Does vancomycin have a future in the treatment of skin infections?

REVIEW URRENT C OPINION

Does vancomycin have a future in the treatment of skin infections? Deirdre J. O’Brien and Ian M. Gould

Purpose of review Despite concerns regarding efficacy and tolerability, vancomycin continues to be the standard treatment for skin and soft tissue infections (SSTIs) when b-lactam antimicrobials cannot be used. This review sought to establish the role of both old and new alternatives to vancomycin. Methods for achieving optimization of vancomycin therapy are also explored. Recent findings Several meta-analyses have demonstrated poorer clinical outcomes when the vancomycin minimum inhibitory concentration approaches the breakpoint of 2 mg/ml. Higher doses should be utilized to optimize pharmacokinetics and pharmacodynamics when higher volumes of distribution occur (e.g. sepsis). Newer agents with established noninferiority to vancomycin include the oxazolidinones linezolid and tedizolid, the lipopeptide daptomycin, the anti-meticillin-resistant Staphylococcus aureus cephalosporin ceftaroline and the glycylcycline tigecycline. Linezolid is thus far the only agent that has been shown to be associated with better clinical and microbiological cure rates. Ceftaroline and tigecycline are broadspectrum agents best reserved for polymicrobial infections (e.g. diabetic foot infections). Summary When vancomycin is used for the treatment of SSTIs, maximizing the dose should be performed to improve efficacy. Cost is often the main limiting factor with regard to the newer agents, but their suitability for outpatient antimicrobial therapy may counteract this. Keywords meticillin-resistant Staphylococcus aureus, outpatient antimicrobial therapy, skin and soft tissue infection, vancomycin

INTRODUCTION

VANCOMYCIN BREAKPOINTS

Few countries have made significant inroads into controlling meticillin-resistant Staphylococcus aureus (MRSA), so it is still a major, and often growing, concern when treating skin and soft tissue infections (SSTIs). The emergence of communityacquired MRSA (CA-MRSA) has further intensified this problem and this is now a major public health concern in its own right especially in the United States. Despite many problems, such as evolving resistance, poor outcomes, minimum inhibitory concentration (MIC) creep, uncertain pharmacokinetics/pharmacodynamics (PK/PD) and toxicity and the increasing popularity of outpatient antimicrobial therapy (OPAT), glycopeptides continue to be the standard of therapy for these conditions. Is this appropriate, or has the time come to switch to alternatives, of which there are a growing number (Table 1) [1–6]?

Recent data illustrate some of the problems we still have with MIC testing after almost 60 years of vancomycin use. Results are strongly methoddependent and few clinical laboratories use the reference methods on which the breakpoints are based [7 ,8]. Recognizing this, recent treatment guidelines pay no notice to MICs [9]. Several meta-analyses, however, have now shown poorer outcome with MICs approaching the breakpoints (>2 mg/l), irrespective of the source of infection or

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Department of Medical Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK Correspondence to Dr Ian M. Gould, Department of Microbiology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK. Tel: +44 1224 554954; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:146–154 DOI:10.1097/QCO.0000000000000048 Volume 27 Number 2 April 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Treatment of skin infections O’Brien and Gould

KEY POINTS Where vancomycin continues to be used to treat SSTI, its use should be optomized through utilization of higher doses.

S. aureus and MRSA, even when measured by reference broth dilution. As explained above, our testing methodology is not fit for the purpose. Moreover, MICs can be affected by storage and subculture, which are usually procedures that isolates are subjected to in such studies [16 ,17 ]. We have shown how this compounds studies of creep. Certainly, it would be surprising if creep did not occur, given the necessary accumulation of multiple, complex mutations required to raise the MIC and the incessant selective pressure for this to occur because of the huge quantity of glycopeptide prescriptions over the past 30 years. Where it is looked for, it can be observed, leading to treatment failure in the patient [18]. &

Several alternatives to vancomycin exist; the increased cost of these agents is often the main barrier to their use. Linezolid appears to be the front runner of all these agents, being the only one thus far convincingly associated with better clinical and microbiological outcomes than vancomycin.

