Efficacy of linezolid versus comparator therapies in Gram-positive infections

Transcription

1 Journal of Antimicrobial Chemotherapy (2003) 51, Suppl. S2, ii27 ii35 DOI: /jac/dkg251 Efficacy of linezolid versus comparator therapies in Gram-positive infections Mark H. Wilcox* Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK Introduction Treatment of Gram-positive bacterial infections is currently a therapeutic challenge because many of these pathogens are now resistant to standard antimicrobial agents. The emergence of multidrug-resistant, Gram-positive pathogens emphasizes the need for new antimicrobial therapy. Linezolid is an oxazolidinone antibiotic with a novel mechanism of action that works by inhibiting bacterial protein synthesis by blocking formation of the initiation complex. It is active against Gram-positive organisms resistant to other antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci (VRE). Results are encouraging from several large-scale, randomized, Phase III trials comparing the efficacy and safety of linezolid with standard comparator agents for the treatment of nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and infections due to MRSA and VRE. Intravenous/oral linezolid is a promising antimicrobial agent and provides the clinician with an additional treatment option, particularly among the limited therapies for resistant Gram-positive bacterial infections. The prevalence of Gram-positive, antimicrobial-resistant pathogens has increased markedly in the past decade. Between 1990 and 1997, the proportions of methicillinresistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant Enterococcus faecium isolates reported in the UK increased 16-, six- and 20-fold, respectively, relative to antibioticsusceptible species. 1 Increasing resistance has led to a growing reliance on glycopeptides, the conventional last therapeutic line of defence for Gram-positive infections. Consequently, vancomycin prescribing has increased dramatically, as reported in one study in which a 161-fold increase in use was observed over a 15 year period. 2 In addition, there has been a disturbing, concomitant increase in the prevalence of isolates with high-level glycopeptide resistance, particularly enterococci, glycopeptide-intermediate S. aureus (GISA) and most recently, clinical S. aureus isolates with high-level resistance to both vancomycin and teicoplanin. 1,3 7 Currently, GISA strains (specifically with reduced susceptibility to vancomycin) appear to be uncommon in centres at which focused surveillance has been performed. 5 However, clinical isolates with reduced susceptibility to glycopeptides have been reported in the UK and other countries. 4,6 For example, the United States Centers for Disease Control and Prevention reported two isolates of vancomycin-resistant S. aureus. 7 These are warning signals that emphasize the need for new therapeutic alternatives for Gram-positive infections. Furthermore, provocative retrospective data suggest that mortality may be significantly higher in patients receiving vancomycin alone, as opposed to those patients receiving combination therapy with rifampicin, for septicaemia caused by an epidemic MRSA strain (EMRSA-15). 8 Clinical improvement is relatively slow following initiation of glycopeptides, 9 and continued administration may result in extended venous access, monitoring of serum levels and prolonged hospital stay. Thus, glycopeptides have significant drawbacks that are exacerbated by the increasing prevalence of vancomycin and teicoplanin resistance in both enterococci and staphylococci. Linezolid is the first licensed member of the oxazolidinone class of antibiotics. With activity against almost all Grampositive pathogens, it is also the first truly new therapeutic alternative to vancomycin. Excellent tissue penetration and 100% oral bioavailability are notable properties of linezolid. Linezolid is approved in Europe and the USA for the treat-... *Tel: ; Fax: ; markwi@pathology.leeds.ac.uk... ii The British Society for Antimicrobial Chemotherapy

