Glycopeptide Antibiotics · 2017. 8. 28. · 914 Van Bambeke et al. so far, this paper reviews the...

Drugs 2004; 64 (9): 913-936LEADING ARTICLE 0012-6667/04/0009-0913/$34.00/0© 2004 Adis Data Information BV. All rights reserved.

Glycopeptide Antibioticsfrom Conventional Molecules to New Derivatives

Françoise Van Bambeke,1 Yves Van Laethem,2 Patrice Courvalin3 andPaul M. Tulkens1

1 Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain,Brussels, Belgium

2 Service des Maladies Infectieuses, Hôpital Saint Pierre, Brussels, Belgium3 Unité des Agents Antibactériens, Institut Pasteur, Paris, France

Vancomycin and teicoplanin are still the only glycopeptide antibiotics avail-Abstractable for use in humans. Emergence of resistance in enterococci and staphylococcihas led to restriction of their use to severe infections caused by Gram-positivebacteria for which no other alternative is acceptable (because of resistance orallergy). In parallel, considerable efforts have been made to produce semisynthet-ic glycopeptides with improved pharmacokinetic and pharmacodynamic proper-ties, and with activity towards resistant strains. Several molecules have now beenobtained, helping to better delineate structure-activity relationships. Two arebeing currently evaluated for skin and soft tissue infections and are in phases II/III. The first, oritavancin (LY333328), is the 4′-chlorobiphenylmethyl derivativeof chloroeremomycin, an analogue to vancomycin. It is characterised by: i) aspectrum covering vancomycin-resistant enterococci (VRE), methicillin-resistantStaphylococcus aureus (MRSA) and to some extent glycopeptide-intermediate S.aureus (GISA); ii) rapid bactericidal activity including against the intracellularforms of enterococci and staphylococci; and iii) a prolonged half-life, allowing fordaily administration. The second molecule is dalbavancin (BI397), a derivative ofthe teicoplanin analogue A40926. Dalbavancin has a spectrum of activity similarto that of oritavancin against vancomycin-sensitive strains, but is not activeagainst VRE. It can be administered once a week, based on its prolonged retentionin the organism. Despite these remarkable properties, the use of these potentagents should be restricted to severe infections, as should the older glycopeptides,with an extension towards resistant or poorly sensitive bacteria, to limit the risk ofpotential selection of resistance.

Glycopeptide antibiotics were introduced in clin- for livestock. The emergence and spreading of resis-ical practice 50 years ago, with vancomycin as the tance in enterococci and staphylococci towards van-only agent for almost 30 years. Teicoplanin was comycin has stimulated active research for new gly-launched in Europe in the mid 1980s and these two copeptides over the last 10 years, leading to themolecules remain the only members in this class production of a series of semisynthetic derivatives.available for human use; however, related deriva- Starting from vancomycin and moving through atives have been used widely as growth promotants short description of the various compounds obtained

914 Van Bambeke et al.

so far, this paper reviews the basis of the selection of may allow for a cooperative binding to theoritavancin and dalbavancin as new glycopeptides ligand.[6,9-12] These dimers are formed by hydro-for clinical development (the chemical structure of gen bonds between the glycopeptide aglycone,these products is presented in figure 1). We also which are maintained in the rigid conformationaldiscuss their advantages and potential role in the state favourable for ligand binding by the sugartherapeutic armament. residues on the glycopeptide molecule.[13]

• Anchoring of the antibiotic in the membrane, as1. Vancomycin and Teicoplanin proposed for glycopeptides carrying a lipophilic

tail, such as teicoplanin derivatives.[11] Lipidmoieties are actually a common determinant in1.1 Mechanism of Actionthe structure of several antibiotics, such as ramo-

Biochemical studies indicate that glycopeptides planin, moenomycin and tunicamycin, which in-inhibit the late stages of peptidoglycan synthesis.[1] hibit steps of peptidoglycan synthesis occurringThe biosynthetic pathway of this polymer involves close to the membrane. This suggests that suchthree steps: (i) the synthesis of cytosolic precursors moieties help to maintain the drug close to theirmade of pentapeptides fixed on a disaccharide; (ii) target. The importance of hydrophobic determi-the coupling of these precursors with a lipid carrier nants has been further emphasised by the obser-and the transfer of the resulting amphiphilic mole- vation that vancomycin derivatives may inhibitcule to the outer surface of the membrane; and (iii) transglycosylation without binding to D-Ala-D-the reticulation between individual precursors by Ala.[14,15]transpeptidation and transglycosylation reactions,accompanied by the release of the lipid carrier and 1.2 Mechanisms and Importanceits recycling to the inner face of the membrane. of ResistanceBacteria incubated with vancomycin accumulate

