This article appears in the following Journal of Antimicrobial Chemotherapy issue: Daptomycin development and clinical experience [View the issue table of contents]
Articles |
Daptomycin in endocarditis and bacteraemia: a British perspective
Microbiology Laboratory, Royal Shrewsbury Hospital, Mytton Oak Road, Shrewsbury, Shropshire SY3 8XQ, UK
* Tel: +44-1743-261161; Fax: +44-1743-261165; E-mail: Rod.Warren{at}sath.nhs.uk
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Abstract |
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Assessment of the place of daptomycin in the treatment of endocarditis and bacteraemia requires assimilation of data from one open-label randomized comparative clinical trial sized for equivalence, from registry data and from case reports. Selected relevant animal models and in vitro data are also considered in an effort to produce an integrated assessment of the current place of daptomycin in treatment. The evidence for the use of daptomycin is best in Staphylococcus aureus bacteraemia and endocarditis, but also includes some data on infections due to Enterococcus spp., especially if vancomycin-resistant. The emergence of resistance in a minority of patients on current dose regimens may mean that trials have to be repeated with higher doses, or the drug used in a combined therapy where rifampicin may be the best choice. In general, equivalence to comparator antibiotic regimens and a correlation for in vitro and in vivo findings have been demonstrated, but there are important gaps in the clinical data including a comparative equivalence trial in streptococcal and enterococcal endocarditis. Clinical benefit might be anticipated, but has not been proved, over aminoglycoside-containing regimens, and economic assessments are critical in the decision as to when and how daptomycin is deployed.
Keywords: MRSA , MSSA , Enterococcus , nephrotoxicity , resistance
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Introduction |
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TopAbstractIntroductionImplications of in vitro...EndocarditisGram-positive bacteraemiaDiscussionFundingTransparency declarationsReferences |
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Four years after its US launch and 20 years after initial development, daptomycin poses an interesting but not exclusively scientific dilemma for those who treat serious infection. It shares with linezolid a spectrum equivalent to that of the old antibiotics, vancomycin and teicoplanin, as well as new glycopeptides in development, and forms part of the range of new compounds generated to deal with multiresistant Gram-positive pathogens. Its use is therefore potentially differentiated from broader-spectrum drugs such as tigecycline and ceftobiprole that, while including multiresistant Gram-positive organisms in their spectrum, also offer Gram-negative activity. Daptomycin as a cyclic lipopeptide antibiotic, much as linezolid as an oxazolidinone, belongs to a class without other products in clinical use. Importantly, the issue for a novel agent is whether it has a competitive advantage that justifies the premium price in health service expenditure usually required to enable pharmaceutical companies to recoup their development costs. Competitive advantage is impossible to analyse from regulatory equivalence studies and also difficult to delineate from case reports, which are usually the total information available in the first 5 years of a modern product’s life. A deeply ingrained British public health perspective of economy, which delays widespread introduction of compounds, perhaps contrasts with the situation in the USA and more individual-patient-based health economies where the chance of advantage in a novel agent justifies any expense. Daptomycin, unlike linezolid, is only available as a parenteral agent. Hence, health economy structures for reimbursement of hospital medicines, and the economics and controls of administering parenteral versus oral drugs in the community [outpatient parenteral antibiotic therapy (OPAT)] versus products licensed only for hospital use, are important in determining usage. Increased savings and comparative efficacy of whole programmes avoiding hospitalization associated with the use of oral linezolid require comparison with daptomycin given as OPAT. The current closest comparators for daptomycin are therefore vancomycin and teicoplanin (in the non-US countries where the latter product is available), and the key questions are: under what circumstances should expensive daptomycin replace cheap vancomycin? and should it entirely replace teicoplanin, which is more costly than vancomycin? Economic evaluations of daptomycin have generally been inadequate, with a single-blinded study showing more rapid resolution of skin and soft tissue infections (SSTIs) when compared with historical vancomycin controls.1 The clinical and experimental use of daptomycin for endocarditis and bacteraemia has recently been the subject of a comprehensive systematic review2 that gives a summary of published data. A further extensive review of experience with daptomycin in its first 4 years has also been published.3
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Implications of in vitro and in vivo properties and toxicology for clinical use |
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Daptomycin has been extensively assessed in serious Gram-positive infection with Staphylococcus aureus, both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA), and vancomycin-resistant enterococci (VRE). Daptomycin as a sole agent offers bactericidal activity, whereas linezolid is always bacteriostatic, as is normally vancomycin.4 Daptomycin is effective in animal models in reducing bacterial counts in vegetations. Performance in these models has been systematically reviewed.5 No advantage has been seen in MRSA in the proportion of valves sterilized or in count reduction, but has been seen in MSSA and enterococcus infections, where results equalled those seen with antistaphylococcal penicillins and the combination of amoxicillin with gentamicin, respectively.5 The assessment of daptomycin has particularly focused on endocarditis. Although there is no clinical information on activity against viridans streptococcal endocarditis, daptomycin shows excellent activity against these organisms in vitro6 and therefore has the potential to be useful not only in patients with resistant organisms, but also in patients with penicillin allergy.
