma [START_REF] Gotfried | Intrapulmonary distribution of intravenous telavancin in healthy subjects and effect of pulmonary surfactant on in vitro activities of telavancin and other antibiotics[END_REF][START_REF] Lodise | Telavancin penetration into human epithelial lining fluid determined by population pharmacokinetic modeling and Monte Carlo simulation[END_REF]. In a staphylococcal biofilm model, telavancin was more effective than vancomycin and teicoplanin, displaying bactericidal activity [START_REF] Gander | Telavancin: in vitro activity against staphylococci in a biofilm model[END_REF].

In phase 3 trials, telavancin demonstrated non-inferiority to vancomycin for the treatment of Gram-positive cSSSI [START_REF] Stryjewski | Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms[END_REF] and is approved in the USA and Canada for this indication. Preliminary data from phase 3 trials of Grampositive nosocomial pneumonia showed that clinical cure rates in clinically evaluable patients at test-of-cure visit were comparable for telavancin and vancomycin [82.7% and 80.9%, respectively; 95% confidence interval (CI) of difference in clinical cure rate -4.1 to 7.7] and were higher for telavancin than vancomycin in patients with MRSA pneumonia (81.8% and 74.1%, A c c e p t e d M a n u s c r i p t 17 respectively; 95% CI of difference -3.5 to 19.3) and VAP (80.3% and 67.6%, respectively; 95% CI of difference -1.8 to 26.8) [START_REF] Rubinstein | Telavancin for hospital-acquired pneumonia, including ventilatorassociated pneumonia: the ATTAIN studies[END_REF].

Telavancin has displayed low potential for resistance development in vitro and in vivo, potentially due to its unique dual mechanism of action [START_REF] Pace | In vitro activity of TD-6424 against Staphylococcus aureus[END_REF][START_REF] Hegde | Pharmacodynamics of telavancin (TD-6424), a novel bactericidal agent, against Gram-positive bacteria[END_REF]. The most common side effects reported for telavancin in the phase 3 cSSSI trials (>10% incidence) were taste disturbance, nausea, headache, vomiting and foamy urine, and in the phase 3 HAP trials (>8% incidence) were diarrhoea, renal impairment, anaemia, constipation and hypokalaemia [START_REF] Stryjewski | Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms[END_REF][START_REF] Rubinstein | Telavancin for hospital-acquired pneumonia, including ventilatorassociated pneumonia: the ATTAIN studies[END_REF]. Renal dysfunction was observed in 3% of telavancin-treated patients and 1% of vancomycin-treated patients in the cSSSI trials [START_REF] Stryjewski | Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by Gram-positive organisms[END_REF] and in 10% of telavancintreated patients and 8% of vancomycin-treated patients in the HAP trials [START_REF] Rubinstein | Telavancin for hospital-acquired pneumonia, including ventilatorassociated pneumonia: the ATTAIN studies[END_REF].

Potential new agents for the treatment of MRSA pneumonia

Agents with activity against MRSA that are currently at various stages of development and investigation for the treatment of pneumonia (and are thus not approved at present) include the lipoglycopeptides dalbavancin and oritavancin, the cephalosporins ceftobiprole and ceftaroline, and the dihydrofolate reductase (DHFR) inhibitor iclaprim.

Lipoglycopeptides: dalbavancin and oritavancin

Dalbavancin is a lipoglycopeptide derived from teicoplanin with Gram-positive activity [START_REF] Roecker | Dalbavancin: a lipoglycopeptide antibacterial for Gram-positive infections[END_REF]. Dalbavancin has the same mechanism of action as vancomycin (Fig. 1) but has a uniquely long half-life (5-7 days), which allows once-weekly A c c e p t e d M a n u s c r i p t 18 intravenous dosing as part of a two-dose regimen [START_REF] Roecker | Dalbavancin: a lipoglycopeptide antibacterial for Gram-positive infections[END_REF]. In vitro studies demonstrated that dalbavancin was bactericidal against S. aureus, including strains resistant to meticillin and strains with reduced susceptibility to vancomycin, although dalbavancin is inactive against pathogens possessing the vanA gene [START_REF] Roecker | Dalbavancin: a lipoglycopeptide antibacterial for Gram-positive infections[END_REF].