The American National Committee for Clinicalcytosolic precursors,[1] suggesting that glycopep-Laboratory Standards (NCCLS) has set up break-tides interfere with the assembly of peptidoglycanpoints for susceptibility and resistance, respectively,and, in particular, with transglycosylation reactionsof ≤4 and ≥16 μg/mL for vancomycin and ≤8 and(figure 2). At the molecular level, the primary target≥32 μg/mL for teicoplanin (see table I for the mainof vancomycin was shown to be the D-Ala-D-Alacharacteristics of the resistant strains). Over theterminus of the precursors. Molecular modelling andyears, two organisms of medical interest, namely theexperimental studies[1-4] indicate that vancomycinenterococci and Staphylococcus aureus, have devel-forms a stoechiometric complex with the D-Ala-oped a different, ingenuous resistance mechanism.D-Ala dipeptide via the formation of five hydrogen

bonds with the peptidic backbone of the glycopep- Resistance of enterococci to vancomycin wastide. The formation of this complex prevents the first reported in 1988.[27,28] The situation has evolvedtranspeptidation reactions by steric hindrance. The quite rapidly in the US, where resistance in bloodtightness of the interaction between the glycopep- isolates reached 13% in 1995 and 26% in 2000.[29]

tide and the D-Ala-D-Ala motif can be enhanced by Colonisation by resistant strains is common in criti-two mechanisms. cally ill and immunosuppressed patients as well as

• Formation of homodimers between glycopeptide in patients hospitalised in wards with high anti-molecules, which has been demonstrated for gly- microbial use. Hospitalisation is probably the maincopeptides of the vancomycin group, such as route for spread of these strains but, currently, out-vancomycin itself,[6] eremomycin[7] or chloroer- patients are also often colonised and may, therefore,emomycin.[8] Organisation of molecules in also represent another important source of contami-dimers confers a structural rigidity that locks the nation.[30] This alarming observation has stimulatedbinding pocket into the correct conformation and drastic measures in terms of hygiene, restriction in

© 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (9)

New Glycopeptides 915

HO OHOH

HN

HOOC

NH

O

OHN

O

NH

O

CONH2O

HN

NH

ONHCH3

HOCI

O

O

O

CI

OO

HOHO

OHO

H2N

HOH3C

CH3

HO OOH

HN

HOOC

ONH

OHN

O

NH

OHN

O

NH

O

HO

OCI

O O

O CI

NH2

OH

NHAc

OHO

HOOH

O

HOHO

HO

HN CO

OHOH

O

OH

OH

O

HO O

HN

HOOC

ONH

OHN

O

NH

OHN

O

NH

O

NHCH3

CI

HO

OH

HOCI

O O

O

OH

O

OH

OH

OH

OH

OHOOC

HOHO

HNCO

O

HO OHOH

HOOC

HN

OHN

O

NH

OCI

O

NH

OHN

CONH2O

NH

ONHCH3

O

O

O

CI

OH3CCH3

H2NHO

OO OH

HOHO

OCH3H2N

OHH3C

HO OHOH

HN

HOOC

NH

OHN

O

NH

OHN

OCONH2

NH

ONHCH3

O

OCI

O O

ClO

OHOH3C

CH3

H2N

OO

OH

HOHO

OHN

H3C

CI

OH

CH3

HO OOH

HN

CO

NH

O

OHN

O

NH

HN

NH

NH

N

HOCI

O O

O O

OH

CI

HO

NHCH3

O

O

O

OHOH

OHOH

OHOOC

HOHO

HNCO

O

Vancomycin

Teicoplanin

LY264826 A40926

Oritavancin Dalbavancin

Fig. 1. Chemical structure of glycopeptides. Upper panel: vancomycin and teicoplanin, which are the two glycopeptides currently availablein clinical settings; lower panel: oritavancin and dalbavancin, two semisynthetic glycopeptides currently under clinical development. Middlepanel: natural derivatives of vancomycin and teicoplanin used for the synthesis of oritavancin and dalbavancin, respectively. The part of themolecule that is common to all glycopeptides appears in bold. The arrows point to the differences between molecules.