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MIC methodology [10,11 ,12 ,13]. Although the majority of the cases were bloodstream infections, there were also cases of pneumonia and SSTIs [4,10,11 ,12 ,13]. Although no randomized controlled studies (RCTs) have been performed, it is difficult to ignore the consistent message, which has been used to argue for lowering the breakpoints [2]. &&

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DETERMINING THE MINIMUM INHIBITORY CONCENTRATION Commercial vancomycin MIC detection methods are usually used. Unfortunately many vancomycin MICs are within 1 log2 dilution from the breakpoints, and method-dependent, so results have poor reproducibility. The precision of automated systems, in particular, has come under greater scrutiny [10], with poor performance noted [7 ,14]. Comparing four commercial systems (Microscan, Vitek-2, Phoenix and Etest) against Clinical and Laboratory Standards Institute reference broth microdilution (BMD) showed 61.8%, 54.3%, 66.2% and 36.7% absolute MIC agreement, respectively, with BMD methods [7 ]. Resistance was also missed, especially heterogenous vancomycin-resistant Staphylococcus aureus (hVISA) [7 ]. Etest, however, often produce values that are one dilution higher than BMD, and this may prove a useful conservative estimate for serious infections [7 ,8,15]. The need for methoddependent breakpoints seems a reasonable stance to adopt, with a breakpoint of more than 1.5 by Etest and more than 1 by BMD, not relying on results of automated systems, at least for critically ill patients.

HETERORESISTANCE Heteroresistance is a complex phenomenon that may be the penultimate state on the journey from fully susceptible to full glycopeptide intermediate Staphylococcus aureus (GISA) status. Laboratory determination of heteroresistance is difficult, with the gold standard population analysis profiling being impracticable in the routine diagnostic laboratory. It may be easiest just to rely on MIC testing, with all its imperfections, as hVISA becomes very common with an MIC more than 2 mg/l. At this MIC, however, there is little point in using a glycopeptide. These strains are, de facto, fully resistant to glycopeptides and have many other changes such as alterations in accessory gene regulation and expression of virulence factors [19–21].

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MIC CREEP There is great debate about whether this exists, or whether it is strain replacement (MIC leap). Certainly, the modal MIC for collected series of isolates is 1 mg/l, both for meticillin-susceptible

PHARMACOKINETICS/ PHARMACODYNAMICS DATA ON VANCOMYCIN Conventional opinion accepts a PK/PD target of an area under the curve/minimum inhibitory concentration (AUC/MIC) ratio of 400, but this is based on very limited human data on pneumonia and animal models. With elevated MICs, such a ratio may require toxic levels of vancomycin and there is limited guidance on how to dose patients to achieve such targets. With an MIC of 1 mg/l, a trough of 20 mg/ml will achieve a ratio of 480. With higher MICs, there have been calls to achieve even higher troughs, up to 30 mg/ml, but these will surely be associated with very frequent nephrotoxicity [22]. Still, most of the toxicity seems reversible and it is not at all clear how detrimental it is to patient outcome. Clearly, renal function will be a major determinant of dose and levels must be measured [10,23,24]. Clinical severity and site of infection will also play a role. In septic shock, better AUC ratios are

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Inexpensive

Moderate

Expensive but cost may be offset if used in OPAT setting

Expensive but Excellent expense may be offset if used in OPAT setting

Not yet available

Expensive

Inexpensive

Vancomycin

Teicoplanin

Daptomycin


Linezolid

Tedizolid

Ceftaroline

Clindamycin

Excellent

No

Excellent

No

No

No

Cost

Greatly increases risk of Clostridium difficile infection

Similar profile to cephalosporins

Reversible thrombocytopenia. Serious partially irreversible side-effects with treatment beyond 28 days in reported cases (optic neuritis and peripheral neuropathy, lactic acidosis) Appears to be more favourable to linezolid but further study required

Reversible changes in CPK. Very rare reports of eosinophilic pneumonitis – also reversible on discontinuation of therapy

Generally well tolerated. Dose-dependent nephrotoxicity (but occurs less frequently than with vancomycin)

Red-man syndrome, thrombophelbitis at injection sites, nephrotoxicity at higher doses

Oral Major adverse bioavailability events

Antimicrobial Agent

Excellent

Excellent

Variable

Rare to date

None to date

Low

Excellent

Excellent

Low

Low

Low

Excellent

Good

Poor

Not required

Not required

Not required

Not required

Not required

Yes

Yes

Comparisons with vancomycin and evidence

Yes

Yes

Yes

Yes

Yes

Yes

No comparator data available

Non-inferiority to vancomycin plus aztreonam demonstrated in two phase III multinational randomized controlled trials. Retrospective analysis of this data showed earlier response rates in the ceftaroline arm of the study

First phase III trial recently published

FDA approved since 2000. Multiple randomized controlled trials demonstrating efficacy

FDA approved since 2004; Randomized trials demonstrating efficacy.