2 M. H. Wilcox ment of hospital-acquired and community-acquired pneumonia and complicated skin and skin structure infections; additional approved indications in the USA include vancomycinresistant E. faecium and MRSA infections and uncomplicated skin and skin structure infections. This review summarizes Phase III study evidence comparing linezolid with established therapies for the treatment of Gram-positive infections. Current indications for treatment with linezolid are based on these clinical trial data. The trial design and choice of comparator agents used in these trials were, in some cases, based on competing premises, such as satisfying different regulatory requirements that exist in various countries. Furthermore, most of these trials were designed and statistically powered to demonstrate equivalence of linezolid with comparators rather than superiority. In some studies, however, sub-analyses were performed to determine whether efficacy differences were apparent. While caution should always be exercised when performing such analyses, this approach may reveal potential advantages of a new drug. Furthermore, information from sub-analyses often guides the design of new studies to verify potential differences evident in pre-licensing trials. The challenge with new antibiotics is to maximize their therapeutic benefit and safeguard their efficacy through judicious prescribing. This review aims to provide health care practitioners with essential data to guide appropriate use of linezolid. Nosocomial pneumonia Significant morbidity, mortality and health care costs are associated with nosocomial pneumonia. 13,14 Nosocomial pneumonia accounts for nearly 50% of nosocomial infections in Europe and 15% of nosocomial infections in the USA. 13 Increasing numbers of nosocomial infections are caused by Gram-positive bacteria, including S. aureus and particularly MRSA. 13,15 A multinational, randomized, double-blind, controlled trial including 90 investigator sites compared the efficacy, safety and tolerability of linezolid with vancomycin in the treatment of adults with nosocomial pneumonia. 13 This clinical trial was the largest to evaluate nosocomial pneumonia caused by Gram-positive pathogens. A total of 396 patients with pneumonia confirmed by chest X-ray or adequate respiratory/sputum specimens for microbiological examination received linezolid [600 mg intravenously (iv) twice daily plus aztreonam; n = 203] or vancomycin (1 g iv twice daily plus aztreonam; n = 193) for 7 21 days. Up to 24 h of non-study antimicrobial therapy was permitted prior to study entry. Patients were removed from the study if only Gram-negative pathogens were isolated at baseline, and aztreonam could be discontinued if Gram-negative pathogens were not identified at baseline. Treatment groups were similar with regard to baseline characteristics. Notably, mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores for linezolid- and vancomycin-treated patients were 15.7 ± 6.5 and 15.4 ± 6.9, respectively, and >50% of patients were 65 years of age, indicating relatively high severity of illness in this patient population. Clinical and microbiological outcomes were evaluated at the test-of-cure visit days after treatment. In clinically evaluable (CE) patients (i.e. those with pneumonia confirmed by X-ray and adequate treatment duration and follow-up), mean durations of treatment were 11.6 ± 3.4 days for linezolid and 10.6 ± 3.1 days for vancomycin. Clinical cure rates for CE patients were similar between linezolid and vancomycin treatment groups [66% (71/107) and 68% (62/91), respectively] (Table 1). Microbiological success rates among microbiologically evaluable (ME) patients (i.e. those CE patients with a confirmed susceptible pathogen isolated from sputum or blood) were 68% (36/53) for linezolid-treated patients and 72% (28/39) for vancomycin-treated patients. Clinical cure rates for intent-to-treat (ITT) and ME patients did not differ significantly between treatment groups. Additionally, eradication rates for S. aureus and S. pneumoniae in ME patients did not differ significantly between the two treatment groups, with pneumococcal eradication (100%) being more common than S. aureus eradication (linezolid, 61%; vancomycin, 65%) in both treatment groups. The most common reasons for treatment discontinuation in both groups were the presence of Gram-negative pathogens, death and lack of efficacy. Treatment discontinuation was not significantly different in the two groups. Discontinuation due to adverse events was more common in vancomycin-treated patients compared with linezolid-treated patients (7.3% and 4.4%, respectively; not significant). The most common adverse event irrespective of relationship to study medication was diarrhoea in both treatment groups (linezolid, 9.4%; vancomycin, 