JAC Advance Access originally published online on October 13, 2006
Journal of Antimicrobial Chemotherapy 2006 58(6):1107-1117; doi:10.1093/jac/dkl393
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Review |
Bactericidal agents in the treatment of MRSA infections—the potential role of daptomycin
Department of Infection, King's College London St Thomas' Hospital, London SE1 7EH, UK
*Tel: +44-207-188-3127; Fax: +44-207-928-0730; E-mail: gary.french{at}kcl.ac.uk
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Abstract |
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Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens. These strains are often multiresistant to several antibiotic classes and are a major cause of serious hospital- and now community-acquired infections and associated morbidity and mortality. As a result of increasing antimicrobial resistance, glycopeptides, such as vancomycin, are widely used as first-line therapy for serious MRSA infections. However, the emergence of glycopeptide tolerance and resistance has complicated treatment and there remains a clinical need for new antibiotics with suitable pharmacokinetic properties with activity against MRSA and other Gram-positive pathogens. Infections caused by MRSA and other bacteria usually respond as well to bacteriostatic agents as to bactericidal ones. Nevertheless, there is evidence that rapid bacterial killing has potential clinical advantages over bacteriostatic therapy in certain infections. Daptomycin, the first of the cyclic lipopeptides, shows rapid bactericidal activity against S. aureus, including strains tolerant or resistant to other agents. This review outlines the methods by which bactericidal and bacteriostatic properties are defined and tested, discusses the potential importance of bactericidal therapy in MRSA and other infections and examines the potential role of daptomycin in treatment.
Keywords: antimicrobial agents , Gram-positive , multidrug resistant , Staphylococcus species
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Introduction |
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Staphylococcus aureus is a major cause of serious hospital- and community-acquired infections and associated morbidity and mortality.1 In recent years, the emergence of methicillin-resistant S. aureus (MRSA) strains resistant to all ß-lactam antibiotics and usually to several other antimicrobial classes has complicated the treatment of S. aureus infections. Prevalence rates of MRSA strains vary between (and within) countries but have increased significantly since the early 1990s. In Europe, the UK, Ireland and Greece have some of the highest rates of MRSA blood culture isolates (44, 41 and 44%, respectively, in 2004).2
Compared with patients infected with methicillin-susceptible S. aureus (MSSA), those infected with MRSA tend to have more serious underlying diseases, longer prior hospitalization, more prior antimicrobial therapy and other adverse prognostic factors.3–5 Nevertheless, when such factors are taken into account, MRSA infections still appear to produce significantly greater mortality, morbidity, length of hospitalization and treatment costs than MSSA infections.6,7
Until recently, most MRSA infections have been primarily healthcare-associated (HA-MRSA), being acquired either after hospital admission or by recent contact with another hospital or healthcare facility such as a care home for the elderly. However, since the late 1990s, true community-acquired MRSA (CA-MRSA) infections have appeared with increasing frequency worldwide, most commonly in the USA and Australia.8 These infections involve distinct community strains and occur in patients with no history of recent healthcare contact.9,10 HA-MRSA and CA-MRSA strains are best defined by genetic characterization, based on the staphylococcal cassette chromosome mec (SCCmec) and the distribution of genes encoding antibiotic resistance and toxin production. The majority of HA-MRSA strains carry SCCmec type I, II or III11,12 and are usually multidrug resistant. In contrast, CA-MRSA strains usually carry SCCmec type IV and its variants, and are susceptible to a wider range of antimicrobial agents. In addition, CA-MRSA strains often resemble community strains of MSSA; they may produce virulence factors such as Panton–Valentine leucocidin (PVL), haemolysins and enterotoxins13,14 and tend to cause primary skin and soft tissue infections. PVL-encoding genes are uncommon among HA-MRSA strains, which mainly cause bloodstream infections and infections of the urinary and respiratory tracts.15 Some CA-MRSA strains have now spread into hospitals and have begun to develop increasing antimicrobial resistance.16 It is likely that these community strains will become increasingly important in the future.
Resistance to ß-lactams and other agents has resulted in the increasing use of glycopeptides, such as vancomycin, as first-line therapy for the treatment of serious MRSA infections.17,18 However, various forms of glycopeptide resistance have appeared in MRSA strains, including rare high-level resistance,19 homogeneous and heterogeneous intermediate resistance19 and glycopeptide tolerance.20 In response to this challenge, a number of new antimicrobials have been developed including the streptogramins (quinupristin/dalfopristin),21 the oxazolidinones (linezolid)22 and, more recently, the cyclic lipopeptides (daptomycin).23–25
In the recently published British Society for Antimicrobial Chemotherapy (BSAC) guidelines on the treatment and prophylaxis of MRSA, the glycopeptides and linezolid are recommended as first-line therapy for serious MRSA infections.17 Quinupristin/dalfopristin has also been used successfully, but its usefulness is limited by high rates of resistance and problems with tolerability and drug interaction profiles.21,26–29 The BSAC guidelines do not make any recommendations about daptomycin as it was not licensed for use when the guidelines were prepared.