Never received FDA approval. This has a significant impact resulting in a paucity of published evidence

Requires prolonged N/A infusion time (>90 min), risk of thrombophlebitis

Concentration at skin/soft Resistance Requirement OPAT tissue site rates for TDM suitability

Table 1. Characteristics of antimicrobials indicated for the treatment of complicated skin and soft tissue infections

Skin and soft tissue infections

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CPK, creatine phosphokinase; EMA, European Medicines Agency; FDA, Food and Drug Administration; N/A, not available; OPAT, outpatient antimicrobial therapy; SSTI, skin and soft tissue injury; TDM, therapeutic drug monitoring.

Shown to be noninferior to vancomycin plus aztreonam in phase III randomised studies Yes Not required Variable Excellent Tigecycline

Expensive

Excellent Co-trimoxazole Inexpensive

FDA and EMA cautions about excess mortality in patients receiving tigecycline as compared to alternative treatments

Good

Yes but less severe SSTI only Variable Stevens–Johnson syndrome and Good Lyell’s syndrome

Not required

No large multicentre comparator trials with vancomycin available. Vancomycin appeared superior in smaller early trials


associated with improved survival [25]. Zelenitsky et al. [26 ] demonstrated improved survival with an AUC/MIC ratio around 600 in seriously ill patients. This backs up some animal data showing such ratios were associated with better cidal activity. In shock, there will be increased volume of distribution which will lower drug levels [5,26 ]. Several studies have also demonstrated that in diabetic patients vancomycin shows much lower soft tissue levels, despite having adequate serum concentrations, further arguing for higher dosing schedules [27,28 ]. Haemofiltration (CVVH) also leads to high extracorporeal removal of vancomycin, if rates more than 45 ml/kg/h are used [29,30]. Severe sepsis can also lead to increased renal clearance, making it even more difficult to maintain the correct levels [31 ]. Levels of less than 10 mg/l were associated with adverse outcome [32]. &&

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MODE OF ADMINISTRATION There is an increasing practice to use vancomycin continuous infusion, although as AUC/MIC ratio is the PK/PD target, the mode of administration should make no difference. Continuous infusion in a pig lung model, however, showed increased efficacy [33] and decreased nephrotoxicity [22]. In severely ill patients, continuous infusion can provide more reliable levels of vancomycin.

ALTERNATIVE AGENTS TO VANCOMYCIN There are numerous potential options as alternatives to vancomycin. Below we discuss some of the more important ones.

Linezolid Linezolid is the first of the oxazolidinone class of antibiotics, a completely synthetic group of antibiotics that inhibit bacterial protein synthesis by binding to 23S rRNA in the catalytic site of the 50S ribosome. This mode of action may be beneficial when treating infections caused by Panton Valentine leukocidin (PVL)-producing S. aureus and had prompted its inclusion in treatment guidelines targeting this (e.g. Health Protection Agency UK Guidance on the diagnosis and management of PVL-associated S. aureus infections in England). It demonstrates bacteriostatic activity against a wide range of Gram-positive bacteria in vitro [34]. It has a favourable pharmacokinetic profile that demonstrates 100% bioavailability and excellent active concentrations in infected soft tissues [35]. It inhibits monoamine oxidase and can induce serotonin toxicity in patients concurrently taking selected



