A plethora of new antibiotics have become available with a licence for use in skin and soft tissue infection (SSTI) . The evidence for clinical use for new agents is based on registration trials which are virtually all double-blind, placebo-controlled trials powered for noninferiority. There is little, if any, evidence for superiority of one agent over another. Choice of agents based purely on drug acquisition costs tends to favour older, cheaper agents. This fails to take into account any other issues such as health economic data, pharmacokinetics, patient characteristics, drug interactions and toxicity. In addition, the criteria for registration trials have changed . Former guidance was for the indication of complicated SSTIs (cSSTI) whose clinical indications included most presentations of soft tissue infection including diabetic foot infection (DFI), chronic ulcers and burns, and lesions whose cause is often polymicrobial, and the primary endpoint was the clinicians’ assessment 7–14 days after the end of treatment. The new criteria are labelled acute bacterial skin and skin structure infections (ABSSSI). These exclude the chronic polymicrobial infections (DFI, ulcers, etc.), and the primary endpoint is an objective measurement of reduction of greater than 20% in lesion inflammation at 48–72 h. Although this makes for tighter data in clinical trials, it narrows the database and provides even less clinical information for real-life clinical situations. Pharmaceutical companies can only promote their agents for use in the narrow clinical confines of their registered drug label, and yet much of the need for newer agents is in complex patients with infection indications which may not have been studied.
A number of questions arise about where these new agents should be placed clinically. Where and when should they be used? Should they be included on hospital formularies or in treatment guidelines? Should they be reserved for use only by ‘infection and antibiotic’ experts? Can they be used off-label? Should they be used in specific patient groups? These are questions that are often asked about new antibiotics and for which there are often no clear answers. This review is a personal opinion on when the newer agents may find clinical use.
There is a danger of being overloaded with abbreviations, and rather than cause confusion between cSSTI and ABSSSI, this review will stick to SSTI which will cover the whole gamut of SSTIs.
IS BACTERICIDAL OR BACTERIOSTATIC AN IMPORTANT CONCEPT IN SKIN AND SOFT TISSUE INFECTION?
Cidality or a static response is a scientific concept, and its clinical relevance is hotly debated. The response to infection is always a balance between the pathogenicity of the organism and the immune response, so cidal activity is theoretically required for bacteraemia, in the immunosuppressed and in infections that are hidden from the immune system such as endocarditis. β-Lactam antibiotics, glycopeptides, daptomycin, cotrimoxazole, fosfomycin and rifampicin are described as bactericidal, whereas oxazolidinones, clindamycin and tigecycline as bacteriostatic. Bacteriostatic and bactericidal categorizations in clinical practice are not absolute and can lead to false assumptions concerning antimicrobial therapy, especially if major pharmacokinetic and pharmacodynamic parameters such as tissue penetration and plasma protein binding are ignored. The bacteriostatic agent linezolid has shown nonsignificant superiority over the bactericidal vancomycin in every controlled study for the treatment of SSTI caused by methicillin-resistant Staphylococcus aureus (MRSA) [3–5], whereas the rapidly bactericidal drug daptomycin has failed to achieve superiority over comparator substances in SSTI [6,7].
There have been no significant advantages for bactericidal agents in the treatment of SSTI. However, in some of the alternative clinical indications discussed in this review, there may be a role for antibiotics that have specific properties that aid resolution of that infection. For example in endocarditis, rapid cidal activity is believed to be an advantage. This might support the choice of β-lactams, glycopeptides and daptomycin for this role. In prosthetic device infection, antibiotics that promote biofilm reduction are likely to be important, and more work on these novel antibiotics needs to be carried out in this area, but rifampicin in combination has found a role here. Infections with organisms that produce toxins and superantigens, for example Panton Valentine leucocidin-producing S. aureus, may best be treated with antibiotics that suppress protein synthesis, such as the oxazolidinones and clindamycin. The ultimate criterion for treatment choice for any infection must be efficacy .