Daptomycin is currently approved by the US Food and Drug Administration (FDA) for the treatment of complicated skin and skin structure infections (cSSSIs) and by the European Agency for the Evaluation of Medicinal Products (EMEA) for the analogous indication of complicated skin and soft tissue infections (cSSTIs). The FDA has also recently licensed daptomycin for the treatment of S. aureus bacteraemia and right-sided infective endocarditis. A European application for these additional indications has recently been submitted.
Daptomycin is highly bactericidal against S. aureus and other Gram-positive bacteria. In earlier years, bactericidal activity was regarded as a desirable characteristic in antimicrobial agents, but its value in modern therapy has been debated.30,31 This article outlines the methods by which bactericidal and bacteriostatic properties are defined and tested, discusses the potential importance of bactericidal therapy for MRSA and other infections and examines the potential role of daptomycin in treatment.
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Defining bactericidal and bacteriostatic activity and tolerance |
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Bacteriostatic and bactericidal agents
Bacteriostatic agents inhibit the growth of bacterial cells but do not kill them, whereas bactericidal agents kill. However, these categories are not absolute, since the killing effect of the drug varies with the test method and the species being tested. Agents may be bactericidal against one group of organisms and bacteriostatic against another. Vancomycin, for example, is normally bactericidal against S. aureus and pneumococci, but bacteriostatic against enterococci;32 chloramphenicol is usually bacteriostatic but may be bactericidal at high concentrations against the organisms of bacterial meningitis;33 azithromycin is bacteriostatic against staphylococci but may be bactericidal against Streptococcus pyogenes;34 linezolid is bacteriostatic against staphylococci and enterococci, but may be bactericidal against streptococci, including Streptococcus pneumoniae;35 and quinupristin/dalfopristin is usually bactericidal against staphylococci and streptococci, but is bacteriostatic against most strains of Enterococcus faecium (it is inactive against Enterococcus faecalis).29
Tolerance
The identification of bactericidal activity is further complicated by the phenomenon of tolerance, in which organisms that are normally killed by a bactericidal agent are merely inhibited.36 Tolerance is often defined as an MBC:MIC ratio of 
32,20,37 but genetically determined and clinically important tolerance is better identified by time–kill studies, where tolerance may be defined as 
90% kill after 6 h.20 Several mechanisms have been associated with this phenomenon.36
Tolerance may be a reversible phenotypic response depending on the growth conditions of the test. Any condition resulting in a slowing or halting of growth may render the organism tolerant to ß-lactam antibiotics.36,38 This phenotypic tolerance is easily produced in vitro by limiting the supply of essential nutrients, and has also been demonstrated in vivo in animal models.36,38 It probably also occurs commonly in vivo during human infections but is difficult to identify.
Phenotypic tolerance may also explain the phenomenon of ‘persisters’, which make up a small proportion (
0.1%) of a bacterial population and comprise cells that are dormant or are replicating more slowly than the majority of the population. These ‘persisters’ are not killed by ß-lactams and some other bactericidal drugs, and grow on agar subculture during time–kill or MBC tests. Persisters do not represent a truly resistant subpopulation and are normally susceptible on retesting.
Another tolerance phenomenon is the ‘paradoxical effect’ that was first described by Eagle and Musselman and is sometimes referred to as the Eagle phenomenon. The rate at which bacteria are killed by ß-lactam antibiotics such as penicillin varies with drug concentration.39,40 At low concentrations penicillin may be bacteriostatic, but as concentrations rise, killing begins and then increases in rate. There is usually a specific concentration zone at which killing is maximal. In most strains, killing does not increase above this concentration; however, in some strains of many species, including S. aureus, killing is reduced at concentrations above this optimum. In their original paper, Eagle and Musselman tested seven strains of S. aureus, three of which showed this paradoxical phenomenon. Amongst these three strains, 99.9% of the initial inocula were killed by the optimal penicillin concentration (0.128 mg/L) within 6 h, but up to 13% survived at 6 h at a concentration of 256 mg/L, and 99.9% killing was achieved only after up to 27 h.