7.8%); however, Clostridium difficile infection was documented in only two vancomycin-treated patients and in no linezolid-treated patients. Potential monoamine oxidase (MAO) inhibition interactions were also evaluated in 118 linezolid-treated patients receiving concomitant therapy with potential MAO interacting drugs, but no clinical evidence of an interaction was observed. The development of antibiotic resistance was not detected during treatment or follow-up in either treatment group. A subgroup analysis according to severity of illness as determined by APACHE II scores suggested that, as expected, clinical cure rates were inversely proportional to baseline APACHE II scores and were comparable between treatments. 22 The clinical cure rates for linezolid-treated patients were 83% (35/42) for APACHE II scores 0 11, 64% (14/22) for scores 12 15, 55% (11/20) for scores and 46% (10/22) for scores Corresponding clinical cure rates for vancomycin-treated patients were 82% (22/27), 79% (26/33), 44% (7/16) and 46% (6/13), respectively. Among patients with baseline APACHE II scores of in the ITT ii28

3 Linezolid in Gram-positive infections Table 1. Summary of linezolid comparator-controlled Phase III clinical trials in clinically evaluable populations a Infection/study type Treatment regimen Treatment duration (days) No. of patients randomized Patients with clinical cure (%) Nosocomial pneumonia double-blind, randomized 13 linezolid 600 mg iv twice daily 7 21 b vancomycin 1 g iv twice daily Community-acquired pneumonia inpatient, open-label, randomized 16 linezolid 600 mg iv twice daily, then 600 mg orally twice daily Skin and soft tissue infections complicated: double-blind, randomized 17 a No significant difference was observed between treatment groups in any study. b Treatment regimen also included optional aztreonam, 1 2 g three times daily. group, linezolid recipients had a significantly lower mortality rate than vancomycin recipients (9.8% versus 26.9%, respectively; P = ). Mortality did not differ significantly according to treatment group for any other APACHE II subgroups in the ITT or CE populations. Although the explanation for this observation is uncertain, it is possible that the subgroup of patients with APACHE II scores between 12 and 15 represents those in whom antibiotic therapy may be expected to influence mortality. In contrast, antibiotic treatment in patients with baseline APACHE II scores 11 or 16 may have little effect on mortality. It must be stressed that these observations result from subgroup analyses, and thus must be confirmed in an appropriately designed study before being considered credible. The explanations too are speculative and the apparent survival advantage of linezolid-treated patients with intermediate baseline APACHE II scores requires further investigation. Nonetheless, linezolid demonstrated efficacy at least equal to that of vancomycin in patients with nosocomial pneumonia. ceftriaxone 1 g iv twice daily b, then cefpodoxime 200 mg orally twice daily linezolid 600 mg iv twice daily, then b mg orally twice daily oxacillin 2 g iv every 6 h, then dicloxacillin 500 mg orally every 6 h uncomplicated: double-blind, randomized 18 linezolid 400 mg orally twice daily clarithromycin 250 mg orally twice daily Methicillin-resistant staphylococcal infections open-label, randomized 19 Vancomycin-resistant enterococcal infections double-blind, randomized 20,21 linezolid 600 mg iv twice daily, then 7 28 b mg orally twice daily vancomycin 1 g iv twice daily linezolid 600 mg iv twice daily or linezolid 600 mg orally twice daily linezolid 200 mg iv twice daily or linezolid 200 mg orally twice daily Hospitalized community-acquired pneumonia Community-acquired pneumonia (CAP) is a leading cause of hospitalization and may occur in previously healthy individuals without predisposing risk factors or in individuals with co-morbidities S. pneumoniae is the most frequent pathogen, particularly among those patients with concurrent bacteraemic pneumonia. 23,25 29 Penicillin-based regimens have been the mainstays of treatment for more than 30 years, but increasing antibiotic resistance to penicillins, extendedspectrum cephalosporins, macrolides and fluoroquinolones threatens the future utility of these agents In a multinational, randomized, open-label Phase III study, 747 adult patients hospitalized with suspected communityacquired pneumonia received either linezolid (600 mg iv twice daily) or ceftriaxone (1 g iv twice daily) followed by a switch to oral therapy (linezolid 600 mg twice daily or cefpodoxime 200 mg twice daily) at the physician s discretion. 16,34 Of these patients, 534 were CE (follow-up assessment days after the end of treatment) and 185 were ME. The treat- ii29