Dalbavancin demonstrated non-inferiority to linezolid for the treatment of cSSSI in phase 3 trials [START_REF] Jauregui | Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections[END_REF]. In these trials, the type and severity of adverse events were similar between the treatment groups, with the most frequent dalbavancin-associated adverse events being nausea, diarrhoea, elevated blood lactate dehydrogenase or -glutamyltransferase level, headache and vomiting [START_REF] Jauregui | Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections[END_REF].

There are no trials currently underway for dalbavancin for the treatment of pneumonia such that further data are required to assess the usefulness of dalbavancin for this indication.

Oritavancin is a semisynthetic lipoglycopeptide derivative of vancomycin. Like telavancin, oritavancin is thought to have a dual mechanism of action involving disruption of cell wall synthesis and membrane permeability (Fig. 1) [START_REF] Domenech | Interactions of oritavancin, a new lipoglycopeptide derived from vancomycin, with phospholipid bilayers: effect on membrane permeability and nanoscale lipid membrane organization[END_REF][START_REF] Kim | Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus[END_REF]. Oritavancin has demonstrated bactericidal activity against stationaryphase and biofilm S. aureus in vitro [START_REF] Belley | Oritavancin kills stationary-phase and biofilm Staphylococcus aureus cells in vitro[END_REF]. Drug concentrations in ELF indicate that oritavancin may need to be dosed more aggressively for the treatment of pneumonia [START_REF] Linden | Vancomycin resistance: are there better glycopeptides coming?[END_REF]. In phase 3 studies investigating oritavancin for the treatment of cSSSI, oritavancin demonstrated comparable efficacy to A c c e p t e d M a n u s c r i p t 19 vancomycin as well as a favourable safety profile. There are no pneumonia trials currently underway; further data are required to assess the usefulness of oritavancin in the treatment of pneumonia.

Cephalosporins: ceftobiprole and ceftaroline

Cephalosporins inhibit bacterial cell wall formation by binding penicillin-binding proteins (PBPs) and preventing peptidoglycan cross-linking in the cell wall (Fig. 1).

Ceftobiprole is a fifth-generation cephalosporin with activity against Grampositive and Gram-negative organisms. As ceftobiprole is structurally engineered to bind to PBP2a, as encoded by the mecA gene of -lactamresistant MRSA, it has bactericidal activity against MRSA [START_REF] Hebeisen | In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci[END_REF]. Ceftobiprole has similar activity to cefepime against P. aeruginosa [START_REF] Walkty | In vitro activity of ceftobiprole against clinical isolates of Pseudomonas aeruginosa obtained from Canadian intensive care unit (ICU) patients as part of the CAN-ICU Study[END_REF]. Ceftobiprole is thought to be stable against staphylococcal -lactamases but its activity does not cover extended-spectrum -lactamase (ESBL)-producing bacteria [START_REF] Hebeisen | In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci[END_REF].

Ceftobiprole demonstrated non-inferiority to vancomycin for the treatment of cSSSI in two phase 3 trials [START_REF] Noel | A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skinstructure infections[END_REF][START_REF] Noel | Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by Gram-positive bacteria[END_REF]. Ceftobiprole has also demonstrated non-inferiority to ceftriaxone, with or without linezolid, for the treatment of CAP requiring hospitalisation in phase 3 trials, with cure rates of 87% for ceftobiprole and 88% for the comparator agents [START_REF] Pharmaceutica | Ceftobiprole shows high cure rates in patients hospitalized with community-acquired pneumonia[END_REF][START_REF] Neuner | New antibiotics for healthcareassociated pneumonia[END_REF]. In a further phase 3 trial, ceftobiprole achieved non-inferiority for the treatment of HAP compared with ceftazidime plus linezolid (clinical cure in clinically evaluable patients 77% A c c e p t e d M a n u s c r i p t 20 for ceftobiprole and 76% for combination therapy), but was inferior for the treatment of ventilated patients; further analysis of this subset of patients is ongoing [START_REF] Neuner | New antibiotics for healthcareassociated pneumonia[END_REF][START_REF]Basilea announces positive top-line data from phase III study of ceftobiprole in hospital-acquired pneumonia[END_REF].