So the answer is that these concepts are probably not of major importance in the choice of antibiotic for SSTIs.
The glycopeptides vancomycin and teicoplanin have been widely employed for several decades to treat resistant gram-positive infections, especially SSTIs but also a wide range of other resistant gram-positive infections including bacteraemia, endocarditis, prosthetic device infection, respiratory and coagulase-negative staphylococcus (CNS) infections. They are cheap and familiar, but there are concerns about toxicity, efficacy, pharmacokinetics and resistance, none of which have resulted in the replacement of these drugs from most hospital formularies. Indeed, they are the first choice of treatment for suspected MRSA infection . Why does their popularity persist when there are newer agents with far better pharmacokinetics, lower toxicity and easier dosage calculation and administration? The main reason is drug acquisition cost, although associated costs of serum monitoring, length of i.v. treatment and hospital stay are rarely taken into account , and in a balanced discussion, it has to be said that the new agents are by and large noninferior, not superior to the old glycopeptides in the narrow confines of the registration trial.
Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens . Telavancin has been licensed for cSSTI and in the United States for nosocomial pneumonia due to gram-positive organisms, but the US Food and Drug Administration (FDA) indicated that it should be used only when alternative treatments are not suitable. The FDA indicated that telavancin has a substantially higher risk of death for patients with kidney problems or diabetes compared with vancomycin [12▪]. It is therefore difficult to see a clinical role for this agent in SSTI or any other infection in view of the significantly poorer safety profile.
Oritavancin is a semisynthetic derivative of a precursor drug closely related to vancomycin. Although it has a similar mode of action to vancomycin, it has activity against some vancomycin-resistant pathogens. In contrast to vancomycin, oritavancin possesses concentration-dependent bactericidal activity against enterococci, Streptococcus pneumoniae and staphylococci, including MRSA. Importantly, it is not affected by the vanA, vanB and vanC-encoded alterations in the bacterial cell wall that confer vancomycin resistance.
A phase III trial has shown oritavancin as a single dose to be noninferior to 7–10 days of vancomycin in adults with acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including MRSA .
Another glycopeptide, dalbavancin also has a long half-life. A phase III trial for dalbavancin has shown that once-weekly intravenous dalbavancin was noninferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection .
Both these drugs may find favour in the treatment of SSTI in patients not admitted to hospital or as part of outpatient parenteral antibiotic treatment programmes. They have the potential to prevent or dramatically reduce the costs of hospital admission and indeed to reduce the costs of home care. They lend themselves to use in the emergency room or physician's office. Physicians have expressed concern about the prolonged half-life of these agents in relation to possible adverse effects, although prolonged adverse effects were not a problem in the registration trials [13,14].
Although a single dose of oritavancin, or once-weekly dalbavancin might have considerable health economic advantages, it could be argued that oral agents would be even more cost-effective. Why use intravenous (i.v.) drugs at all when there are oral treatments with agents with high oral bioavailability (see oxazolidinones below)? The debate over intravenous or oral treatment preference has not been resolved. There are widespread anecdotal and cultural views that intravenous administration of antibiotic is preferable early in treatment. Intravenous treatment is clearly an advantage in patients with sepsis and shock, in which case the patient ought to be monitored in a hospital anyway, or those whose gastrointestinal absorption may be compromised, but also there seems to be an element of ‘medical mystique’ in i.v. administration as a procedure that ought to be carried out by hospitals or specialists. If patients are able to absorb from the gastrointestinal tract and a drug has high oral bioavailability, there is no logical reason why treatment cannot be commenced orally, avoiding i.v. lines and administration. More clinical data is required comparing the efficacy of i.v. versus oral treatment in different patient groups.