4 M. H. Wilcox ment groups were demographically comparable and had similar durations of antibiotic therapy (10.9 days for linezolid and 10.8 days for ceftriaxone/cefpodoxime). S. pneumoniae (73%) was the most commonly isolated organism followed by S. aureus (22%), Haemophilus influenzae (12%) and Moraxella catarrhalis (4%) (total is greater than 100% due to patients having more than one microorganism at baseline). Clinical cure rates were not significantly different between the two treatment groups overall (90.8% versus 88.6% in the linezolid and ceftriaxone/cefpodoxime groups, respectively) (Table 1). Likewise, microbiological success rates were comparable for linezolid- and ceftriaxone/cefpodoxime-treated patients (89.9% and 87.1%, respectively). There were no significant differences in overall pathogen eradication rates between the two treatment groups. Eradication rates noted in evaluable patients with S. pneumoniae pneumonia were 89% (63/71) and 90% (62/69) in the linezolid and ceftriaxone/ cefpodoxime groups, respectively (P = 0.830). Penicillinintermediate S. pneumoniae (PISP) was eradicated in seven of nine linezolid-treated patients and nine of nine cephalosporin-treated patients, and PRSP was isolated in five patients, with eradication reported in all cases. Linezolid demonstrated similar efficacy against S. aureus when compared with the cephalosporins, with eradication rates in evaluable patients of 90% (18/20) for linezolid and 77% (13/17) for the cephalosporins (P = 0.266). Given the small numbers of patients with H. influenzae or M. catarrhalis at baseline who received concomitant aztreonam, comment on the efficacy of linezolid alone in these patients is premature. Importantly, no pathogen eradication failures were attributed to development of linezolid or ceftriaxone/cefpodoxime resistance. Of 51 evaluable patients with S. pneumoniae bacteraemia, clinical cure rates were significantly higher in linezolidtreated patients compared with cephalosporin-treated patients [93% (27/29) versus 68% (15/22), respectively (P = 0.021)]. This finding of linezolid superiority over the cephalosporins in this subgroup of patients was not explained by any baseline demographic or clinical characteristic. However, mean patient age was 10 years older in this subgroup than in the ITT group, but overall age distributions were similar. 35 Further comparative study of linezolid and β-lactam antibiotics for the treatment of CAP, and more specifically, for concurrent S. pneumoniae bacteraemia would be of interest to support these striking findings. As mentioned previously, it must be stressed that such observations resulting from subgroup analyses require confirmation. Skin and skin structure infections Complicated infections Intravenous penicillinase-resistant penicillins or cephalosporins are the standard agents used to treat complicated skin and skin structure infections due to Gram-positive bacteria. However, decreased susceptibility of Gram-positive pathogens and inadequate treatment of these infections may result in treatment failure and/or significant co-morbid infections, such as osteomyelitis. In a randomized, double-blind, Phase III, multicentre study, treatment with linezolid (600 mg iv twice daily followed by oral linezolid 600 mg twice daily when clinical improvement was observed by the investigator) was compared with oxacillin (2 g iv four times daily followed by oral dicloxacillin 500 mg four times daily) in patients with complicated skin and skin structure infections. 