In serial-passage studies of ceftobiprole against MRSA, PBP2a-mediated resistance has been observed, with high-level resistance also observed in a mecA-negative MRSA strain, suggesting that multiple mechanisms of resistance development may be possible [START_REF] Banerjee | In vitro selection and characterization of ceftobiprole-resistant methicillin-resistant Staphylococcus aureus[END_REF]. The clinical relevance of this in vitro resistance is unresolved.

Ceftobiprole is generally well tolerated. In single-dose [START_REF] Schmitt-Hoffmann | Single-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers[END_REF] and multiple-dose [START_REF] Schmitt-Hoffmann | Multiple-dose pharmacokinetics and safety of a novel broadspectrum cephalosporin (BAL5788) in healthy volunteers[END_REF] pharmacokinetic evaluations in healthy volunteers, no serious adverse events were reported and most events were mild. In phase 3 trials of cSSSI, the overall incidence of adverse events was similar between ceftobiprole-and vancomycin-treated patients [START_REF] Noel | A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skinstructure infections[END_REF][START_REF] Noel | Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by Gram-positive bacteria[END_REF]. In phase 3 and pharmacokinetic studies, nausea, dysgeusia, vomiting and headache were the most common adverse events [START_REF] Noel | A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skinstructure infections[END_REF][START_REF] Noel | Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by Gram-positive bacteria[END_REF][START_REF] Schmitt-Hoffmann | Single-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers[END_REF][START_REF] Schmitt-Hoffmann | Multiple-dose pharmacokinetics and safety of a novel broadspectrum cephalosporin (BAL5788) in healthy volunteers[END_REF].

Ceftaroline has demonstrated a greater range of Gram-positive activity than other members of the cephalosporin class, including activity against S. aureus strains that are resistant to meticillin, linezolid and daptomycin [START_REF] Fenoll | In vitro activity of ceftaroline against Streptococcus pneumoniae isolates exhibiting resistance to penicillin, amoxicillin, and cefotaxime[END_REF][START_REF] Ge | In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States[END_REF][START_REF] Kanafani | Ceftaroline: a cephalosporin with expanded Gram-positive activity[END_REF][START_REF] Sader | Antimicrobial activities of ceftaroline and ME1036 tested against clinical strains of community-acquired methicillin-resistant Staphylococcus aureus[END_REF][START_REF] Sader | Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains[END_REF].

Ceftaroline also has activity against some Gram-negative organisms but is not active against P. aeruginosa and its activity is reduced against ESBLproducing bacteria. Ceftaroline achieved non-inferiority to vancomycin plus aztreonam in phase 3 trials for cSSSI [START_REF] Kanafani | Ceftaroline: a cephalosporin with expanded Gram-positive activity[END_REF][START_REF]positive results from phase III clinical studies of ceftaroline for the treatment of complicated skin and skin structure infections[END_REF]. In two phase 3 trials for Although the broad spectrum of ceftaroline can be considered a favourable attribute, some believe that its use for the treatment of MRSA infections may result in the emergence of resistant Gram-negative isolates, although this is yet to be investigated [START_REF] Kanafani | Ceftaroline: a cephalosporin with expanded Gram-positive activity[END_REF]. This may be of particular concern given that ceftaroline is not active against P. aeruginosa, a common VAP pathogen.

In a phase 2 study of ceftaroline for the treatment of cSSSI, the overall incidence of adverse events was similar between ceftaroline and standard cSSSI treatment [START_REF] Talbot | Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections[END_REF]. The most common treatment-related adverse events (≥6% frequency) for ceftaroline were crystalluria, headache, insomnia, nausea and elevated levels of blood creatine phosphokinase, alanine aminotransferase or aspartate aminotransferase. Safety data from the CAP trials have not yet been published.