Glycopeptides with prolonged half-life may have advantages in conditions involving prosthetic device infection, particularly those with infection caused gram-positive pathogens of low pathogenicity. ‘Precious’ long i.v. lines or ventriculoperitoneal shunt infections could be treated by administration of long-life glycopeptide locked in the lumen of these devices. These agents may also find use, alone or in combination, in the treatment of prosthetic joint infection, prosthetic valve endocarditis and continuous ambulatory peritoneal dialysis infection.
Tigecycline is indicated for SSTI, including those caused by MRSA, and intra-abdominal infection and in the United States for community-acquired pneumonia in which there is suspected or proven resistance to, intolerance of or there are comorbidities preventing the use of other available agents. This qualifying recommendation is based on a noted imbalance of mortality in the tigecycline arm of some trials and meta-analyses in relation to the comparator . So tigecycline has found a role as a drug of last resort or salvage therapy, and it has been widely used in combination for the treatment of many infections caused by multidrug-resistant gram-negative infection in which it has an important role to play [16–19]. In the registration trials, it showed comparative efficacy with vancomycin and aztreonam in infections caused by gram-positive and gram-negative bacteria . In real-life studies, tigecycline has performed well in complex seriously ill patients with SSTI both as monotherapy and in combination [18,19,20▪▪].
In a series of studies looking at the use of tigecycline across several European countries in real-life conditions [20▪▪,21▪,22], the majority of patients (58%) received tigecycline for the treatment of cSSTIs (n = 254) or complicated intra-abdominal infections (n = 785). Tigecycline was given at the standard dose (100 mg and 50 mg twice daily) to the majority of patients for a mean duration of 11 days. The main reasons for prescribing tigecycline were failure of previous therapy (46%), requirement for broad-spectrum antibiotic coverage (41%) and suspicion of a resistant pathogen (39%) [21▪]. Tigecycline was prescribed as first-line therapy in 36% of patients and as monotherapy in 50%.
Concern about the use of tigecycline in bacteraemic patients relates to relatively low serum levels of the drug in comparison with tissue levels. However, in patients who are bacteraemic tigecycline has often performed effectively [20▪▪,21▪,22,23] and resulted in infection resolution.
Tigecycline seems to have found a role in later stage infections, often as a secondary treatment, in complex patients who are likely to be severely ill and may have multidrug-resistant Gram-positive and Gram-negative infections. Thus, it has a fairly unique role amongst the novel antibiotics . It could also be considered as earlier empirical therapy in more complex patients with comorbidities with soft tissue or intra-abdominal infection and possibly hospital-acquired pneumonia (although it was found to perform poorly in ventilator-associated pneumonia), who may be infected with multidrug-resistant organisms either gram-positive or gram-negative. It could be considered as a carbapenem-sparing antibiotic, and should be used more widely as part of diverse prescribing within a controlled antimicrobial stewardship programme.
Linezolid is now a well established agent licensed for SSTI and community-acquired pneumonia (CAP). It is highly bioavailable with a gram-positive spectrum active against multidrug-resistant strains. In soft tissue infection, it has the potential for empirical early oral treatment, avoiding i.v. drug administration, keeping the patient out of hospital or enabling earlier discharge . It is recommended for MRSA infections, as an initial or alternative therapy for the following conditions: SSTI [5,4], DFI , pneumonia, osteomyelitis, septic arthritis, meningitis, brain abscess, subdural empyema, spinal epidural abscess and septic thrombosis of the cavernous or dural venous sinus [25–27], the latter based on the excellent CNS concentrations achieved . Linezolid also may reduce toxin production in pneumonia, although whether this improves clinical outcomes is not yet clear [26,27].
It has a role in long-term oral treatment of complex infections including osteomyelitis, vertebral discitis, prosthetic device infection and even tuberculosis, because of its oral administration and good bioavailability. Long-term use may be limited in some patients by adverse effects, bone marrow suppression and peripheral neuropathy. Nevertheless linezolid has great potential in these off-label conditions. It has had mixed results in bacteraemia and endocarditis. Linezolid should play an important health economic role in early i.v.–oral switch and earlier discharge from hospital [28,29,30▪▪].