17 All patients were treated for days, with follow-up days after the completion of therapy. In patients whose cultures yielded isolates resistant to study medication treatment was discontinued unless they showed clinical improvement and did not require concomitant antimicrobial therapy. Aztreonam was permitted for patients requiring therapeutic coverage for suspected Gram-negative pathogens. Primary efficacy variables included clinical cure rates in the ITT and CE populations and microbiological success rates in the ME population. Safety and tolerability were evaluated in the ITT population. Of the 826 randomized patients, 819 were included in the ITT analysis, with demographic and baseline characteristics similar between the treatment groups. Among the ITT patients, 600 (298 linezolid and 302 oxacillin/dicloxacillin) were CE and 294 (143 linezolid and 151 oxacillin/dicloxacillin) were ME. The most common diagnoses in both treatment groups in the ITT population were cellulitis (44%), skin abscess (15%) and erysipelas (10%). Deep infection at the primary site was observed in 81% of linezolid-treated patients and 77% of comparator-treated patients. Clinical cure rates in the ITT population were 70% and 65% in the linezolid and oxacillin/dicloxacillin groups, respectively (P = 0.141). The clinical success rates in the CE patients were higher (89% and 86% for linezolid and oxacillin/dicloxacillin, respectively) (Table 1). Among ME patients, the microbiological success rates were 88% for linezolid-treated patients and 86% for oxacillin/dicloxacillintreated patients. There were no significant differences between treatment groups with regard to species-specific pathogen eradication rates. Both treatment groups fared well with respect to adverse events, and the majority of events were mild to moderate in intensity. No serious drug-related adverse events were reported in the linezolid group. Interestingly, although overall antibiotic discontinuation rates were similar between the linezolid- and oxacillin/dicloxacillin-treated patients (3% versus 5.5%), antibiotic-related discontinuation rates were significantly lower in the linezolid group compared with the oxacillin/dicloxacillin group (1% versus 3.6%, P = 0.014). It has been suggested that linezolid s efficacy in treating skin and skin structure infections may be related to the high concentrations achieved in the skin and its ability to inhibit ii30

5 Linezolid in Gram-positive infections bacterial virulence factor and toxin production in S. aureus and Streptococcus pyogenes at concentrations well below the MICs. 36 Agents such as linezolid, which have both antibacterial properties and the ability to inhibit the synthesis of bacterial toxins, may provide improved efficacy and clinical outcomes in these Gram-positive bacterial toxin-mediated infections. 17 Uncomplicated infections Oral linezolid (400 mg twice daily) was compared with oral clarithromycin (250 mg twice daily) in a multinational (Europe, Asia, Australia, South Africa and South America), randomized, double-blind, Phase III controlled study in patients with uncomplicated skin and skin structure infections. 18 Treatment duration was 7 14 days, with follow-up 7 21 days after completion of therapy. Patients were required to have an infection site that could be sampled for Gram s stain and culture. Patients with a complicated infection, abscesses requiring surgical drainage, superinfected eczema or those receiving potentially effective antibiotic therapy in the 7 days prior to the study were excluded. Among the 332 patients randomized, 166 were treated with linezolid and 166 were treated with clarithromycin. At baseline, the most common pathogens were S. aureus and S. pyogenes. Cellulitis, skin abscesses and furuncles were the most frequent diagnoses in both treatment groups. Of the 124 CE patients treated with linezolid, 113 (91%) were clinically cured compared with 114 (93%) of 123 patients treated with clarithromycin (Table 1). The corresponding microbiological success rates for ME patients were 98% and 97%, respectively (P = 0.67). 37 Data were combined from up to four of the following Phase III studies (all powered to demonstrate equivalence) that included patients with skin and skin structure infections to determine the effectiveness of linezolid in different clinical subcategories. Two studies compared linezolid with clarithromycin for uncomplicated skin and skin structure infections, 18,37 one study compared linezolid with oxacillin followed by dicloxacillin for complicated skin and skin structure infections, 17 and one study compared linezolid with vancomycin for infections due to methicillin-resistant Staphylococcus species. 19 Combined, these studies enrolled a total of 2364 patients, 1188 of whom received linezolid. Among the CE patients from all four studies, 125 linezolidand 113 comparator-treated patients were diagnosed with infected wounds or surgical incisions. 