Susceptible strain

ddl

UDP

Transpeptidase

Transglycosylase

UDP UMP UDP UDP

VanSVanS

VanR -PVanR

-P

ddl VanX VanT

VanHpyr

VanA-E

UDP UMP UDP UDP

L-ser

UDPvan operon

VanY

Transglycoslase

Transpeptidase

Resistant Enterococcus (VRE)

Intermediate resistant Staphylococcus aureus (VISA)

Transpeptidase

Transglycoslase

Glycopeptide

N-acetylmuramic acid

N-acetylglucosamine

Tripeptide

Interpeptide bridge

Lipid carrier

D-Ala

D-Lac

D-Ser

Depsipeptide

Fig. 2. Peptidoglycan synthesis in glycopeptide-susceptible bacteria (upper panel), in glycopeptide-resistant enterococci (middle panel) andin glycopeptide-intermediate staphylococci (lower panel).[2,5] In susceptible strains, peptidoglycan precursors are ending by D-Ala-D-Alatermini synthesised by D-Ala:D-Ala ligases (ddl). Glycopeptides interact with D-Ala-D-Ala termini of pentapeptides (through five hydrogenbonds) at the cell surface, preventing transglycosylation reactions and therefore peptidoglycan reticulation. The figure also illustrates howdimerisation of glycopeptide molecules or anchoring in the membrane by a hydrophobic tail may increase the tightness of this interaction.Hydrophobic derivatives may also inhibit the transglycosylation step without binding to peptidoglycan precursors. In glycopeptide-resistantenterococci, the presence of glycopeptides activates the signal-transducing system VanS (sensor) – VanR (regulator), which allowstranscription of the resistance genes. These include enzymes involved in the hydrolysis of D-Ala-D-Ala termini (VanX and VanY) or in thesynthesis of precursors ending by either D-Ala-D-Lac (VanH and VanA, VanB or Van D) or D-Ala-D-Ser (VanT and VanC, VanE or VanG),characterised by a lower affinity for glycopeptides. In glycopeptide-intermediate staphylococci (so-called VISA [vancomycin-intermediateStaphylococcus aureus] or GISA [glycopeptide-intermediate S. aureus] strains), more murein monomers are supplied and incorporated inthe peptidoglycan, in which more free D-Ala-D-Ala residues remain present because of a decreased level of reticulation. More glycopeptidemolecules are therefore trapped in the multiple layers of the thicker cell wall but fewer reach their target at the cell membrane. UDP = uridinediphosphate; UMP = uridine monophosphate; VRE = vancomycin-resistant enterococci.



Table I. Main characteristics of glycopeptide-resistant bacteria

Resistance Bacterial species Expression Mechanism of resistance MIC range of Referencestype glycopeptides (mg/L)

vancomycin teicoplanin

VanA Enterococcus faecium Inducible (by vancomycin Modified target 64–1000 16–512 16

E. faecalis and teicoplanin) (D-Ala-D-Lac)

E. avium

E. durans

E. hirae

E. mundii

E. raffinosus

E. gallinarum

E. casseliflavus

Staphylococcus aureus Inducible (by vancomycin Modified target 17-20and teicoplanin) (D-Ala-D-Lac)

VanB E. faecium Inducible (by vancomycin) Modified target 4–1000 0.5–1 16

E. faecalis (D-Ala-D-Lac)

Streptococcus bovis 21

VanC E. gallinarum Constitutive/inducible Modified target 2–32 0.5–1 16

E. casseliflavus (D-Ala-D-Ser)

E. flavescens

VanD E. faecium Constitutive Modified target 64–128 4–64 16,22(D-Ala-D-Lac)

VanE E. faecalis Inducible (by vancomycin) Modified target 16 0.5 16,23(D-Ala-D-Ser)

VanG E. faecalis Inducible (by vancomycin) Modified target 16 0.5 24(D-Ala-D-Ser)

VISA S. aureus Thickened cell wall with 8 8–32 5,25increased proportion ofD-Ala-D-Ala termini

GRSA S. aureus Stop codon in the gene of 26PBP4

GRSA = glycopeptide-resistant Staphylococcus aureus; MIC = minimum inhibitory concentration; VISA = vancomycin-intermediateStaphylococcus aureus.