This paradoxical effect has not been fully explained, although several theories have been proposed:40–43 it may be a simple phenotypic effect resulting from slowing of growth at higher drug concentrations; the production of uncross-linked cell wall at low penicillin concentrations may be necessary for cell lysis and this may not happen at high concentrations when peptidoglycan synthesis may be totally inhibited; bacteria possess multiple penicillin binding proteins that vary in their affinities for penicillin and inhibition of one component might lead to cell death, whereas inhibition of another might reduce the rate of killing; finally, some autolytic enzymes responsible for cell death may be inhibited by high penicillin concentrations.
Voorn et al.44 demonstrated the effect of the Eagle tolerance phenomenon in a rat model of endocarditis, using a cloxacillin non-tolerant strain of S. aureus and its phenotypically tolerant variant. In vitro killing of the tolerant strain by cloxacillin was maximal near the MIC but paradoxically decreased at higher concentrations. This was also reflected in vivo; higher doses of cloxacillin were less effective in reducing bacterial numbers in vegetations caused by the tolerant strain, but not in those caused by the non-tolerant one.
The clinical significance of ‘persisters’ and the paradoxical effect is unclear. Of greater importance is tolerance associated with genetic changes, such as the development of defective autolytic systems,45 which results in reduced rates of killing in time–kill studies. The effects of this genetic tolerance are more amenable to study both in vitro and in vivo than phenotypic tolerance. Voorn et al.46,47 conducted experiments on the treatment and prophylaxis of endocarditis in a rat model using a cloxacillin non-tolerant S. aureus strain and its tolerant variant. Cloxacillin was significantly less effective in both treatment and prophylaxis of infections with the tolerant strain than with the non-tolerant strain.
There have also been some clinical studies in humans potentially supporting the view that serious infections with ß-lactam-tolerant strains of S. aureus respond less well to ß-lactam therapy than those due to non-tolerant strains.48,49 However, due to the difficulties of defining tolerance in these cases, the true clinical significance of this phenomenon is uncertain.36
Mode of action and bactericidal activity
The bactericidal activity of an antimicrobial agent against a particular organism tends to be related to its mechanism of action.30 In general, agents that disrupt the cell wall or cell membrane, or interfere with essential bacterial enzymes, are likely to be bactericidal, whereas those agents that inhibit ribosome function and protein synthesis tend to be bacteriostatic.
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Measurement of bactericidal and bacteriostatic activity |
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 TopAbstractIntroductionDefining bactericidal and... Measurement of bactericidal and... Vancomycin resistance and...Clinical importance of...The potential use of...ConclusionsTransparency declarationsReferences |
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In vitro methods
Methods used to determine bactericidal activity in vitro include the measurement of the MBC, time–kill curves and serum bactericidal tests (SBTs). All these in vitro tests have theoretical and technical difficulties and are relatively poorly reproducible.30,31,50 The US CLSI has published standard methods for the performance of some of these tests.51,52
Minimum bactericidal concentration (MBC)
The MIC of an antibacterial agent for a given organism is the lowest concentration of the agent required to inhibit the growth of an inoculum of the bacterium in a standard test. The MBC is the minimal concentration of antibiotic that kills the inoculum and can be determined from broth dilution MIC tests by subculturing to agar media without antibiotics. In time–kill studies, the MBC is the minimal amount of antibiotic that results in a 99.9% decrease in the initial inoculum within 24 h in a standard test. An agent is usually regarded as bactericidal if the MBC is no more than four times the MIC.
However, MBC measurements are subject to technical variation and have several theoretical limitations.31,50,53 MBC determinations are normally performed against logarithmic growth phase cultures; in clinical infections organisms may be growing more slowly and in these conditions the bactericidal activity of some agents may be reduced or lost.54,55 Although MBCs may give a general indication of bactericidal activity, time–kill curves give a more meaningful measurement.
Time–kill kinetic studies
In time–kill kinetic studies, culture broth containing dilutions of the test drug is seeded with a standard inoculum of the test organism and the rate of killing determined by counting survivors on plain agar at timed intervals.53 This method may be used during drug development to determine: (i) whether an agent is bactericidal (99.9% kill or a 3 log10 cfu/mL reduction in colony count from the initial inoculum) or bacteriostatic (<3 log10 cfu/mL reduction) for different species under the conditions of the test; (ii) whether killing is concentration- or time-dependent; (iii) whether some strains of species that are normally killed develop tolerance; and (iv) the effect of drug combinations.