38 Of these CE linezolid recipients, the cure rate was 82% compared with 78% for comparator recipients. For patients with a pathogen isolated at baseline, the microbiological success rate for linezolid was 85% (73/86) compared with 77% (68/88) for comparator recipients. 38 For CE patients, cellulitis or erysipelas was diagnosed in 283 linezolid- and 300 comparator-treated patients. Clinical cure rates at follow-up for these groups were 92% and 88%, respectively. The three most common pathogens in patients enrolled in all four studies were S. aureus, S. pyogenes and Streptococcus agalactiae. For ME patients in these groups, pathogen eradication was achieved in 89% of linezolid-treated patients and 85% of comparator-treated patients. 39 Overall, S. aureus eradication rates in the three skin and skin structure infection studies were 91% (203/223) for linezolid-treated patients and 86% (227/264) for comparatortreated patients. Corresponding data for streptococcalinfected patients were 90% (71/79) for linezolid and 86% (60/ 70) for comparator recipients. 40 Together, these findings consistently show that iv/oral linezolid 600 mg twice daily is as effective as β-lactam antibiotics and lend further support for the use of linezolid in the management of skin and skin structure infections. Methicillin-resistant staphylococcal infections S. aureus is a common cause of nosocomial pneumonia, skin and skin structure infections and bacteraemia. 13,41,42 The increasing worldwide prevalence of MRSA is a significant concern due to the limited number of antimicrobial agents effective against this organism. 43,44 In 1975, 2% of S. aureus isolates from US National Nosocomial Infections Surveillance hospitals were methicillin resistant compared with 40% in Historically, MRSA was a nosocomial pathogen, but increasing numbers of community-acquired MRSA infections are being reported. 45 Newer agents that are effective, safe and more convenient than traditional glycopeptide therapies for use in patients with methicillin-resistant staphylococcal (MRS) infections are needed. Consistent in vitro antimicrobial activity against methicillin-resistant staphylococci and MRSA is an important attribute of linezolid. Linezolid has also proven to be effective in the clinical management of MRS and MRSA infections. Intravenous to oral linezolid 600 mg twice daily (n = 240) was compared with vancomycin iv (n = 220) (dosing dependent on renal function) for up to 4 weeks in a multicentre, open-label, randomized trial of hospitalized patients with suspected or proven MRS infections. 19 Clinical and microbiological outcomes were evaluated days after treatment completion. Among the 254 CE patients, 124 received linezolid and 130 received vancomycin. Patients with pneumonia, skin and skin structure infections, urinary tract infections or bacteraemia caused by suspected or proven MRS species, mainly MRSA and methicillin-resistant Staphylococcus epidermidis, were included. S. aureus was identified in 80% of the microbiological intent-to-treat (MITT) population, with 93% identified as methicillin resistant. Mean treatment duration was similar between treatment groups (15.4 versus 13.8 days for linezolid and vancomycin groups, respectively). Clinical cure rates in evaluable patients with documented MRSA infections were similar in the linezolid and vancomycin groups (73% versus ii31

6 M. H. Wilcox 73%) (Table 1). MRSA eradication rates were similar between linezolid and vancomycin treatment groups (61% versus 63% for linezolid and vancomycin, respectively). Efficacy results were similar when grouped according to baseline diagnosis of the patient, with no significant differences in cure rates among evaluable patients with MRSA skin and skin structure infections (80% versus 73%), pneumonia (75% versus 75%) or bacteraemia (60% versus 70%) in the linezolid and vancomycin groups, respectively. Pharmacoeconomic analyses reported previously by Li et al. 46,47 show that use of oral linezolid for the treatment of presumed MRSA infection may result in substantial cost savings. Elsewhere in this supplement, Dr Dilip Nathwani discusses these data comparing hospital length of stay and other health-economic measures for patients with MRS infections treated with linezolid or vancomycin. Vancomycin-resistant enterococcal infections Vancomycin-resistant enterococci (VRE) were first reported in Europe during the late 1980s and are prevalent worldwide. 48 Enterococci are the second leading cause of nosocomial infections, accounting for 9% of all bacteraemias and up to 15% of all urinary tract, intra-abdominal, pelvic and wound infections. 