Despite the bactericidal activity of the drug, clinical failure associated with emergence of raised MICs is now well described in staphylococci isolated from patients treated with daptomycin,7–18 although this seems to be a rare event, occurring in bacteraemia/endocarditis with a frequency of only 5%.19 Emergent daptomycin resistance seems to be more common in S. aureus strains with intermediate resistance to glycopeptides (GISA),20–22 which often (but not always) manifests as heteroresistance, although daptomycin resistance was not evident in initial laboratory tests.23,24 There may be multiple mechanisms of decreased daptomycin susceptibility,25–27 some of which are not associated with emergence of the GISA phenotype28,29 and some that are.30 Daptomycin resistance due to VanA-producing strains of MRSA is improbable given daptomycin’s activity against enterococci with this gene. It may be that increasing the dose of daptomycin would reduce the emergence of the current resistance phenotypes by narrowing the described mutant selection window for daptomycin.31
Failure associated with resistance emergence is also described, albeit less frequently, with enterococcal infection. Enterococcus faecium is about 4-fold less susceptible (MIC90 = 4 mg/L) than Enterococcus faecalis.32 Reports of emergence of resistance are described with E. faecalis,33–35 E. faecium36–40 and Enterococcus durans.41 Resistance is unrelated to the occurrence of vanA, B or C resistance genes.42
The emergence of resistant strains and concerns with regard to optimizing therapy have led to use of the drug in combination with agents synergic in vitro such as gentamicin,43 rifampicin44–47 or β-lactams.44,46,48,49 Many individual case reports and registry reports in endocarditis describe such combined use despite the use of daptomycin monotherapy in clinical trials. However, no evidence of useful gentamicin synergy in pharmacokinetically-based human simulation experiments has been reported.50
An assessment of the efficacy of daptomycin in rabbit endocarditis models51 suggested that failure and high staphylococcal counts in vegetations were associated with daptomycin MICs >2 mg/L, but that doubling the dose of daptomycin reduced vegetation counts by 3 logs with apparently daptomycin-resistant strains. Studies of progressively increased dosing showed more bactericidal activity and no emergence of resistance.52 Higher dose regimens were also more effective in another animal model using GISA and VRE.53 Assessment in an in vitro thrombus model did not produce evidence of efficacy of increased dosing against resistant isolates.54 Both rifampicin and gentamicin improved activity against some, but not all, daptomycin-resistant isolates.
Staphylococcal and enterococcal bacteraemias commonly originate from catheters colonized with a biofilm of the organism. It is usually necessary to remove catheters colonized with S. aureus to reduce the risk of endocarditis and distant staphylococcal abscesses, osteomyelitis or discitis. In an in vitro model, daptomycin was significantly better than vancomycin, linezolid and tigecycline in eradicating MRSA from biofilms, and there was an additional effect when rifampicin was added to daptomycin.55 The rank order of improvement varied with the plastic and the organisms involved and the model used, but daptomycin performed well in all models.56,57 The efficacy of daptomycin when catheters have or have not been removed has not been separately analysed in most reports.