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serotonin reuptake inhibitors. Serious side-effects do occur, most commonly in those receiving greater than 28-day treatment, thus cautioning the prescription of the drug beyond this time frame. These include myelosuppresssion (especially thrombocytopenia) reversible on discontinuation of the drug and, more rarely albeit partially irreversible, optic neuritis and peripheral neuropathy [36]. Although uncommon, these serious sideeffects nonetheless limit the clinical use of this drug. Resistance remains infrequent and may be caused by mutations in the 23S ribosomal rRNA (e.g. G2576T) or ribosomal protein L3 by the presence of the cfr gene [37 ]. The cfr gene has been reported to cause transferable linezolid resistance and has been associated with outbreaks of resistant strains [38]; VISA, hVISA and vancomycin-resistant S. aureus strains usually remain susceptible. A recent Cochrane review comparing the safety and efficacy of linezolid and vancomycin for the treatment of SSTI, including nine RCTs totalling 3144 participants, found that linezolid was associated with a significantly better clinical and microbiological cure rate in adults. The daily cost of outpatient treatment with oral linezolid was less than that of intravenous vancomycin and the median length of hospital stay was 3 days shorter with linezolid [39 ]. A similar conclusion was reached by Watkins et al. [40], and a phase IV clinical trial of oral linezolid versus intravenous vancomycin in patients with ischaemic/vascular issues suggested better tissue diffusion and clinical outcome with linezolid [41 ]. In summary, linezolid is an effective alternative to vancomycin and one that offers greater clinical efficacy with the added benefit of an excellent oral option. Increased cost if prescribed in the in-hospital setting and concerns regarding side-effects with treatment required for longer than 28 days are its main shortcomings. &

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SSTI, designed to evaluate early clinical response, tedizolid was found to be noninferior to linezolid [45 ]. Further studies are required to establish what role tedizolid will play in the treatment of SSI. &&

Daptomycin Daptomycin is the first in the new antibiotic class called the cyclic lipopeptides. It has activity against a wide range of Gram-positive organisms in which it causes depolarizion of the cell membrane and cell death through the inhibition of DNA, RNA and protein synthesis. It also inhibits peptidoglycan biosynthesis [46]. It demonstrates bactericidal activity against S. aureus and thus is an attractive alternative to vancomycin when SSTI and bloodstream infection co-exist. Reversible skeletal muscle toxicity was found during the preclinical studies and shown to be associated with elevated creatine phosphokinase (CPK) levels. As a result of this, regular monitoring of CPK is advised throughout the duration of therapy. Acute eosinophilic pneumonia has also been reported as a rare side-effect (24 cases described in the medical literature to date), and the potential for the occurrence of this during therapy should be noted among prescribers [47 ]. The initial multicentre phase III clinical studies comparing daptomycin (4 mg/kg intravenously every 24 h for 7–14 days) with penicillinase-resistant penicillins (4–12 g intravenously per day) or vancomycin (1 g intravenously every 12 h) for the treatment of complicated SSTI demonstrated noninferiority against these agents with a statistically significant reduction in treatment duration compared with vancomycin [48]. Since those studies, analysis of ‘real world’ use has confirmed the safety and efficacy of daptomycin in this setting [49 ,50,51] and also in elderly populations [52 ]. Many users would now advocate prescribing higher doses than those of the initial studies, especially when bloodstream infection co-exists alongside SSTI [53 ]. Daptomycin resistance remains rare but is concerning, especially as it has been reported as occurring during therapy [54]. The exact mechanism of resistance is not yet fully elucidated and a number of mutations have been described [55,56 ]. Most interestingly, sensitization to oxacillin has been demonstrated in daptomycin-resistant MRSA strains – a phenomenon that has been described as the seesaw effect. This has also been found with other b-lactam antibiotics including co-amoxiclav, cefotaxime, imipenem [57 ] and ceftaroline [58 ]. Increasing the dose of daptomycin and b-lactam combination therapy may be the best means of limiting the emergence of resistant strains, which &

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Tedizolid Tedizolid is a next-generation oxazolidinone that has shown potential to circumvent some of the shortcomings of linezolid [42 ]. Like linezolid, it inhibits protein synthesis and may be administered orally or intravenously. It too demonstrates excellent bioavailability and tissue penetration. Unlike linezolid, however, no myelosuppression has been shown to occur with the standard treatment dose of 200 mg once daily [43,44]. Tedizolid does not inhibit monoamine oxidases in vivo. In its first phase III international multicentre trial involving 667 adults with acute bacterial &&

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are especially likely to occur in high inoculum infections of SSTI with undrained foci [55]. One of the main arguments against daptomycin is that it is more costly to administer than vancomycin in the in-hospital setting. Several pharmacoeconomic models have been published negating this reasoning when OPAT services are utilized. As daptomycin can be administered via a 2-minute once-daily injection in most patients without the requirement of therapeutic drug monitoring, its suitability in managing patients in OPAT situations cannot be disputed [59]. Daptomycin is a suitable alternative to vancomycin for SSTI. As with linezolid, cost remains the main barrier; however, its suitability for OPAT may refute some of this argument.