Dihydrofolate reductase inhibitors: iclaprim

Iclaprim is a synthetic diaminopyrimidine that functions by inhibiting the microbial DHFR enzyme, which depletes the bacterial cell of thymidine monophosphate and thus affects RNA, DNA and protein synthesis (Fig. 1) [START_REF] Neuner | New antibiotics for healthcareassociated pneumonia[END_REF]. Iclaprim is bactericidal against clinically important Gram-positive pathogens, including MRSA [START_REF] Sader | Potency and bactericidal activity of iclaprim against recent clinical Gram-positive isolates[END_REF][START_REF] Weiss | Bactericidal activity of iclaprim against methicillin-sensitive and -resistant Staphylococcus aureus[END_REF]. Iclaprim appears to have a lower potential for resistance development than trimethoprim. Additionally, resistance is less likely to develop as a result of the use of other MRSA A c c e p t e d M a n u s c r i p t 22 antimicrobials, as iclaprim has a different mechanism of action than many of the agents that are currently available or in development. However, the antibacterial effect of DHFR inhibitors can be antagonised in vitro by supplementing thymidine owing to bacterial uptake of exogenous thymidine and its subsequent conversion into thymidine monophosphate by thymidine kinase, bypassing the DHFR inhibition [START_REF] Entenza | Efficacy of iclaprim against wild-type and thymidine kinase-deficient methicillin-resistant Staphylococcus aureus isolates in an in vitro fibrin clot model[END_REF][START_REF] Jm | Reversal of activity of trimethoprim against Grampositive cocci by thymidine, thymine and 'folates[END_REF]. Because thymidine is found in large concentrations in human pus, some believe that iclaprim and other DHFR inhibitors are less effective in purulent infections [START_REF] Proctor | Role of folate antagonists in the treatment of methicillinresistant Staphylococcus aureus infection[END_REF].

In a phase 2 trial comparing iclaprim with vancomycin for the treatment of cSSSI, clinical cure was similarly high for patients treated twice daily with iclaprim 0.8 mg/kg, iclaprim 1.6 mg/kg or vancomycin 1 g (92.9%, 90.3% and 92.9%, respectively) [START_REF] Krievins | Multicenter, randomized study of the efficacy and safety of intravenous iclaprim in complicated skin and skin structure infections[END_REF]. Iclaprim was well tolerated during this investigation. Of 32 patients who received iclaprim 1.6 mg/kg, 2 patients experienced pruritus and erythema that was deemed related to the study drug, whereas no patients who received iclaprim 0.8 mg/kg reported any adverse event. Two phase 3 studies demonstrated the non-inferiority of iclaprim to linezolid for the treatment of cSSSI while indicating a favourable safety profile [START_REF] Arpida | Pivotal phase III data confirm the efficacy and safety of Arpida's intravenous iclaprim in treating patients with complicated skin and skin structure infections[END_REF].

Iclaprim showed good pulmonary distribution in healthy human subjects [START_REF] Andrews | Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men[END_REF]. Potential pathogens and recommended empirical antimicrobial therapy for the treatment of nosocomial pneumonia according to the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines [

  ) [46]. Linezolid has activity against Gram-positive pathogens, including bacteriostatic in vitro A c c e p t e d M a n u s c r i p t 10 activity for staphylococci, but has limited activity against Gram-negative bacteria [46].

  1) [72]. Q/D has demonstrated good in vitro activity against many Gram-A c c e p t e d M a n u s c r i p t 13 negative and Gram-positive pathogens, including S. aureus resistant to meticillin and vancomycin [72]. Q/D is approved for the treatment of MRSA pneumonia in some European countries but not in the USA [72]. The ATS/IDSA nosocomial pneumonia guidelines do not recommend Q/D for the treatment of MRSA pneumonia owing to clinical cure rates being lower than those of vancomycin in clinical trials (30.9% for Q/D vs. 44.4% for vancomycin in the bacteriologically evaluable population, and 19.4% vs. 40%, respectively,in the all-treated population with a baseline pathogen)[START_REF] Thoracic | Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia[END_REF][START_REF] Fagon | Treatment of Gram-positive nosocomial pneumonia. Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group[END_REF].