Historically, antimicrobial combinations were usually used in left-sided endocarditis, although this has reduced with the progressively higher prevalence of high-level gentamicin- and streptomycin-resistant enterococci, which do not show penicillin/aminoglycoside synergy. The option of combining daptomycin with aminoglycoside is available for enterococcal and streptococcal strains that lack aminoglycoside-modifying enzymes mediating high-level resistance, but whether this is advantageous needs to be established. The alternative combination of vancomycin with gentamicin used in enterococcal endocarditis in patients allergic to penicillins is notoriously nephrotoxic, although toxicity with vancomycin alone is rare. Toxicity of teicoplanin with gentamicin is rarer than with vancomycin and gentamicin.58 It is important to note that 79% success rates were reported with the use of teicoplanin alone in early trials in endocarditis resulting from a variety of organisms, so the comparison of daptomycin with teicoplanin is relevant.59 A key issue in the use of daptomycin in endocarditis is therefore the efficacy of the agent used alone, or the absence of nephrotoxicity if the agent is used in combination with gentamicin.
VRE are still relatively uncommon in the UK with mandatory surveillance suggesting <1000 patients per annum.60 Indeed, only an average of 6.1% of enterococci were resistant in a European survey,61 and not all of these will have the genotype producing cross-resistance to teicoplanin. Vancomycin resistance and vanA are more common in E. faecium. In 2006, in a BSAC surveillance in a limited range of hospitals in the UK,62 26 of 81 E. faecium were vancomycin-resistant compared with 4 of 142 E. faecalis. High-level gentamicin resistance is now very common with 47.9% of E. faecalis and 37% of E. faecium having MICs 
128 mg/L. Gentamicin is therefore becoming less relevant to the treatment of enterococcal endocarditis in general and new regimens are necessary, not just because of vancomycin resistance, but also because of resistance to the synergy between vancomycin, or penicillins, and gentamicin. Overall, the nephrotoxicity aspects of combined gentamicin use are being diminished by the progressive loss of utility of this agent. It is relevant to ask whether daptomycin could have a place as the empirical drug of choice in endocarditis to provide a Gram-positive antibacterial spectrum and whether high-dose penicillin therapy by continuous infusion, or glycopeptides alone, have any practical place in treatment now that daptomycin is available.
The use of daptomycin in the event of unwanted effects with either vancomycin or linezolid has been well described in registry reports, with treatment failures due to either toxicity or vancomycin resistance comprising the majority of indications for daptomycin use recorded in the registry. Individual case reports include the effective use of daptomycin in vancomycin-induced neutropenia.63 An unusual effect of daptomycin is muscle toxicity, and animal work led to an increase in the inter-dose interval from 8 to 24 h.64 Higher dosing must therefore be cautiously done. Less frequent dosing in renal failure, although with higher areas under the curve (AUC), has not been systematically explored in animal models of muscle toxicity, but no myotoxicity was reported in 111 patients receiving haemodialysis.65 The issue of dosage control for efficacy, without rapid availability of assays, may become a problem if the standard dosage was to be increased and if toxicity is dose-related. This is also a concern in areas where experience is limited, such as in the morbidly obese,66 in paediatrics67 and in continuous haemofiltration.68 An unusual approach to the problem is to determine the daptomycin dose based on vancomycin clearance rather than creatinine clearance.69
With a product licence for use in bacteraemia (essentially a laboratory finding rather than a single clinical condition) and SSTI, experience has accumulated with the use of daptomycin in many infections where Gram-positive organisms have disseminated from a local site. However, information on the site of origin of the bacteraemia is not always considered in relation to outcome, and there is a shortage of comparative studies in local infections and differential analysis of bacteraemic cases. As the primary clinical condition is what is being treated in many cases, and bacteraemia is a measure of systemic spread of an advanced local infection, this is surprising and clinically unhelpful.