antimicrobial use and surveillance to try to control The mechanism of resistance in enterococci re-or even reverse the situation.[29] In sharp contrast, lies on synthesis of peptidoglycan by an alternativeresistance of enterococci in Europe is minimal (3%) pathway, which produces precursors ending inand observed only in nosocomial infections;[31] out- D-Ala-D-Lac or D-Ala-D-Ser instead of D-Ala-D-breaks have been reported but remain sporadic. Ala and concomitantly eliminates precursors endingCarriage of resistant enterococci in animals, how- in D-Ala-D-Ala. The replacement of D-Ala by D-ever, is frequent in Europe and is thought to be due Lac suppresses one of the five hydrogen bondsto the massive use of avoparcin, a glycopeptide between the glycopeptides and their target, whichantibiotic used as growth promoter in animal leads to a 1000-fold decrease in the binding affini-feed,[32,33] but which has the same mode of action as ty.[2,37] The substitution in D-Ser causes a conforma-vancomycin and, therefore, shares cross-resistance. tional change, which also reduces vancomycin affin-The ban on avoparcin use instituted by EU countries ity, although not as markedly as with D-Lac. To behas caused, in most countries, a fall in the preva- phenotypically detectable and significant, resistancelence of resistance in both animals and requires the coordinated action of several enzymeshumans.[29,34-36] (see figure 2). Thus, the bacteria need to synthesise



Table II. In vitro activity of oritavancin and dalbavancin compared with those of vancomycin and teicoplanina

Organism MIC range (mg/L) References

vancomycin oritavancin teicoplanin dalbavancin

Staphylococcus aureus

methicillin-susceptible 0.13–1 0.13–1 0.25–8 ≤0.03–0.5 490.25–2 0.06–4 0.125–4 0.06–0.5 50-55

methicillin-resistant 0.5–4 0.13–4 0.13–8 0.06–1 49

0.25–4 0.03–8 0.06–8 0.06–1 50-55

vancomycin-intermediate 8 1–8 8–32 2 56-58

Staphylococcus epidermidis

methicillin-susceptible 0.13–1 0.25–1 0.25–16 ≤0.03–0.25 490.25–2 ≤0.03–8 ≤0.03–16 50,54

methicillin-resistant 1–4 0.25–4 1–16 ≤0.03–1 490.5–4 0.25–16 0.125–16 50,54

Staphylococcus haemolyticus

methicillin-susceptible 1–4 0.06–1 1–32 ≤0.03–0.25 490.25–4 0.12–8 ≤0.12–8 50,54

methicillin-resistant 0.5–8 0.13–1 2–128 ≤0.03–4 491–4 1–4 0.5–>16 50,54

Other coagulase-negative staphylococci

methicillin-susceptible 0.5–2 0.06–0.5 0.13–4 ≤0.03–0.13 490.25–4 ≤0.01–2 ≤0.12–32 ≤0.03–0.25 51-53

methicillin-resistant 0.5–4 ≤0.03–0.5 0.06–32 ≤0.03–0.13 490.25–8 0.015–4 0.06–64 0.06–1 51-53

Streptococcus pyogenes 0.5–0.5 0.016–0.13 0.008–0.06 ≤0.002–0.06 490.25–0.5 0.06–0.5 ≤0.03–0.12 55

Streptococcus pneumoniae

penicillin-susceptible 0.13–0.5 ≤0.002–0.06 0.008–0.06 0.016–0.13 490.06–0.5 ≤0.002–0.12 ≤0.01–0.25 51,52,54,55

penicillin-resistant 0.25–2 ≤0.002–0.06 0.016–0.13 0.008–0.13 490.06–1 0.002–0.25 ≤0.01–0.25 51,52,54,55

Viridans streptococci

0.25–2 ≤0.12–2 ≤0.03–0.06 53penicillin-susceptible 0.12–1 ≤0.01 ≤0.01–0.5 52penicillin-resistant 0.25–1 0.01–0.06 ≤0.01–0.5 52β-Haemolytic streptococci 0.25–1 ≤0.12–0.25 ≤0.03–0.12 53

Enterococcus spp.

vancomycin-susceptible 0.25–4 0.06–0.25 0.13–0.5 0.06–0.13 49

≤0.01–4 ≤0.03–2 ≤0.012–8 ≤0.03–1 50-54,59VanA >128 0.06–1 64–>128 0.5–>128 49

64–>256 0.06–1 32–>256 50

VanB 8–128 ≤0.03–0.13 0.13–8 0.02–2 498–128 0.25–1 0.125–0.5 60

VanC 4–16 ≤0.03–1 0.125–4 50Bacillus spp. ≤0.12–1 ≤0.015–0.5 ≤0.12–4 ≤0.03–2 53,54Corynebacterium spp. 0.25–0.5 ≤0.12–1 ≤0.03–0.12 53