Studies in combination with a b-lactamase inhibitor are well underway [65 ]. Unfortunately, MRSA strains with increased MICs to ceftaroline have already been described but thus far remain rare [66 ]. Of note, the ‘seesaw effect’, whereby susceptibility to b-lactam antimicrobials increases as glyco and lipopeptide susceptibility to MRSA decreases, has also been demonstrated for ceftaroline [67 ]. As it is a broad-spectrum cephalosporin, the propensity to cause Clostridium difficile infection is likely to be present and it would seem prudent to reserve its use for scenarios wherein polymicrobial infection is present (e.g. diabetic foot infections, perineal and postabdominal surgical infections), and surveillance to establish this exact risk should be undertaken.

Tigecycline

Co-trimoxazole

Tigecycline is a broad-spectrum agent with activity against MRSA, vancomycin-resistant Enterococcus spp. and extended spectrum b-lactamase (ESBL)producing Enterobacteriaceae. It was developed to overcome tetracycline resistance and belongs to the group of antibiotics known as ‘glycylcyclines’. It binds to the acceptor site of the bacterial 30S ribosomal subunit, thereby inhibiting protein synthesis, and is available in intravenous form only. It has a favourable pharmacokinetic profile, including a large volume of distribution that results in extensive distribution to the tissues [60]. RCTs that have assessed the efficacy of tigecycline have demonstrated that it is noninferior to vancomycin plus aztreonam in treating SSTI [61]. Concern regarding the use of tigecycline arose following the publication of a pooled analysis of 13 trials showing an increase in all-cause mortality in patients receiving tigecycline as opposed to comparator regimens. This led the European Medicines Agency to issue a warning to restrict the use of tigecycline to clinical scenarios in which alternatives are not suitable [62]. Despite this caveat tigecycline will remain a valuable option in an era of increasing bacterial resistance, especially where polymicrobial infection with multiresistant Enterobacteriaceae exists.

Co-trimoxazole is a useful agent with activity against many Gram-positive and negative bacteria and is available in both oral and intravenous formulations. Its association with Stevens–Johnson syndrome greatly diminished its popularity and as a result of this its use is often on an off-license only basis in many countries (e.g. United Kingdom). In an RCT evaluating the efficacy and safety of vancomycin versus co-trimoxazole in hospitalized intravenous drug users, vancomycin was found to be more efficacious, at least with regard to the more serious infections [68]. The increase in CA-MRSA has seen a resurgence of interest in its use and it has been successfully used to treat less severe SSTI in which the vancomycin MIC was greater than 2 mg/ml [69 ,70]. It is best reserved for less severe SSTI or as a step-down for vancomycin and/or other agents once clinical improvement has been established.

Ceftaroline Ceftaroline is a broad-spectrum cephalosporin that offers potent activity against both MRSA and nonESBL-producing Enterobacteriaecae while maintaining the safety and tolerability profile of other cephalosporins. It has been proven to be noninferior to vancomycin plus aztreonam for the treatment of SSTI in a multicentre phase III RCT [63], and in a post-hoc analysis of these studies patients treated with ceftaroline demonstrated an earlier clinical response rate [64 ]. &

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Clindamycin Clindamycin is another older agent with excellent efficacy at treating SSTI where isolates remain susceptible. It is also enjoying increased popularity in an era of CA-MRSA wherein its ability to negate toxin production makes it an intuitive choice. Unfortunately, because the link between it and Clostridium difficile infection was established, a judicious risk–benefit analysis should be undertaken prior to its use. Resistance rates vary between countries, so empirical use must be directed by the pattern of local epidemiology.