49 Enterococci are often resistant to traditional antibiotic therapies, and until the advent of linezolid and quinupristin/dalfopristin, therapeutic options for VRE infection were severely limited. The efficacy of linezolid in patients with VRE infections was assessed in a randomized, double-blind, multicentre, dose-comparative, Phase III study. 20 At study initiation, a preferred antimicrobial regimen for the treatment of VRE infections did not exist, making it difficult to design a drugcomparative Phase III study. Therefore, this trial was conducted in an attempt to assess the efficacy of two linezolid doses in the treatment of patients with VRE infections. One hundred and forty-five patients were randomized to treatment with iv or oral linezolid (600 mg twice daily or 200 mg twice daily) for 7 28 days. The infection categories included urinary tract infection (most common), skin and soft tissue infection (second), bacteraemia of unknown origin (third), peritonitis, intra-abdominal infection, catheter-related infection and pneumonia. Test-of-cure occurred at the follow-up visit, 7 60 days after the end of therapy depending on the source of infection. The average duration of antibiotic treatment was similar between groups for both CE patients (n = 88; 15.0 days in the 200 mg group and 16.1 days in the 600 mg group) and ME patients (n = 65; 15.7 days in the 200 mg group and 16.8 days in the 600 mg group). The microbiological outcome for CE patients at follow-up was superior for the 600 mg linezolid group (88% success rate) compared with the 200 mg linezolid group (62% success rate) (P = 0.007). Similar microbiological success rate differences were observed in the ME patients (86% in the 600 mg group versus 59% in the 200 mg group; P = 0.015). Based on these dose response rates, the 600 mg, twice-daily dosing regimen appears to be highly effective in the management of VRE infections. Interestingly, the response rates observed in patients receiving the 600 mg, twice-daily dose in this study were similar to those observed in subjects given linezolid (600 mg twice daily either iv or orally to adults, or 10 mg/kg in children) as part of the linezolid compassionate-use programme. 50 In the latter study, of the 397 infections that occurred in 386 patients, 71% of infections were caused by VRE. Test of cure was assessed at the last evaluable time point after treatment completion. In evaluable patients the clinical and microbiological cure rates were both 79%, suggesting that linezolid appears to have similar efficacy in the tightly controlled clinical trial environment, as well as in real world clinical settings. Linezolid versus teicoplanin in patients with suspected or proven Gram-positive infections Once reserved for use only as a last resort, the glycopeptides vancomycin and teicoplanin are increasingly instituted as treatment for presumed resistant Gram-positive infections. Vancomycin is more commonly used; although teicoplanin is thought to have some advantages over vancomycin, including a longer half-life, two to four times higher activity in vitro, reduced toxicity and once-daily administration. However, the emergence of resistant strains of S. aureus, coagulase-negative staphylococci, S. pneumoniae, E. faecium and Enterococcus faecalis to one or both glycopeptides has created a need for novel antibiotics with specific anti-gram-positive activity. Linezolid was compared with teicoplanin in 430 patients with suspected or proven Gram-positive infections. 51 Patients received iv/oral linezolid 600 mg every 12 h (n = 215) or iv/ intramuscular teicoplanin (n = 215) for up to 28 days. In the ITT population the clinical cure rate with linezolid was superior to that of teicoplanin [92% (155/169) versus 83% (147/178); P = 0.005, 95% CI: 0.025, 0.132], with a statistically significant treatment advantage of 9.1% for linezolid. Clinical cure rates were also higher for the linezolid versus teicoplanin groups for skin and soft tissue infections (97% versus 93%, P > 0.05), pneumonia (96% versus 93%, P > 0.05) and bacteraemia (89% versus 57%; P = 0.009, 95% CI: 10.2, 53.4), respectively (ITT group). Comparable results were also demonstrated in the MITT population. Pathogen eradication rates were higher (but were not significant) for linezolid versus teicoplanin for all pathogens combined (82% versus 70%, respectively; P = ), and linezolid was more effective than teicoplanin in eradicating all reported S. aureus species, including MRSA. Adverse events were similar between the treatment groups. Events were of mild to ii32