Continued next page



Table II. Contd

Organism MIC range (mg/L) References

vancomycin oritavancin teicoplanin dalbavancin

Listeria spp. 0.25–2 ≤0.03–0.125 0.06–0.25 50Clostridium difficile 0.5–4 0.016–2 0.064–0.5 0.125–0.5 61,62

Clostridium perfringens 0.025–4 0.016–2 0.064–4 0.03–0.125 61,62

Haemophilus influenzae ≥16 16–32 8–64 53,54a When two rows of data appear for a single species, the first one refers to studies where the drugs are compared against the same

strains; the second one represents the range of MICs reported in other publications.

MIC = minimum inhibitory concentration.

D-Lac (VanH) or D-Ser (VanT) and D-Ala-D-Lac an abundant extracellular material of still ill-charac-or D-Ala-D-Ser (VanA, B, D or C, E, G), and to terised nature and an impaired ability to divide.[43]

degrade D-Ala-D-Ala (VanX) or to remove D-Ala These phenotypic changes can be explained by thefrom growing precursors (VanY) or both (VanXY). production of an altered peptidoglycan with an in-Moreover, a two-component regulatory system creased proportion of free D-Ala-D-Ala termini(VanS-VanR) resulting in induction by either van- (less reticulation), which can trap vancomycin mole-comycin (VanB, C, E, G phenotype) or vancomycin cules and prevent their access to the target at theand teicoplanin (VanA phenotype) plays a critical cytosolic membrane (figure 2). The thickened cellrole.[2,16,22,23] The resistance proteins are encoded by wall of a VISA strain may contain up to two to fourgenes physically grouped in operons that are located times more D-Ala-D-Ala residues than that of aon plasmids or in the chromosome, and can be easily susceptible strain and is able to bind up to three totransferred, even between different species.[2,38,39] six times more vancomycin molecules before pep-Six phenotypes of resistance have been described tidoglycan synthesis becomes impaired.[5] This(see table I), which differ by the genetic support, the mechanism also implies a reduced cross-linkage ofregulation of expression and the level of resistance peptidoglycan. The latter has been suggested to re-conferred. An intriguing phenotype of glycopeptide sult from decreased activity of penicillin-bindingdependence has also been described, in which syn- proteins (PBPs)[26] or from an alteration of mureinthesis of the D-Ala-D-Ala-ending peptidoglycan precursors.[44] Yet multiple, additive, but not clearlyprecursors is impaired through a mutation in the host identified mutations, are probably necessary to ob-ligase. Induction of production of the resistance tain resistance. VISA and GISA also need to importproteins by glycopeptides restores peptidoglycan a larger amount of precursors than normal strains,synthesis by allowing production of precursors end- which compromises their fitness in an antibiotic-ing in D-Ala-D-Lac.[40,41] free environment. This explains why VISA and

GISA tend to lose their resistance when relievedResistance in S. aureus first emerged in the formfrom vancomycin pressure, giving rise to the so-of strains with elevated minimum inhibitory concen-called hetero-VISA phenotype.[45] Moreover, atration (MIC) values towards vancomycin (or bothglycopeptide-tolerant phenotype has been observedvancomycin and teicoplanin), which have beenin clinical isolates of MRSA, in which MICs ofnamed vancomycin-intermediate S. aureus (VISA)glycopeptides are not affected but minimum bacteri-or glycopeptide-intermediate S. aureus (GISA).cidal concentrations (MBCs) are considerably in-Originally described in Japan in 1996 in methicillin-creased.[46] In a still more frightening fashion, tworesistant S. aureus (MRSA),[25] VISA and GISAMRSA strains with high levels of resistance to van-strains have now been isolated in numerous coun-comycin and teicoplanin have now been reported intries, particularly from patients having received pro-two different hospital institutions in the US.[17-20]longed vancomycin therapy.[5,42] These bacteria are

characterised by a thickened cell wall, production of Both of these strains harbour the vanA gene cluster,



indicating that they had acquired the corresponding some extent, bone and cartilage, but not in theset of genes from enterococci. Should such strains CNS.[63]

spread in hospitals, treatment options would rapidly In vitro pharmacodynamic models show that van-become very limited.[47] comycin exhibits time-dependent bactericidal ac-

tivity against most Gram-positive organisms. How-ever, vancomycin is essentially bacteriostatic