CONCLUSION Despite much debate on breakpoints, development of resistance and MIC measurement, the glycopeptides are still the standard of therapy for SSTI. Although there are pointers to faster response and



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better microbiological cure rates with newer drugs, primary endpoints from registration studies and other RCTs show non-inferiority of vancomycin. Given its low price, it is likely to stay as the favoured treatment option for non life-threatening SSTI, at least in the inpatient setting when a b-lactam cannot be used. For life-threatening SSTI, newer agents are increasingly favoured and would definitely be used more frequently if they were not so expensive. Better studies are urgently needed. Acknowledgements None. Conflicts of interest D.J.O. reports receiving honoraria and unrestricted educational grants from Pfizer Ltd. and unrestricted educational grants from Astellas Pharma Ltd. I.M.G. reports: GSK – Consultancy/lecture fees; MSD – Consultancy/lecture fees; AstraZeneca – Consultancy/ Lecture fees; Becton Dickinson – Consultancy; Astellas – Consultancy; Novartis – Consultancy/lecture fees; Pfizer – Consultancy/lecture fees; Biomerieux – Consultancy; The Medicines Company – Consultancy; Cepheid – Consultancy; Cubist – Consultancy. In his capacity as President of the International Society of Chemotherapy, he has frequently requested meeting support from a wide range of Diagnostic and Pharma companies, including many of those involved in the manufacture of diagnostics and antibiotics for MRSA.

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Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother 2006; 50:1372–1375. 28. Duane TM, Weigelt JA, Puzniak LA. Linezolid and vancomycin in treatment of & lower-extremity complicated skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus in patients with and without vascular disease. Surg Infect 2012; 3:147–153. This article emphasizes the better tissue penetration of linezolid.



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Martinez-Olondris P, Rigol M, Soy D. Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillinresistant Staphylococcus aureus in ventilated pigs. Crit Care Med 2012; 40:162–168. 34. MacGowan AP. Pharmacokinetic and pharmacodynamics profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 2003; 51 (Suppl 2):17–25. 35. Stein GE, Schooley S, Peloquin CA, et al. Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections. J Antimicrob Chemother 2007; 60:819–823. 36. Beekmann SE, Gilbert DN, Polgreen PM. Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network survey. Diagn Microbiol Infect Dis 2008; 62:407– 410. 37. Flamm RK, Farrell DJ, Mendes RE, et al. LEADER surveillance program results & for 2010: an activity and spectrum analysis of linezolid using 6801 clinical isolates from the United States (61 medical centers). Diagn Microbiol Infect Dis 2012; 74:54–61. This study describes 7 years of experience of surveillance of linezolid, demonstating that the rate of resistance of linezolid in S. aureus remains stable at 0.06% of isolate analyses. Of note, two cases of cfr-mediated resistance were found in this cohort. 38. Sa´nchez GM, De la Torre MA, Morales G, et al. Clinical outbreak of linezolidresistant Staphylococcus aureus in an intensive care unit. J Am Med Assoc 2010; 303:2260–2264. 39. Yue J, Dong BR, Yang M, et al. Linezolid versus vancomycin for skin and soft && tissue infections. Cochrane Database Syst Rev 2013; 7:CD008056. A very extensive comparison of the performance of linezolid and vancomycin with regard to SSTI demonstrating superiority of linezolid with regard to clinical cure, microbiological cure and SSTI treatment-related mortality. It does raise the caveat that the most of the studies were supported by the pharmaceutical company that makes linezolid, recommending that well designed independently funded RCTs be performed to confirm the evidence. 40. Watkins RR, Lemonovich TL, File TM Jr, et al. An evidence-based review of linezolid for the treatment of methicillin-resistant Staphylococcus aureus (MRSA): place in therapy. Core Evid 2012; 7:131–143. 41. Itani KMF, Biswas P, Reisman A, et al. Clinical efficacy of oral linezolid & compared with intravenous vancomycin for the treatment of methicillin-resistant Staphylococcus aureus – complicated skin and soft tissue infections: a retrospective, propensity score matched, case-control analysis. Clin Ther 2012; 34:1667–1673. This study uses propensity score matching to control for baseline charcteristics between groups receiving oral linezolid and intravenous vancomycin. It showed that there was 100% success of patients in the oral linezolid group as compared with 85.6% of the vancomycin group. This is another study echoing the findings of the Cochrane review. 42. Urbina O, Ferrandez O, Espona M, et al. Potential role of tedizolid phosphate && in the treatment of acute bacterial skin infections. Drug Des Devel Ther 2013; 7:243–265. A comprehensive review of the new oxazolidinone, tedizolid, encompassing PK/PD characteristics, side-effects and efficacy. 43. Prokocimer P, Bien P, Munoz A, Aster R. Hematologic effects of TR-701, linezolid and placebo administered for 21 days in healthy subjects [abstract]. In: 48th Conference on Antimicrobial Agents and Chemotherapy; October 25–28, 2008; Washington DC. 44. Bien P, Prokocimer P, Munoz KA, Bohn J. The safety of 21-day multiple ascending oral doses of TR-701, a novel oxazolidinone prodrug antibiotic [abstract]. In: 19th European Congress of Clinical Microbiology and Infectious Diseases; May 16–19, 2009; Helsinki, Finland. 45. Prokocimer P, De Anda C, Fang E, et al. Tedizolid phosphate vs linezolid && for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. J Am Med Assoc 2013; 309:559– 569. This is the first phase III multinational RCT involving tedizolid, demonstrating noninferiority to linezolid. Similar investigator-assessed clinical success rates and treatment emergent adverse events were observed. 46. Rybak MJ. The efficacy and safety of daptomycin: first in a new class of antibiotics for Gram-positive bacteria. Clin Microbiol Infect 2006; 12:24–32.