Time–kill studies have shown that combining cell-wall-active agents, such as ß-lactams and vancomycin, with aminoglycosides results in synergy owing to enhanced penetration of the aminoglycoside.56 Recent studies have demonstrated that gentamicin acts synergistically with vancomycin against MRSA, while rifampicin is antagonistic.57 The bacteriostatic linezolid decreased the activity of gentamicin or vancomycin against MRSA, but was additive with rifampicin.58
Serum bactericidal activity
In the SBT,59 the ability of the patient's serum to kill the infecting organism (measured as the titre that kills 99.9% of the inoculum) is assayed around the expected times for the peak and trough serum concentrations. The SBT assesses the interaction of the pathogen, the antimicrobial agent and some aspects of host response, but it cannot assess other prognostic factors such as the contribution of host immunity, drug tissue penetration or the focus and severity of the infection. In earlier times, the SBT was used to assess and monitor treatment of bacterial endocarditis. However, the test was found to be predictive of bacteriological cure but not of ultimate clinical outcome.60,61 Furthermore, it is difficult to perform and has poor reproducibility. Although a standardized method was established in the 1980s59 and a CLSI guideline was published in 1998,51 in a UK external quality assessment exercise reported in 1997, only 34% of laboratories achieved acceptable results.62
The SBT is no longer in routine use for clinical monitoring of antimicrobial therapy. Instead, the bactericidal activity of an antimicrobial is usually determined during drug development and this property is taken into account when the drug is used clinically.
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Vancomycin resistance and tolerance in S. aureus |
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Glycopeptides have a pivotal role in the present therapy of MRSA infections. There has, therefore, been considerable interest in the emergence of various forms of in vitro resistance and tolerance to these agents. These resistance phenomena are complex, they have appeared, so far, in relatively few strains, and their clinical significance is uncertain. However, glycopeptide resistance in MRSA strains is of potentially great importance and may further compromise treatment.
Vancomycin resistance in S. aureus
S. aureus isolates are usually inhibited in vitro by vancomycin concentrations of 0.5–2 mg/L. Isolates with vancomycin MICs of 8–16 mg/L are referred to as vancomycin-intermediate S. aureus (VISA), and those with vancomycin MICs of 32 mg/L are designated vancomycin-resistant (VRSA).19 Vancomycin-resistant or -intermediate isolates usually show similarly reduced susceptibilities to teicoplanin and may be referred to as glycopeptide-resistant or glycopeptide-intermediate S. aureus (GRSA or GISA).
Full (high-level) vancomycin resistance
Fully vancomycin- and teicoplanin-resistant S. aureus isolates are rare: only four such isolates (all methicillin-resistant) have been reported—all from the US—between 2002 and 2005.63–67 High-level resistance is encoded in these strains by the vanA transposon, probably acquired from vancomycin-resistant enterococci (VRE).19
Intermediate vancomycin resistance
Intermediate vancomycin resistance in MRSA was first reported from Japan in 1997.68,69 One strain, Mu50, showed true homogeneous vancomycin-intermediate resistance (VISA), with a vancomycin MIC of 8 mg/L by microbroth dilution. A second strain, Mu3, showed heterogeneous resistance (hVISA): when grown in a drug-free medium, Mu3 produced subpopulations with varying degrees of vancomycin resistance; when grown in the presence of vancomycin 8 mg/L, Mu3 produced subclones with vancomycin MICs of 8 mg/L at a frequency 106 cfu/mL. A survey of more than 1000 MRSA isolates from 203 Japanese hospitals in 1996 found no further homogeneous vancomycin resistance. However, the prevalence of MRSA heterogeneously resistant isolates was 10–20% in Japanese University hospitals and 1% in non-University hospitals.69
Intermediate resistance to vancomycin in S. aureus is associated with a variety of alterations in cell wall structure and metabolism. These result in thickened cell walls with reduced peptidoglycan cross-linking that trap or sequester vancomycin molecules, impeding their antimicrobial function.70–73
Since the initial Japanese reports 10 years ago, VISA have been found throughout the world, but they remain uncommon, and only about 100 such isolates have been reported.74 Approximately 90% of these strains show heterogeneous resistance and 10% are homogeneous.75 In contrast to Hiramatsu's report of 1997, a study carried out by Ike et al. in 2001 found no VISA or hVISA among more than 6000 MRSA isolates from nearly 300 Japanese hospitals.76 Similarly, an analysis of more than 600 MRSA isolates from 33 US hospitals in 1997 failed to identify any homogeneous VISA and only two hVISA.77 A survey in 1998–99 of 303 epidemic MRSA EMRSA-15 and EMRSA-16 isolates from more than 50 hospitals in England and Wales found no homogeneous VISA and only one hVISA.78
VISA prevalence rates are, however, affected by the definitions of resistance and the test methods. Homogeneous VISA can be detected by broth dilution incubated for a full 24 h, but the detection of hVISA is more difficult.72 Wootton and colleagues proposed that hVISA should be confirmed by comparing the area under the population analysis profile curve with that of Mu3 as a reference;79 hVISA strains have a ratio of 0.90. Using this method, these authors found no VISA or hVISA amongst 100 MRSA isolated at Southmead Hospital in Bristol between 1983 and 1999.79
Although so far they have occurred infrequently, vancomycin-intermediate strains can arise from MRSA during treatment with vancomycin, especially when low concentrations of the drug are used.80 hVISA have appeared in all five of the major pandemic clones of MRSA and homogeneous VISA has arisen in two of these.75 It is likely that heterogeneous VISA will continue to emerge independently from existing circulating MRSA strains and that homogeneous VISA strains will develop from heterogeneous ones.