A c c e p t e d M a n u s c r i p t 15 Tigecycline

 15 is approved in the USA and some European countries for the treatment of complicated skin and skin-structure infections (cSSSIs) and complicated intra-abdominal infections as well as for the treatment of CAP (not including infections caused by MRSA) in the USA.Early clinical experiences with tigecycline for the treatment of VAP and/or bacteraemia caused by MDR Acinetobacter baumannii were positive.

A

  c c e p t e d M a n u s c r i p t 21 bacterial CAP requiring hospitalisation, ceftaroline demonstrated noninferiority to ceftriaxone [117].

A phase 2

 2 trial comparing iclaprim with vancomycin for the treatment of non-CAP pneumonia has been terminated for non-clinical reasons[127]. Further data from pneumonia trials are required to assess the potential usefulness of this agent in the treatment of drug-resistant pneumonia.

  MRSA has become an important pneumonia pathogen with high morbidity, mortality and healthcare costs and with relatively few agents approved for the treatment of MRSA pneumonia. Vancomycin exhibits poor penetration into lung tissue, and increasing MIC values for S. aureus are associated with treatment failure and poor microbiological eradication. Older agents such as fosfomycin, fusidic acid and rifampicin in combination with vancomycin are theoretically effective; however, clinical data from RCTs are lacking. Linezolid has exhibited better performance than vancomycin in post hoc analyses from clinical studies with regard to mortality and pathogen eradication. However, in the only RCT (which was considered underpowered) there was no advantage of linezolid with regard to survival, only in respect to secondary end-points.Studies have indicated that teicoplanin may not be as effective as linezolid for the treatment of Gram-positive infections, and Q/D has demonstrated lower efficacy than vancomycin for the treatment of MRSA pneumonia. Some RCTs of novel MRSA antibiotics for nosocomial pneumonia have produced disappointing results. Of the newer drugs discussed in this article, thus far only telavancin has achieved comparable clinical cure rates to vancomycin for the treatment of nosocomial pneumonia in phase 3 trials, although it is currently not approved for this indication. Whether any of the agents discussed here will provide a viable alternative for the treatment of MRSA pneumonia will be revealed in the future.

A

  c c e p t e d M a n u s c r i p t 24 In summary, there is an urgent need for new antimicrobials that have good safety profiles, adequate lung penetration, low potential for resistance development and clinical efficacy for the treatment of MRSA pneumonia.AcknowledgmentEditorial support was provided by Emily Hutchinson, a medical writer at Envision Pharma, funded by Astellas Pharma, Inc.FundingNone.Competing interestsMWP has received fees for lectures from Pfizer and Wyeth and is a member of the international advisory board of Wyeth. TW has received fees for lectures from Pfizer and Johnson & Johnson and is a member of the international advisory board of Astellas, Johnson & Johnson, and Cerexa.Ethical approvalNot required.

Fig. 1 .

 1 Fig. 1. (A) Sites of action of current and potential antimicrobial agents for the

A c c e p t e d M a n u s c r i p t 2 HAP,

 2 VAP and HCAP in patients with late-onset disease or risk factors for MDR pathogens and all disease severity Pathogens as above, plus: -acquired pneumonia; VAP, ventilator-associated pneumonia; MDR multidrug resistant; MSSA, meticillin-susceptible Staphylococcus aureus; HCAP, healthcare-associated pneumonia; ESBL, extended-spectrum -lactamase; MRSA, meticillinresistant S. aureus.

Table 1

 1

	1]

The frequency of penicillin-resistant S. pneumoniae and MDR S. pneumoniae is increasing; levofloxacin or moxifloxacin are preferred to ciprofloxacin. In the authors' opinion, ciprofloxacin as empirical antimicrobial therapy for early-onset HAP is insufficient owing to limited activity against pneumococci, which occur frequently in early-onset pneumonia.

b If an ESBL-positive strain, such as K. pneumoniae, or an Acinetobacter spp. is suspected, a carbapenem is a reliable choice. If L. pneumophila is suspected, the combination antibiotic regimen should include a macrolide (e.g. azithromycin), or a fluoroquinolone (e.g. ciprofloxacin or levofloxacin) should be used rather than an aminoglycoside.