47. Phillips J, Cardile AP, Patterson TP, et al. Daptomycin-induced acute eosinophilic pneumonia: analysis of the current data and illustrative case reports. Scand J Infect Dis 2013; 45:804–808. This is a review of the published cases of daptomycin-induced acute eosinophilic pneumonia to date. This article reviews the postulated pathogenesis behind this phenomenon and also proposed a scoring system to aid clinicians in the diagnosis of this condition. 48. Sabol K, Patterson JE, Lewis JS, et al. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 2005; 49:1664–1665. 49. Rege S, Mohr J, Lamp KC, et al. Safety of daptomycin in patients completing & more than 14 days of therapy: results from the Cubicin outcomes registry and experience. Int J Antimicrob Agents 2013; 41:421–425. This is a comprehensive analysis of all adverse events occurring in 2263 patients receiving daptomycin at a median initial dose of 6 mg/kg intravenously. An elevation in CPK was noted in 2.2% cases. 50. Brown JE, Fominaya C, Christensen KJ, et al. Daptomycin experience in critical care patients: results from a registry. Ann Pharmacother 2012; 46:495–502. 51. Aikawa N, Kusachi S, Mikamo H, et al. Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections. J Infect Chemother 2013; 19:447–455. 52. Konychey A, Heep M, Moritz RK, et al. Safety and efficacy of daptomycin as & first-line treatment for complicated skin and soft tissue infections in elderly patients, an open-label, multicentre, randomized phase lllb trial. Drugs Aging 2013; 30:829–836. This is a ‘real life’ study notable for evaluating the safety and efficacy of daptomycin in patients over 65 years. 53. Gould IM, Miro´ JM, Rybak MJ. Daptomycin: the role of high-dose and && combination therapy for Gram-positive infections. Int J Antimicrob Agents 2013; 42:202–210. This is an article putting forth the argument that higher dose daptomycin and combination treatment be considered, especially in difficult to treat infections. The evidence to date demonstrating the safety of daptomycin at higher doses is discussed. 54. Sharma M, Riederer K, Chase P, et al. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2008; 27:433–437. 55. Patel D, Husain M, Vidaillac C. Mechanisms of in-vitro selected daptomycinnonsusceptibility in Staphylococcus aureus. Int J Antimicrob Agents 2011; 38:442–446. 56. Song Y, Rubio Y, Jayaswai RK, et al. Additional routes to Staphylococcus & aureus daptomycin resistance as revealed by comparative genome sequencing, transcriptional profiling and phenotypic studies. PLoS ONE 2013; 8:e58469. This is a study examining some of the molecular mechanisms leading to daptomycin resistance in S. aureus. 57. Mehta S, Singh C, Plata KB, et al. b-Lactams increase the antibacterial activity && of daptomycin against clinical methicillin-resistant Staphylococcus aureus strains and prevent selection of daptomycin-resistant derivatives. Antimicrob Agents Chemother 2012; 56:6192–6200. This is an article discussing the ‘seesaw’ effect together with data showing that daptomycin/b-lactam combinations may significantly enhance both the in-vitro and in-vivo efficacy of anti-MRSA therapeutic options against daptomycin resistant MRSA infections and represent an option in preventing daptomycin resistant selection in persistent or refractory MRSA infections. 58. Rose WE, Schulz LT, Andes D, et al. Addition of ceftaroline to daptomycin & after emergence of daptomycin-nonsusceptible Staphylococcus aureus during therapy improves antibacterial activity. Antimicrob Agents Chemother 2012; 56:5296–5302. This is yet another study demonstrating the efficacy of combination b-lactam/ daptomycin for daptomycin resistant MRSA strains, the b-lactam in this case being ceftaroline. Clearly further studies in this area are urgently needed. 59. Bounthavong M, Zargarzadeh A, Hsu DI, et al. Cost-effectiveness analysis of linezolid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus: complicated skin and skin structure infection using Bayesian methods for evidence synthesis. Value Health 2011; 14:631– 639. 60. Muralidharan G, Micalizzi M, Speth J, et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005; 49:220–229. 61. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005; 41:S341–S353. 62. European Medicines Agency. Questions and Answers on the Review of Tygacil (Tigecycline): Outcome of a Renewal Procedure (17 February 2011). http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_ QA/human/000644/WC500102228.pdf. [Accessed 14 November, 2013] 63. Corey GR, Wilcox M, Talbot GH. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010; 51:641–650. &