Vancomycin tolerance in S. aureus
Vancomycin tolerance in S. aureus has been reported in several studies.20,81,82 Even in the original paper describing ß-lactam tolerance in S. aureus,45 most of the strains also showed cross-tolerance to vancomycin. The mechanism of tolerance in S. aureus is unclear, although it is sometimes associated with autolysis deficiency.38
Most vancomycin-tolerant isolates are also tolerant to teicoplanin.20 Tolerance is not routinely identified and its incidence amongst S. aureus isolates is unclear. However, vancomycin tolerance appears to be more common in MRSA than in MSSA strains and in isolates from cases of endocarditis than from other causes of bacteraemia.20
The clinical significance of vancomycin tolerance in S. aureus and its relationship to vancomycin-intermediate resistance
There is evidence of vancomycin treatment failures in patients infected with hVISA strains.68,69,83,84 However, such strains remain uncommon and most patients who have failed with vancomycin therapy have been successfully treated with alternative agents such as linezolid or a combination of rifampicin and fusidic acid.83 Similarly, a number of small studies and case reports document poor clinical response to vancomycin therapy in bacteraemia and/or endocarditis caused by vancomycin-tolerant strains of S. aureus, and the need to use additional agents to produce a bactericidal effect.20,85–88
Sakoulas et al.89 found vancomycin MICs for isolates of MRSA from bacteraemic patients to vary from <0.5 to 2 mg/L. There was also variation in the rate of killing by vancomycin in vitro but this was not related to the MIC. Although these strains had vancomycin MICs within the susceptible range, in a multivariate analysis, there was a statistically significant relationship between the clinical outcome of vancomycin therapy and vancomycin MICs and bactericidal killing. Similarly, Domenech et al. showed that the bactericidal activity of glycopeptides decreases significantly with slight increases in MICs in vivo in a mouse S. aureus peritonitis model.90
This raises the possibility that MRSA strains are responding to the pressure of vancomycin therapy by a range of metabolic changes leading to a spectrum of increasing vancomycin MICs, heterogeneous and homogeneous intermediate resistance, and/or tolerance. Several genetic alterations associated with these changes are being investigated, including those in the accessory gene regulator agr. This operon regulates many metabolic pathways, increasing production of secreted virulence factors such as extracellular toxins, and decreasing cell-associated virulence factors such as adhesins. It also controls the expression of autolysins. Sakoulas et al. observed a significant association between a poor clinical response to vancomycin therapy and agr group II polymorphism in MRSA isolates, and suggest that the loss of agr function has survival benefits for MRSA strains, including the ability to resist the action of vancomycin.80,91
Other workers have shown that vancomycin tolerance in some VISA strains results from down-regulation of autolysin gene activity produced by other mechanisms.92 More work is needed to define the role of gene mutations that lead to a range of adaptive vancomycin resistance phenotypes, including heteroresistance and tolerance.
Jones has assessed the prevalence and significance of vancomycin tolerance by analysing S. aureus isolates from the global SENTRY surveillance project.93 Amongst more than 35 000 S. aureus strains isolated between 1998 and 2003 (5000–7000 isolates per year), there was no evidence of increasing vancomycin resistance over time when analysed by vancomycin MICs (no ‘MIC creep’). The proportion of isolates with vancomycin MICs >2 mg/L ranged from 0 to 0.1% per year, and there were none with vancomycin MICs >4 mg/L (except for some VISA strains from Hong Kong in 2000).
Jones also analysed separately 17 VISA strains, 88 hVISA strains (confirmed by population analysis profiling), 3 vancomycin-resistant (VRSA) strains and 105 wild-type (wt) MRSA strains. Vancomycin tolerance was defined as either an MBC:MIC ratio of 32, or an MBC:MIC ratio of 16 associated with a vancomycin MBC of 32 mg/L. In this analysis, 15% of wild-type MRSA strains met the definition of tolerance, compared with 74% of hVISA and all the VISA and VRSA strains.