1.3 Pharmacological Propertiesagainst enterococci[71] but may become bactericidalwhen combined with an aminoglycoside.[72,73] Van-

The spectrum of activity of glycopeptides covers comycin activity is adversely affected by a largeessentially the Gram-positive organisms and a few inoculum but not by acidic pH. The drug also dem-anaerobes, and their activity against Gram-negative onstrates faster killing rates against actively grow-organisms is most often marginal (table II). Vanco- ing organisms, which can be easily understood onmycin and teicoplanin have a similar intrinsic ac- the basis of its mechanism of action.[74] Finally,tivity, except against streptococci, which are more glycopeptides produce persistent effects (postantibi-susceptible to teicoplanin.[48] otic effect lasting 1–6 hours[71,75]). While the dosage

The key pharmacokinetic properties of glycopep- recommendations for glycopeptides have insisted ontides are summarised in table III. The most striking low dosages because of the fear of toxicity, recentdifference between vancomycin and teicoplanin is developments in our understanding of pharmaco-their capacity to bind serum proteins, which is much dynamics have allowed a more rational basis forhigher for teicoplanin than for vancomycin. This recommendations. The first models suggested thatexplains the prolonged half-life of teicoplanin in the the free serum concentration of glycopeptides needsorganism. However, high protein binding also needs to remain above the MIC for the infecting organismto be taken into account for activity predictions for a prolonged period and, therefore, concluded that(table IV), since only the free serum fraction is activity was primarily driven by the so-called ‘timedirectly active. Teicoplanin, perhaps because of its above MIC’ parameter.[76,77] However, more recentlipophilic character, is characterised by a higher and thorough studies have indicated that the para-volume of distribution than vancomycin, allowing it meter which best predicts efficacy is the area underto reach therapeutic concentrations in fat, muscles the plasma concentration-time curve (AUC)/MIC(including pericardium and myocardium) and, to ratio,[56] as usually found for most antimicrobials

Table III. Pharmacokinetic properties of glycopeptides as observed after administration of conventional clinical dosesa

Parameter Vancomycin Oritavancin Teicoplanin Dalbavancin

Peak concentration (mg/L) 20–50 31b 43 300

Trough concentration (mg/L) 5–12 (24h) 1.7 (24h)b


Table IV. Pharmacodynamic parameters predictive of glycopeptide efficiency calculated for conventional dosages (see table III)

PK/PD parameter Maximum reachable MIC based on PK/PD parameters

vancomycin 15 mg/kg bid teicoplanin 6 mg/kg od oritavancin 3 mg/kg od dalbavancin 15 mg/kg od

AUC/MIC = 125a

total 4 4 1 185

free 2 0.4 0.1 4

Cmax/MIC = 10a

total 10 4 3 30

free 5 0.4 0.3 0.6

a Target values based on general PD considerations for antibiotics in the absence of actual data for all glycopeptides (lower Cmax/MIC ratio may be sufficient on the basis of available data for vancomycin and teicoplanin).

AUC = area under the concentration-time curve; bid = twice daily; Cmax = peak concentration; MIC = minimum inhibitory concentration; od= once daily; PD = pharmacodynamic; PK = pharmacokinetic.

exhibiting time-dependent killing and significant 1.4 Clinical Use: Pros and Conspostantibiotic effect.[78] However, in non-neutropen-

Originally introduced into clinical practice asic animals, the ratio of the free serum peak concen-an agent active against β-lactamase-producing S.tration to the MIC (Cmax-free/MIC) also plays aaureus, vancomycin remained largely unused be-determinant role in efficacy.[79] This Cmax-free/MICcause of development of less toxic alternatives,

ratio needs to reach at least 5–6 for vancomycin and namely the β-lactamase-resistant penicillins (methi-2–3 for teicoplanin (note that the determination of cillin, isoxazolyl penicillins) and cephalosporins, asthe peak and trough levels for these drugs, which are well as the introduction of β-lactamase inhibitors

such as clavulanic acid (mainly in Europe) or sul-determined in routine in hospital laboratories, can bebactam, which have become highly popular whenused for calculation of both Cmax/MIC and AUC/combined with ampicillin or amoxicillin (mostlyMIC ratios). As a consequence, glycopeptides areagainst Gram-negative bacteria, however). Yet oral-