Tedizolid is a recently available oxazolidinone-class antibiotic, licensed and indicated for the treatment of ABSSSIs caused by susceptible isolates of the following gram-positive microorganisms: S. aureus (including MRSA and methicillin-susceptible isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (including S. anginosus, Streptococcus intermedius and Streptococcus constellatus) and Enterococcus faecalis.
The registration trial showed that 6 days of tedizolid treatment was noninferior to 10 days of linezolid [31▪]. It is not entirely clear from this trial whether 6 days of tedizolid was noninferior to 6 days of linezolid, but, like linezolid, this agent has the potential for health economic advantages in treatment out of hospital or earlier discharge. There may be further advantages over linezolid. Tedizolid has a lower (200 mg) single daily dose, greater potency, with lower minimum inhibitory concentrations than linezolid to most gram-positive species, and favourable pharmacokinetics . It will have a similar clinical role to linezolid, and could potentially be used in all the indications listed above. Further data need to be collected on its role in complex infections – prosthetic device infection and osteomyelitis. There is the potential, not yet established, that adverse effects from long-term treatment may be lower than with linezolid due to the lower dose. There was a signal in the registration trials to suggest a lower rate of bone marrow suppression and neuropathy, but as yet data on long-term treatment are lacking [31▪].
The most promising roles for linezolid and tedizolid are in keeping patients out of hospital. They have never been trialled against standard treatment regimens, that is betalactams, macrolides for sensitive strains and older oral drugs for MRSA such as cotrimoxazole and doxycycline. Many hospitals will have as their guidance for the empirical management of SSTI combinations of different i.v. betalactams, lincosamides and macrolides, for example i.v. flucloxacillin and clindamycin. If an oral course of oxazolidinone was more than or as effective as standard i.v. therapy, then this could represent a major health economic advantage and free up hospital beds as well as being more acceptable to patients . A common practice in the United Kingdom in emergency rooms has been to treat ‘nonseptic’ patients with SSTI with once-daily i.v. ceftriaxone, chosen principally for its longer half-life, but why start with i.v. drugs at all?
Ceftaroline is a novel cephalosporin and indicated in adults for the treatment of the following infections: cSSTI and CAP [33,34]. It is the first β-lactam with activity against MRSA, and has all the advantages of β-lactams: familiarity of use over many decades, good tolerability and low rate of adverse effects. It also has activity against penicillin-resistant pneumococci, and so has a role for treating community-acquired pneumonia in which such organisms are prevalent. The activity of ceftaroline against S. aureus extends to heteroresistant vancomycin-intermediate, vancomycin-resistant and daptomycin-nonsusceptible isolates [35▪▪].
Like tigecycline, ceftaroline has the advantage of gram-positive activity (including MRSA) and gram-negative activity, although ceftaroline is not active against strains of enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) unlike tigecycline. Nevertheless, it may have a role in the empirical treatment of more complex patients with comorbidities who may be infected with MRSA. In these patients, it is reassuring to have the possibility of using a β-lactam with activity against MRSA. The broader spectrum may lend itself to the treatment of complex SSTI such as DFI and surgical or traumatic wound infections in which the causative organisms could be gram-positive or gram-negative. The registration trials show that there may be an early response in defervescence of fever and reduction in inflammation with ceftaroline . Along with other β-lactams, its pharmacokinetics is favourable with good serum and cerebrospinal fluid levels making this agent suitable for treating bacteraemia and suspected meningitis alone or in combination. Ceftaroline has been used in combination with daptomycin (below) as a potent and effective combination treatment for complex MRSA sepsis [35▪▪].