These results indicate that vancomycin MICs are not increasing and VISA remain uncommon. However, tolerance is very common amongst hVISA isolates. Jones suggests that S. aureus with vancomycin MICs >2 mg/L should be regarded as intermediately resistant, and that these strains are likely to be vancomycin-tolerant and may not respond well clinically to glycopeptide therapy.
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Clinical importance of bactericidal activity |
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Severe infections are often not cured by antibiotics alone; this usually requires drainage or removal of infected material and a competent immune system. However, antimicrobial therapy is often essential for rapid cure by eradicating or reducing the bacterial load.94
Most infections respond just as well to bacteriostatic agents as to bactericidal ones30,31 but, in theory, bacterial killing should produce a faster resolution of infection and improved clinical outcome.95 The more rapid elimination of a bacterial pathogen should also reduce the likelihood of the emergence of resistance and spread of infection.
Although the theoretical benefits of bacterial killing are widely accepted, there are limited data demonstrating the superior activity of bactericidal agents in clinical practice.31 In part, this is because most serious infections are nowadays treated with single drugs or combinations of drugs with bactericidal action and comparisons with bacteriostatic agents are not performed. An exception has been recent studies of Gram-positive infections (including MRSA), where the bacteriostatic oxazolidinone linezolid has been demonstrated to be as effective as the bactericidal glycopeptides vancomycin and teicoplanin.96–98
Randomized clinical trials (RCTs) do not usually include patients with the complicated serious infections that might benefit from rapid bacterial killing, and do not identify antibiotic-tolerant isolates. However, there is a significant body of non-RCT evidence that tends to support the view that outcomes are better with bactericidal therapy in certain situations. These include: results from animal infection models; improved outcomes in patients with febrile neutropenia or endocarditis; treatment failures in meningitis where the bactericidal activity of a ß-lactam has been inhibited by the addition of a bacteriostatic agent; and vancomycin treatment failures or poorer outcomes in infections with vancomycin-tolerant MRSA, enterococci and pneumococci.
Bacteraemia and endocarditis
In the mid-1980s, a study of Gram-negative bacteraemia in (mainly) cancer patients showed that a successful clinical response was significantly associated with a peak serum bactericidal titre of 1:8 in non-neutropenic patients (P < 0.0001) and 1:16 in neutropenic patients (P < 0.001).99 Since then, neutropenic sepsis has been treated routinely with bactericidal agents and there are no other trial data comparing bactericidal with bacteriostatic regimens.
Gonzalez et al.100 reported on patients with bacteraemic S. aureus pneumonia. In this study patients with MSSA bacteraemic pneumonia treated with vancomycin had a significantly greater mortality than those treated with cloxacillin (47% of 17 versus none of 10, P < 0.01), and vancomycin therapy was an independent predictor of mortality. The reasons for this difference in outcome have not been fully elucidated, but possibilities include the slower bactericidal activity of vancomycin,100,101 and its poorer penetration into lung tissue.100,102
In early studies of the antimicrobial treatment of bacterial endocarditis, the bacteriostatic sulphonamides or low doses of penicillin were ineffective against streptococcal infections, but high bactericidal penicillin concentrations were curative.103 In patients with S. aureus endocarditis, bactericidal therapy produced a more rapid clinical and microbiological cure and resulted in a significantly lower mortality than bacteriostatic therapy.49 In another study, the addition of gentamicin to nafcillin resulted in more rapid clinical and microbiological response in S. aureus endocarditis but had no effect on mortality.104
Small and Chambers105 noted that in a group of intravenous drug users with MSSA endocarditis, clinical responses were worse with vancomycin therapy than with nafcillin. They quoted 11 other papers showing similar problems with vancomycin in these patients, and suggested that the differences in outcome might be due to the slow bactericidal activity of vancomycin against staphylococci. However, in contrast to these findings, an earlier study by Levine et al.106 in drug users with MRSA endocarditis reported that vancomycin therapy was adequate for cure in most patients.
Because of this experience, bacterial endocarditis is now universally treated with bactericidal agents or combinations, with the aim of sterilizing the vegetations in order to halt their growth and prevent relapse when treatment is stopped. The potential problems of infection with VISA and vancomycin-tolerant strains have been discussed previously.
Meningitis
Antibiotics active against bacterial cell wall in vitro, such as the ß-lactams, are bactericidal for actively dividing cells but fail to kill when organism division is halted by the addition of a bacteriostatic drug. This is thought to be the explanation of the significantly greater mortality rates in some reports of children with bacterial meningitis treated with ß-lactams combined with chlortetracycline145 or chloramphenicol146,147 compared with ß-lactam monotherapy.