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Skin and soft tissue infections 64. Friedland HD, O’Neal T, Biek D. CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2012; 56:2231–2236. This is a retrospective analysis of the CANVAS 1 and 2 data using the new suggested Food and Drug Administration criteria for the evaluation of new agents to treat SSTI showing a numerically higher earlier clinical response with ceftaroline as compared with vancomycin plus aztreonam. Further studies should be undertaken to verify this finding. 65. LouieA,Castanheira M,LiuW,etal.Pharmacodynamicsofb-lactamaseinhibition && by NXL104 in combination with ceftaroline: examining organisms with multiple types of b-lactamases. Antimicrob Agents Chemother 2012; 56:258–270. This is an in-vitro study examining the effect of adding a non b-lactam b-lactamase inhibitor to ceftaroline. This work looks quite promising at overcoming the challenges posed by many b-lactamases encountered in clinical practice including Klebsiella pneumoniae carbapenemase and CTX-M. 66. Mendes RE, Tsakris A, Sader HS. Characterization of methicillin-resistant & Staphylococcus aureus displaying increased MICs of ceftaroline. J Antimicrob Chemother 2012; 67:1321–1324. Molecular characterization of clinical strains of S. aureus with elevated ceftaroline MICs showing that the increase in MIC correlated with decreased binding affinity for PBP2a. &

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67. Werth BJ, Steed ME, Kaatz GW. Evaluation of ceftaroline activity against heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-intermediate methicillin-resistant S. aureus strains in an in vitro pharmacokinetic/pharmacodynamic model: exploring the ‘seesaw effect’. Antimicrob Agents Chemother 2013; 57:2664–2668. This is another study supporting the ‘seesaw’ effect hypothesis. 68. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med 1992; 117:390–398. 69. Campbell ML, Marchaim D, Pogue JM. Treatment of methicillin-resistant & Staphylococcus aureus infections with a minimal inhibitory concentration of 2 mg/mL to vancomycin: old (trimethoprim/sulfamethoxazole) versus new (daptomycin or linezolid) agents. Ann Pharmacother 2012; 46:1587– 1597. This is the study showing the efficiacy of co-trimoxazole for the treatment of MRSA infections wherein the MIC of vancomycin was 2 mg/ml, albeit the success was seen in younger patients with less severe illness and fewer comorbidities. 70. Wood JB, Smith DB, Baker EH. Has the emergence of community-associated methicillin-resistant Staphylococcus aureus increased trimethoprim-sulfmethoxazole use and resistance?: a 10-year time series analysis. Antimicrob Agents Chemother 2012; 56:5655–5660.

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