New compounds do not always have predictable effects, but even so, regulatory studies, despite earlier comment, do have a place. Daptomycin has excellent in vitro activity against pneumococci, but is inactivated by pulmonary surfactant. With this background knowledge, it is not surprising that there is minimal assessment of daptomycin in pneumococcal bacteraemia associated with pneumonia and in pneumococcal bacteraemia associated with meningitis, although there is reason to think that the compound might be particularly effective in the latter indication provided the meninges were inflamed permitting drug passage.70,71 There are animal data showing effectiveness in S. aureus meningitis,72 but in vitro data suggest that Listeria strains have MICs similar to E. faecium, which may place them beyond the range treatable with daptomycin, at current dosage, in meningitis.73 There are other Gram-positive pathogens for which known in vitro efficacy has not been tested clinically, including Bacillus spp., Clostridium spp. and Listeria spp., but there is a dearth of detailed data on efficacy in bacteraemic infections with Streptococcus pyogenes and Streptococcus agalactiae.
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Endocarditis |
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Trials
As the only comparative trial19 to date is discussed in detail in another paper in this Supplement,74 this article focuses on other available data from the published literature. Significant findings to compare with other data include the emergence of resistance to daptomycin treatment, the occurrence of nephrotoxicity in patients treated not only with vancomycin and gentamicin but also penicillins and gentamicin, and frequent failure in left-sided endocarditis.
In a multivariate analysis of outcome in 800 Gram-positive infections, including 29 cases of endocarditis,75 the absence of endocarditis and good renal function were predictors of success. Further analysis of 49 cases of endocarditis (26 left-sided, 11 right-sided and 12 bilateral) from the same registry was carried out.76 Of these, 59% were due to S. aureus (83% MRSA) and 29% involved Enterococcus spp. (43% VRE). Additional cases were due to coagulase-negative staphylococci (CoNS) and there was a single case of viridans streptococcal endocarditis. These cases were a selected series with 88% receiving prior antibiotics. An earlier interim analysis77 had shown that 30% of those previously treated with vancomycin (n = 27) had switched because of toxicity compared with 60% of those previously treated with linezolid (n = 5).
Daptomycin dose in left-sided endocarditis was significantly greater (>6 mg/kg) and the outcome was similar, regardless of whether left- or right-sided endocarditis was studied.76 The mean dose was greater than in the open-label randomized comparative trial where left-sided endocarditis failure rates were more frequent. The number of patients treated was greater than in the comparative trial, with 12 of 28 evaluable cures when the drug was used alone in left-sided endocarditis compared with 2 of 13 used alone in right-sided infections. A substantial number of patients were classified as improved and this is not clearly defined in the registry studies. Of all cases, 29% were non-evaluable and 65% received additional effective antibiotics. Aminoglycosides were the most common concomitant antibiotics used in staphylococcal endocarditis, but 18% each received vancomycin or rifampicin.76 Failure rates between 8% and 20% are recorded in an analysis of 61 patients in successive years.78
An analysis of MRSA endocarditis showed that 10 of 23 improved.79 An analysis of 49 cases of left-sided S. aureus endocarditis (11 also right-sided) has also been carried out.80 MRSA endocarditis was treated for a median of 43 days and MSSA bacteraemia for 30 days. Failure occurred in 14%, and 31% were non-evaluable; here again there was no significant difference between left- and right-sided endocarditis. Although not statistically significant (P = 0.34), responses in MRSA endocarditis were poorer (7/41 failures) than in MSSA endocarditis (0/8 failures).