Patients with meningitis caused by vancomycin-tolerant isolates of S. pneumoniae had a worse 30 day survival than those with non-tolerant isolates (49% versus 86%; P = 0.048).148 In one case study, vancomycin tolerance was associated with relapse of pneumococcal meningitis, despite appropriate therapy with ß-lactams and vancomycin.149 This failure of vancomycin therapy in vancomycin-tolerant pneumococcal meningitis mirrors the failure of bacteriostatic therapy of other meningeal infections and underlines the importance of bactericidal therapy in this condition.
Osteomyelitis
Osteomyelitis is most commonly caused by S. aureus and infections with MRSA strains are increasing. In the mid-1980s, in a small study of patients with acute and chronic osteomyelitis, serum bactericidal titres accurately predicted clinical cure or failure.150 Nowadays, treatment of osteomyelitis is nearly always with high-dose bactericidal agents or combinations. In animal models of osteomyelitis there is no direct relationship between bactericidal activity in vitro and cure in vivo. In some animal studies, the addition of rifampicin to other antibiotics resulted in more effective bone sterilization despite a lack of evidence for synergy, perhaps due to better drug penetration.107,108 Treatment failure in human osteomyelitis is usually related to failure of the antibiotics to reach the infecting organisms when there is necrotic bone or a foreign body present. There is limited evidence that supports the view that a bactericidal regimen is advantageous in the treatment of osteomyelitis where antibiotic bone penetration may be compromised.
Reduced potential for resistance development
If pathogens are killed rather than inhibited, resistance mutations that might emerge as the result of antibiotic pressure are eliminated. For example, failure to eradicate bacteria in the treatment of respiratory tract infections (RTIs) may affect the spread of resistant clones between patients and throughout the community.109,110
Recently, the concepts of the mutant prevention concentration (MPC) and mutant selection window (MSW) have been used to investigate the relationship between drug exposure and the development of resistance. It was demonstrated with a dynamic in vitro model that S. aureus mutants resistant to fluoroquinolones are selectively enriched when antibiotic concentrations fall inside the MSW (the period of exposure that is above the MIC but below the MPC).111 More recently, Firsov and colleagues showed that selection of mutants resistant to daptomycin and vancomycin occurred at concentrations that fell inside the MSW, but not at concentrations outside of it.112
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The potential use of daptomycin as a bactericidal agent in serious Gram-positive infections |
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Daptomycin shows activity against a wide range of Gram-positive organisms including both drug-susceptible and multidrug-resistant staphylococci and is rapidly bactericidal for these species, both in vitro and in vivo.113–115 Some bactericidal antibiotics, most notably ß-lactams, cause bacterial cells to lyse. This can be potentially harmful, as it may release bacterial endotoxins and other inflammatory cell components into the circulation, triggering cytokine cascades and potentially leading to septic shock and multiple organ failure.116,117 Daptomycin kills bacteria with negligible cell lysis, thereby reducing this risk.118 Minimizing the release of bacterial cell components may be a means of improving outcome in patients with serious infections.119
Bactericidal activity in vitro
In contrast to other classes of bactericidal antibiotics, the rapid bactericidal activity of daptomycin does not require cell division or active metabolism, and daptomycin retains bactericidal activity against non-growing S. aureus cells under a variety of physiological conditions.120 However, the importance of this in clinical therapy requires further investigation.121
The bactericidal activities of daptomycin, vancomycin, linezolid and quinupristin/dalfopristin against MRSA and VISA have been compared in vitro using time–kill studies.122 Daptomycin had bactericidal activity equal to or greater than the other agents against all organisms tested, killing 3 log10 cfu/mL by 8 h. Cha et al.123 used pharmacodynamic modelling to characterize the relationship between daptomycin exposure and bactericidal activity in vitro against MRSA, GISA and VRE isolates. Simulated daptomycin doses of 3–7 mg/kg once daily showed rapid and pronounced bactericidal activity against these multidrug-resistant strains.123
An in vitro model with simulated endocardial vegetations was used to evaluate the impact of high (9.5 log10 cfu/g) and moderate (5.5 log10 cfu/g) inocula of MSSA and MRSA on the activities of nafcillin, linezolid, vancomycin and daptomycin.124 At a moderate inoculum, nafcillin (MSSA only), vancomycin and daptomycin demonstrated equivalent and significant (P < 0.01) bactericidal activities (99.9% kill) (Figure 1). At high inocula, daptomycin showed bactericidal activity against both MSSA and MRSA by 24 h and was the only agent to achieve high-level bactericidal activity throughout the 72 h experiment.