7 Linezolid in Gram-positive infections moderate severity, with rapid resolution following treatment. Adverse events were more common in the linezolid versus teicoplanin patients (30% versus 17%) and were consistent with events associated with oral antibiotic use, with headache and gastrointestinal effects (nausea, vomiting, diarrhoea) the most common events. Overall, linezolid was well tolerated and clinically superior to teicoplanin in the treatment of presumed resistant Gram-positive infections. 51 Diabetic foot infections Diabetic foot infections are often polymicrobial in nature; however, aerobic Gram-positive bacteria that are multidrug sensitive and multidrug resistant (MRSA, VRE) are frequent causative pathogens. In a randomized (2:1 ratio), open-label, multicentre study, the clinical and microbiological efficacy and tolerability of iv and oral linezolid 600 mg every 12 h were compared with either iv ampicillin/sulbactam g every 6 h or oral co-amoxiclav mg every 8 12 h in hospitalized and ambulatory patients for 7 28 days. Intravenous vancomycin was permitted in ampicillin/sulbactamtreated patients for suspected or proven MRSA infection, and patients in both arms were permitted iv aztreonam for suspected or proven Gram-negative organisms. Patients were evaluated for osteomyelitis, which included analysis using the probe-to-bone test, but when this diagnosis was made, the study design permitted a maximum of only 28 days of antimicrobial therapy. Of 371 enrolled patients, 241 received linezolid, 120 received aminopenicillin β-lactamase inhibitor and 10 received no treatment. Baseline demographic and clinical characteristics were similar between treatment groups. Clinical cure rates were comparable for patients treated with linezolid or aminopenicillin β-lactamase inhibitor in the ITT [81.3% (165/203) versus 71.3% (77/108), respectively) and CE [82.8% (159/192) versus 73.3% (74/101), respectively] populations. Superior clinical cure rates were observed in the linezolid compared with aminopenicillin β-lactamase inhibitor treatment groups among ME patients [81.0% (119/147) versus 66.7% (36/54), respectively; 95% CI: 0.2, 28.4, P = 0.038], patients with infected foot ulcers [ITT: 81.4% (131/161) versus 67.9% (57/84); 95% CI: 6.0, 25.2, P = 0.025] and patients without osteomyelitis [ITT: 86.8% (138/159) versus 71.7% (66/92); 95% CI: 4.5, 25.7, P = 0.004]. No significant differences in patient microbiological success rates were noted between treatment groups in either the MITT or ME populations [MITT: 67.8% (120/ 177) versus 62.9% (56/89); ME: 72.2% (114/158) versus 63.0% (34/54) in the linezolid versus aminopenicillin β-lactamase inhibitor treatment groups, respectively]. Overall pathogen microbiological outcomes were also similar between linezolid and the aminopenicillin β-lactamase inhibitors, with high eradication rates noted for S. epidermidis [MITT: 90.0% (18/20) versus 100.0% (9/9), respectively], other coagulase-negative staphylococci [MITT: 71.4% (15/21) versus 76.9% (10/13), respectively], S. aureus [MITT: 72.2% (57/79) versus 63.8% (30/47), respectively] and S. agalactiae [75.0% (27/36) versus 64.7% (11/17), respectively). Linezolid and the aminopenicillin β-lactamase inhibitors were well tolerated; the majority of adverse events were mild to moderate in intensity. Drug-related adverse events were more common in the linezolid group [26.6% (64/241) versus 10.0% (12/120); P = 0.003], with the most frequently reported events being diarrhoea and nausea. Reversible anaemia [4.6% (11/241)] and thrombocytopenia [3.7% (9/241)] were noted in patients receiving linezolid for 14 days. Overall, linezolid was well tolerated and offered at least equal or superior efficacy over aminopenicillin β-lactamase inhibitors in the treatment of predominantly Gram-positive foot infections in diabetic patients. 52 Summary The increased incidence of antimicrobial-resistant Grampositive pathogens has made treatment of these infections more complicated. Linezolid has consistent activity against both susceptible and resistant Gram-positive organisms and is available in iv and oral formulations, which enhances convenience for the physician and the patient. 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