An analysis of 30 cases of enterococcal endocarditis (15 VRE) has also been reported.81 Of these, 67% received concomitant therapy including gentamicin (30%), vancomycin (25%), cephalosporins (25%) and rifampicin (20%). Success rates were 73%, with apparently no difference in the small number of cases receiving monotherapy with daptomycin. Experience with endocarditis due to CoNS is very restricted.82
Renal insufficiency does not apparently jeopardize the outcome of treatment of endocarditis using recommended dosage reductions in two small series of eight cases each.83,84 Experience in haemodialysis patients is limited to five cases.65
Treatment of prosthetic paravalvular abscess without surgery is very difficult, but surgery carries a high mortality. A case report describing successful use of monotherapy in this condition is therefore noteworthy.85 Treatment of endocarditis associated with a coronary stent is also difficult, and a case report describing success with 41 days of daptomycin therapy at 12 mg/L is of importance.86
Assessment of the potential role of daptomycin in endocarditis
The emergence of resistance in 5% of S. aureus cases suggests that combination therapy should be used at the current low doses of daptomycin, 4–6 mg/kg daily. The evidence of nephrotoxicity when penicillins are used in combination with gentamicin,19 let alone vancomycin, suggests that the use of gentamicin in combination with daptomycin, although it produces speedier bacterial killing in vitro, will be undesirable. When pharmacodynamically modelled, the evidence that the gentamicin concentrations produced in humans when given with daptomycin do not exert such synergic kill in serum also suggests that gentamicin synergy will not produce enhanced killing. Rifampicin would seem to be a better choice for combination therapy and this is supported by animal studies,47 but lacks any comparative clinical trial data in combination with daptomycin to support its use in staphylococcal endocarditis.
The closeness of the MIC for E. faecium to the daptomycin breakpoint, the high frequency at least for the UK of E. faecium strains among VRE and the high prevalence of gentamicin resistance in vancomycin-resistant E. faecium also suggest the need for an adjunctive agent other than gentamicin in the treatment of enterococcal endocarditis due to E. faecium. Rifampicin may be a suitable agent, but it is not clear if it interferes with the bactericidal activity of daptomycin. The use of penicillin can be considered for synergy despite the higher-than-average MIC for E. faecium, due to abnormal penicillin-binding proteins. The optimal therapy for these organisms needs urgent resolution. Animal model studies suggest that against vancomycin-susceptible and -resistant E. faecalis and vancomycin-resistant E. faecium, daptomycin is not only effective but more so than teicoplanin.87
Given the bactericidal effect of daptomycin and its activity in vegetations in animal models, daptomycin could usefully replace vancomycin, an agent which, when used alone, is said to be an inadequate therapy for endocarditis and is usually used with gentamicin to produce bactericidal synergy. There is a dearth of evidence, but this is probably the case for teicoplanin too, as it has similar characteristics. Daptomycin might offer advantages in all endocarditis situations where gentamicin has hitherto been used with penicillins for synergic effect. However, the absence of clinical information in streptococcal endocarditis and on daptomycin monotherapy in enterococcal endocarditis precludes this recommendation at present. In enterococcal endocarditis, the use of daptomycin with an aminoglycoside, if the strain does not show high-level resistance, or with rifampicin, should offer less nephrotoxicity than gentamicin with vancomycin given the information on synergic nephrotoxicity of vancomycin with gentamicin derived from published studies58 and the comparative assessment of daptomycin in S. aureus endocarditis of gentamicin with vancomycin.19 However, in the latter study, the high incidence of nephrotoxicity of gentamicin with penicillins is unlikely to be bettered with daptomycin plus gentamicin combinations, and the use of daptomycin with rifampicin may be an important advance. Endocarditis is sufficiently rare, its prognosis sufficiently grave and its inpatient treatment and renal support sufficiently expensive that a health economic assessment would be likely to suggest that no significant extra expense was incurred in this innovation in treatment. Such an economic assessment is needed.
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Gram-positive bacteraemia |
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Trials
Daptomycin has been assessed in a formal comparative randomized open-label trial sized for equivalence for staphylococcal bacteraemia and endocarditis.19 Excluding the endocarditis cases previously discussed, 182 patients with bacteraemia, 121 complicated by persistence, spread of infection or failure to remove a prosthesis within 4 days, were included across the two trial arms. Cases were treated for 10–14 days if uncomplicated and 28–42 days if complicated. With one exception, daptomycin therapy was monotherapy compared with combination therapy in a high proportion of the comparator study arm. Outcome was equivalent. Treatment failures were 13% to 18% more frequent in complicated bacteraemia in both treatment arms reflecting failure to undertake necessary surgical treatment. Overall, combining patients with both bacteraemia and endocarditis, renal dysfunction occurred in 11% of the patients receiving daptomycin and 26.3% of the patients receiving comparator therapy commonly including gentamicin.