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Daptomycin binds reversibly to plasma proteins, primarily albumin (90% at 4 g/100 mL) in a concentration-independent manner.125 However, daptomycin binds only weakly to albumin (dissociation constant 90.3 µM), and serum proteins have only a small effect on antibacterial activity: daptomycin MICs typically increase by only two doubling dilutions in the presence of 4% human albumin (
75% effective protein binding).126 Arithmetic mean MICs in 95% solutions of human and mouse sera, in 5% human albumin solution and in broth show that daptomycin is 2- to 4-fold more active than predicted from calculations of free drug concentrations.127 Bactericidal activity in vivo
Studies employing the thigh infection model in neutropenic mice have shown that daptomycin demonstrates potent, concentration-dependent bactericidal activity with prolonged post-antibiotic effects against S. aureus and enterococci, dynamically linked primarily to the 24 h area under the curve (AUC)/MIC ratio and Cmax/MIC.128–130 Over a 24 h period, free daptomycin concentrations averaging one to two times the MIC are needed for a bacteriostatic effect and two to four times the MIC for >99% killing.
Other animal models have been used to investigate the efficacies of daptomycin and comparative agents for the treatment and prophylaxis of MSSA and MRSA endocarditis, including a cloxacillin-, vancomycin- and teicoplanin-tolerant strain.82 Daptomycin, vancomycin and teicoplanin were similarly effective against the same S. aureus strains,82,131–133 but diminished susceptibility to both daptomycin and teicoplanin developed in an MSSA strain during one experiment.132
In an experimental rabbit pneumococcal meningitis model, daptomycin was significantly superior to the standard regimen of a combination of vancomycin with ceftriaxone.134 The mean penetration of daptomycin into inflamed meninges was 6% and 90% of CSF samples were sterilized after 4 h.134
A number of recent studies have reported a correlation between reduced daptomycin susceptibility and VISA.135–137 Cui et al.135 reported a thickening of the cell wall in such VISA strains, and demonstrated a correlation between cell wall thickness and increases in both vancomycin and daptomycin MICs. However, it should be noted that this correlation is based on MICs alone and the effect of cell wall thickening on the MBC of daptomycin requires further investigation. So far, tolerance to daptomycin has not been demonstrated.
Effectiveness in clinical trials
In clinical trials, daptomycin has comparable efficacy to standard therapy (vancomycin or penicillinase-resistant penicillins) for the treatment of cSSTIs.138 It has also been used successfully in the treatment of bone and joint infections, and is as effective as standard therapy (vancomycin or penicillinase-resistant penicillins plus initial synergistic gentamicin) for the treatment of bacteraemia and right-sided infective endocarditis caused by S. aureus, including MRSA. Daptomycin is not indicated for the treatment of community-acquired pneumonia (CAP). The lack of efficacy of daptomycin in CAP is thought to be due to a reduction of daptomycin activity in the presence of lung surfactant.139 Daptomycin maintains its bactericidal activity in the stationary phase of bacterial growth but the importance of this in clinical therapy requires further investigation.121
Resistance to daptomycin in wild-type strains of S. aureus is rare. Spontaneous resistance is uncommon, emerging in vitro at a rate <10–10, but resistance can be induced by serial passage in increasing concentrations of antibiotics.114 There have been a few reports of daptomycin resistance in clinical isolates of MRSA occurring during therapy in patients with prolonged treatment courses,140,141 and/or with sequestered infection.140,142 In the recent clinical trial of daptomycin at 6 mg/kg, intravenously, once-daily for the treatment of S. aureus bacteraemia and infective endocarditis, six of the patients failed on daptomycin therapy due to persistent or relapsing infection. All six patients had deep-seated infections such as complications of endocarditis, bone and joint infections, or inadequately drained abscesses.143,144 Further investigation of the reasons for failure in these cases is in progress.
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Conclusions |
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MRSA and other multiresistant Gram-positive bacteria have emerged as serious pathogens over the past decade, and increasing resistance has compromised therapy. The glycopeptides are the first-line therapy for MRSA infections, but emerging resistance and tolerance to these agents has underlined the need for new antibiotics with suitable pharmacokinetic properties effective against these pathogens.
Infections with MRSA and other bacteria usually respond as well to bacteriostatic agents as to bactericidal ones. However, the evidence reviewed here supports the view that rapid bacterial killing has potential clinical advantages over bacteriostatic therapy in certain infections.
Daptomycin, the first of the cyclic lipopeptides, shows rapid bactericidal activity against S. aureus, including strains tolerant or resistant to other agents, and has been effective in a variety of infections. Further trials are needed to evaluate the importance of the bactericidal activity of daptomycin in clinical practice.
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Transparency declarations |
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Professor G. L. French has been an advisor and speaker for Chiron BioPharmaceuticals.
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Acknowledgements |
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The author would like to thank Chiron BioPharmaceuticals for their assistance in preparing this manuscript.
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References |
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