probably best given by discrete administrations withly administered vancomycin became popular for

a total daily dose sufficiently large to match with the treatment of Clostridium difficile-associated diar-MIC of the infecting organism. A recent study com- rhoea and colitis.[86] The pandemic of nosocomialparing vancomycin 30 mg/kg once daily versus two MRSA infections which started in the mid 1970s,

and the fact that these strains were resistant not onlyadministrations for the treatment of patients withto all β-lactam agents but often also to aminoglyco-bacteraemia or arthritis did not show a significantsides, macrolides, lincosamides and fluoroquino-difference between the two groups in terms of clin-lones,[87] heralded the return of vancomycin for sys-

ical response (>92% in both cases;[80] however, notemic use. Alternatives such as fusidic acid, rifampi-

patients with endocarditis were included in this cin and cotrimoxazole have indeed been poorlystudy). On a pharmacodynamic basis, there is there- studied and did not compete in the face of thefore little reason to administer vancomycin by con- extensive data and the everyday experience avail-

able with glycopeptides.[88] Moreover, easy selec-tinuous infusion[81,82] even though other parameterstion of resistant mutants (especially for rifampicinsuch as more sustained concentrations in given tis-and fusidic acid when used alone) or toxicity prob-sues, or cost containment and ease of administration,lems has further limited their use. As we have seen,

have been advocated.[83,84] (Note that the stability however, resistance developed in enterococci almostand compatibility of vancomycin with other drugs in in parallel with the increase in vancomycin use inrelation to its use by continuous infusion are current- the US.[89-91] This led health authorities and con-ly under investigation.[85]) cerned clinicians to try to restrict glycopeptide usage



in order to maintain the activity of these usefulagents for situations where alternatives were notusable.[90,92-95] The introduction of quinupristin/dalfopristin and linezolid in the late 1990s has notreally changed this situation, since both drugs areexpensive, have rare but potentially worrying ad-verse effects (haematological toxicity for long-course linezolid treatments, thrombophlebitis, ar-thralgias and/or myalgias, and drug interactions forquinupristin/dalfopristin), and are already facingemergence of resistance.[96-101] In particular, linezo-lid-resistant strains are now increasingly reported,not only in enterococci but also in S. aureus, whichcould become a clinically significant problem in thefuture.

The recommendations presented in table V wereissued in 1995 by the Hospital Infection ControlPractices Advisory Committee in the US(HICPAC[102]) and have been adopted, with adapta-tions, in most countries (see Gordts et al.[103] forBelgium). These recommendations have been fur-ther extended to special populations (see Nourse etal.[104] for children). In summary, and outside thefield of bacteriologically documented MRSA infec-tions, empirical therapy with glycopeptides shouldbe limited to severe infections in immuno-compromised patients (e.g. burn patients, clinicalsepsis in the intensive care unit) when local epide-miological data show a high percentage of MRSA,and/or to life-threatening infections associated withthe presence of foreign bodies (often infected withmethicillin-resistant coagulase-negative staphylo-cocci; e.g. indwelling percutaneous catheters, pros-thetic cardiac valves). Indeed, animal models and

Table V. Appropriate clinical use of glycopeptides, based on therecommendations from Hospital Infection Control Practice AdvisoryCommittee (HICPAC)[102] for vancomycin and on pharmacodynamicconsiderations (table IV and Gruneberg et al.[105])

Situations in which the use of glycopeptides is appropriateor acceptable

Treatment

Serious infections caused by β-lactam-resistant Gram-positivemicroorganisms

Infections caused by Gram-positive microorganisms in patientswho have serious allergies to β-lactam agentsAntibiotic-associated colitis failing to respond to metronidazoletherapy or potentially life-threatening

Prophylaxis

Endocarditis following certain procedures in patients at high riskfor endocarditis

Major surgical procedures involving implantation of prostheticmaterials or devices at institutions that have a high rate ofinfections caused by methicillin-resistant Staphylococcus aureus(MRSA) or methicillin-resistant S. epidermidis

Situations in which the use of glycopeptides should bediscouraged

Routine surgical prophylaxis other than in a patient who has alife-threatening allergy to β-lactam agentsEmpirical antimicrobial therapy for a febrile neutropenic patient,unless initial evidence indicates that the patient has an infectioncaused by Gram-positive microorganisms and the prevalence ofinfections caused by MRSA in the hospital is substantial