The evaluation of bacteraemia data for CoNS depends on the certainty that it represents infection rather than contamination and on information on whether the line or other intravascular foreign body is removed in the course of therapy. Success rates reported for patients with blood cultures growing CoNS in registry studies are very high (97% to 100%), but the supporting data are not adequate to be sure that all of the 70 patients evaluable had genuine infections or to assess whether daptomycin therapy alone without catheter removal was efficacious.82
In an overall registry study, 209 of 279 catheter-related bacteraemias were considered evaluable.88 This analysis includes more patients than a formally published series.89 Clinical success rates were slightly higher for staphylococci (93%) than for enterococci (87%). Methicillin-susceptible staphylococci (whether S. aureus or CoNS) had marginally better outcomes then the methicillin-resistant strains; 76% of the patients had previously received vancomycin and 32% of these had VRE. This does affect the assessment of successful outcome, as does coincident antibiotic use, and there is no information in the publication that cultures were still positive after the vancomycin and before the daptomycin was started.
Information is available from the same registry on 111 bacteraemias in patients requiring renal replacement therapy, 39% of whom received 6 mg/kg daptomycin, with lengthening of dosage interval proportional to renal status.83 Cure and improvement rates were 84%; 40% of these infections were with MRSA with an average time to clinical response of 3.5 days and a mean duration of therapy of 20 days. More clinical details are available in a related report on haemodialysis patients.65 Anomalously, one analysis includes patients in whom the pathogen responsible for a bacteraemia was unknown, i.e. suggesting the use of the term bacteraemia as a clinical entity—but this only comprised 13 of 126 patients with a diagnosis of bacteraemia. Those patients with unconfirmed bacteraemia had only a 62% response rate compared with 92% in those with a proven Gram-positive pathogen.90
Registry information on 76 Gram-positive bacteraemias without catheters permits fewer conclusions because it is not clear what clinical entity was being treated;90 41% of these were due to S. aureus and 42% to enterococci. Failure rates were over 10% for MRSA infections. In a further study of SSTIs, success was seen in 21 of 24 bacteraemic cases,91 but such cases were commonly diabetic and had severe infections requiring stay in intensive care.92 Similarly, success rates in bacteraemic patients with osteomyelitis were 88%.93
Registry reports on enterococcal bacteraemia with a definitive source show a daptomycin success rate of 14 of 14 catheter/prosthesis-related bacteraemias and 13 of 14 non-catheter-related bacteraemias, with a mean response time of 3 days.94 Daptomycin has been used at 4–6 mg/kg/day in VRE bacteraemia in neutropenic patients.95 The high figure of five of nine therapy failures with two deaths is a disappointing result.
Persistent MRSA bacteraemia in prosthetic joint infection after removal of the prosthesis and use of vancomycin and rifampicin is unusual, and clearance of the bacteraemia in such a case by daptomycin with rifampicin is noteworthy.96
Assessment of the potential role of daptomycin in Gram-positive bacteraemia
The findings in bacteraemia in general mirror those in endocarditis assessments, particularly those with S. aureus infection. Complicated bacteraemias have substantially lower success rates than uncomplicated bacteraemia suggesting that the bactericidal action of daptomycin is not a substitute for adequate surgical interventions in deep-seated infections. However, the series and case reports encourage a view that if surgery is clinically contraindicated, daptomycin may offer occasional, surprising cures.
In general, registry experience correlates broadly with the clinical trial. There is good evidence for efficacy in renal impairment where catheter management, associated endocarditis and the potential problem of falsely high vancomycin levels in fluorescence polarization immunoassays can be problematic. Outcomes with vancomycin are inferior to the use of anti-staphylococcal penicillins in haemodialysis patients infected with MSSA, so daptomycin efficacy may be important. However, the numbers treated in haemodialysis-associated bacteraemia are, so far, modest. Furthermore, given initial problems with dosing and unwanted effects on muscle in normal patients with twice-daily but not once-daily dosing, the issue of the relationship of toxic effects to the AUC will need careful consideration. It is likely that the increased dosage interval in renal impairment compensates for any increase in AUC because of reduced clearance of the drug. Dialysis clearance may vary with filter and methodology, and dosage schedules are fixed rather than moderated by level measurement. Further formal comparative studies of daptomycin in moderate to severe renal failure on replacement therapy are desirable.