Potential ‘off-label’ uses are numerous. Ceftaroline's activity against all methicillin-resistant staphylococcal species makes it an attractive empirical treatment for possible infection following surgery involving prosthetic device implantation be that cardiothoracic, neurosurgical, vascular or orthopaedic. In these complex surgical procedures, early infection can be devastating and life threatening but also difficult to diagnose. Early treatment of fever or inflammation with an antibiotic such as ceftaroline while awaiting further diagnostic tests, can give reassurance of comprehensive antimicrobial coverage and efficacy.
Ceftobiprole is another anti-MRSA cephalosporin with a similar spectrum to ceftaroline, although with some activity against amp-C producing enterobacteriaceae but not ESBL producing strains and greater antipseudomonal activity . As with ceftaroline combinations, combination of ceftobiprole with other agents may result in potent synergy. Combination with daptomycin may increase activity against daptomycin-susceptible but vancomycin-resistant enterococci . Both of these cephalosporins will be combined with existing or novel β-lactams, such as avibactam to broaden the spectrum and the range of indications from skin and soft tissue and respiratory infections to urinary and intra-abdominal infections. This will have the advantage of having further agents which can spare carbapenem use.
Daptomycin is indicated for the treatment of infections in adults with cSSTI , or right-sided infective endocarditis caused by S. aureus[7,39,40]. Its cidal activity supports its use in bacteraemia, although superiority has not been demonstrated in clinical trials [41,42]. Indeed in one trial, daptomycin was associated with a higher rate of microbiological failure than vancomycin and the development of reduced susceptibility. In enterococcal bacteraemia, linezolid, a supposedly static antibiotic, was as effective as daptomycin .
As an exclusively i.v. antibiotic, it has a role in hospital for complex gram-positive infections. It also has potential roles in the initial hospital therapy of bacteraemia, endocarditis and bone and joint infection, including those associated with prosthetic devices. Its role in combination with other agents is an interesting area for further assessment [35▪▪,37].
The majority of SSTIs are caused by S. aureus[43,44], with an increasing proportion resistant to multiple antibiotics, and most new antibiotics that have been licensed in the past decade have been for this indication. Changes in the regulatory trial requirements  have made for more precise and closely defined registration trials, but have resulted in an increasing gap between the official, labelled indication for new antibiotics and what they may be used for in clinical practice. Clinicians are constantly faced with patients who do not conform to the licensed criteria for many new antibiotics. In many indications, further clinical trials are simply not practical to perform. There is a need therefore for well documented real-life observational data; such has been established for daptomycin  and tigecycline [20▪▪].
Indications in which these new agents may have potential use are listed in Table 1. These are likely to include bone and joint infections, prosthetic device infections, endocarditis and infections in which penetration can be a challenge such as the central nervous system and ischaemic limbs. Other characteristics of the antibiotics are listed in Table 2.
The threat of global antibiotic resistance has meant that antimicrobial stewardship programmes are increasingly important to improve the quality of antimicrobial prescribing and to reduce inappropriate antibiotic use . These new antibiotics can play roles that assist this. Certain agents, such as the glycopeptides and daptomycin, can be used in outpatient parenteral antibiotic therapy [46,47]. Linezolid and tedizolid, as oral therapy, can be used to avoid i.v. therapy altogether but still reduce or avoid hospital stay. Tigecycline may play a role as a carbapenem sparing agent, as ceftaroline and ceftobiprole may, once they are combined with novel β-lactamase inhibitors.
It is fortunate that there is now a wide range of antibiotics for treating cSSTI [48,49], and they all have a role in different clinical scenarios. Registration trials give evidence of clinical efficacy within a very narrow range of clinical conditions and patient characteristics. In real life, many of these agents will be used by clinicians in a much wider clinical context, and it is important that the data on efficacy, microbiological eradication and adverse effects is captured.
Financial support and sponsorship
Conflicts of interest
M.D. has been on advisory boards and speaker's bureaus for Pfizer, AstraZeneca, Bayer and Cubist. He is the General Secretary of the British Society for Antimicrobial Chemotherapy and on the executive committee of the International Society of Chemotherapy.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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