Registry data on enterococcal infections seem promising, particularly where the infections are catheter-related. However, enterococcal bacteraemias are often transient, may respond apparently to antibiotics with minimal in vitro activity and, in up to half the laboratory-defined cases, may not be clinically significant,97 so assessment requires clinical information on these infections. Results so far in haematology are not encouraging, but assessment is difficult. Comparisons with linezolid are needed for VRE infections in all clinical specialties as for MRSA infection.
There is a dearth of data on other Gram-positive infections. Data on CoNS infections with regard to whether catheters can be maintained, the activity of daptomycin against biofilms and on the emergence of resistance in such strains are needed. Data on streptococcal infections where penicillins are inappropriate (e.g. allergy) would be useful. This needs to be seen in the context of the efficacy of daptomycin in soft tissue infections and in specific clinically defined conditions where initial therapy is empirical.
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Discussion |
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TopAbstractIntroductionImplications of in vitro...EndocarditisGram-positive bacteraemiaDiscussionFundingTransparency declarationsReferences |
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Daptomycin has so far been largely used for multiresistant pathogens and in sepsis due to S. aureus. Advantage, economic or therapeutic, has not yet been demonstrated, but the profile of unwanted effects compared with other agents suggests that the compound has potential advantages in staphylococcal and enterococcal endocarditis, especially with resistant strains. The possibility of a more general advantage in treatment of endocarditis either initially and empirically or in penicillin-allergic patients requires further clinical experience. The drug may be particularly useful in the presence of bacteraemia associated with prostheses where medical risks preclude early surgery. It is possible that the drug may be useful to maintain lines that are difficult to replace or prostheses at high risk of chronic infection, but critical studies have not yet been undertaken. Comparative information on higher doses and use in combinations must consider not only outcome but also economics and unwanted effects.
The absence of efficacy in pneumonia limits the intensive care use of the drug to SSTIs. In the European market, attention must be paid to whether the drug should replace teicoplanin, and its place in infection in neutropenia, where trials suggest that linezolid is contraindicated, needs to be formally evaluated. Economic assessments comparing the drug with linezolid for total treatment including inpatient stay and outpatient use are still required, and blinded assessments may be needed to establish if the drug’s bactericidal effect permits shorter courses of parenteral treatment than some other agents. Daptomycin registry data, while useful in encouraging higher dosage in left-sided endocarditis, are no substitute for rigorous protocols and clinical trials in likely critical indications, and the clinical trial programme for this drug should not be interrupted on the basis of current limited licensed use, or due to any differences in perception of development need between drug developers and worldwide licensees, as many promising clinical indications, of which bacteraemia is only a descriptive part, have not yet been systematically evaluated.
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Funding |
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TopAbstractIntroductionImplications of in vitro...EndocarditisGram-positive bacteraemiaDiscussionFundingTransparency declarationsReferences |
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R. E. W. received an honorarium from Novartis for the production of this article. The editorial support of MSC Ltd was funded by Novartis.
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Transparency declarations |
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TopAbstractIntroductionImplications of in vitro...EndocarditisGram-positive bacteraemiaDiscussionFundingTransparency declarationsReferences |
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This article is part of a Supplement sponsored by Novartis.
R. E. W. has undertaken consultancy for Pfizer UK, Janssen-Cilag, Merck and Co. and its subsidiary Merck, Sharp and Dohme, and Wyeth and speaking engagements for Merck and Co. and Merck, Sharp and Dohme. He has received support to attend clinical meetings from Pfizer UK, Merck, Sharpe and Dohme, and Wyeth and has received a research grant from Merck, Sharpe and Dohme. He is a stockholder in Glaxo-Smith-Kline and Johnson and Johnson.
The editorial support of MSC Ltd in the research and preparation of this manuscript is acknowledged.
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References |
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