Treatment in response to a single blood culture positive forcoagulase-negative staphylococci, if other blood cultures takenduring the same time frame are negative

Continued empirical use for presumed infections in patientswhose cultures are negative for β-lactam-resistant Gram-positivemicroorganisms

Appropriate dosagesa,b

Vancomycin 15 mg/kg twice daily

Teicoplanin 6–12 mg/kg once daily (after three loading doses of6 mg/kg every 12 hours)

a Higher intravenous doses are needed for treating peritonitis inpatients undergoing peritoneal dialysis.[106,107]

b Dosage reduction required in patients with renalinsufficiency.[63,64]

clinical studies have shown that vancomycin is lessbactericidal than isoxazolyl penicillins against with the exception of true β-lactam allergy. Of thesemethicillin-sensitive staphylococci (causing pro- severe infections by multiresistant staphylococci,longed periods of fever and persistence of positive the main indications for vancomycin are, therefore,blood cultures). This should preclude its use (and, restricted to: (i) serious diphtheroid infectionsdespite fewer data, the use of teicoplanin) when such (when the strain is penicillin resistant or the patientstrains are involved, especially in life-threatening has IgE-mediated allergy to β-lactam agents); (ii)infections (e.g. endocarditis). Therefore, their indis- penicillin-resistant Streptococcus pneumoniae in-criminate use in non-documented infections (or infections of the CNS in combination with cefotaximefections caused by Gram-positive strains susceptible or ceftriaxone; and (iii) antibiotic-associated colitisto other common agents) should be discouraged that is life-threatening or fails to respond to metroni-



dazole (only oral vancomycin; low faecal concentra- lycosides or other drugs toxic for these organs.[112]

Infrequent toxic manifestations include neutropenia,tions by intravenous route and few data with teico-thrombocytopenia, fever, bullous dermatosis, necro-planin). Routine prophylaxis with glycopeptidestising cutaneous vasculitis and toxic epidermalshould also be prohibited[102,103] and restricted tonecrolysis.[113] Teicoplanin has been claimed to beprevention of bacterial endocarditis in penicillin/less toxic than vancomycin.[114] However, a difficul-ampicillin-allergic patients at risk, undergoing gas-ty relates to the fact that the recommended doses oftrointestinal or genitourinary procedures (plusteicoplanin have been increasing over time and thatgentamicin), or dental procedures (vancomycinmost comparative studies with vancomycin werealone). In selected surgical wards with a high inci-done with teicoplanin doses (typically ≤6 mg/kg)dence of methicillin-resistant staphylococci infec-that are now considered insufficient (table V).tions, a single dose before surgery may be used inTherefore, further studies are needed to evaluateprosthetic surgery, but one should always try totoxicity of teicoplanin in the current conditions ofsolve the underlying fundamental hygiene problem.use.Teicoplanin could be used in most of the same

indications, with the exception of the CNS infection,2. New Developments in thebecause of the poor penetration of the drug in theGlycopeptide Areainfected compartment. Its main advantages are the

possibility of administering it by the intramuscularGiven the potential of glycopeptides in severe

route with a once-daily schedule (because of itsinfections, considerable effort has been made to

longer half-life) and a lower incidence of adverseobtain new derivatives with improved pharmacolog-

effects. However, several indications are less docu-ical properties and activity against resistant strains.

mented than for vancomycin, and there are no wellBecause of a highly complex structure, which makes

conducted, large, comparative studies between the total synthesis of glycopeptides very challeng-two drugs. In severe infections (as in S. aureus ing,[115] most of the new molecules obtained so farendocarditis), teicoplanin needs to be given at a dose are semisynthetic derivatives of existing, naturalof at least 12 mg/kg/day once daily, after a mini- glycopeptides. Structure-activity relationshipsmum of three to four loading doses (each given (SARs) are presented in figure 3, based on ourevery 12 hours). current understanding of the molecular mode of

interaction between glycopeptides and their pharma-Safety issues need also to be taken into accountcological target. Modifications can be subdividedand may limit glycopeptide use in given popula-into three main categories, each of them concerningtions. Earlier, vancomycin was notorious for toxici-distinct domains of the molecule and affecting thety related to impurities and to histamine releasegeneral mode of action of vancomycin in various(causing the so-called ‘red man syndrome’). Theseways. Other recent strategies have explored the for-adverse effects have been markedly reduced throughmation of hybrid or dimerised molecules, or thebetter purification procedures and by giving the drugsynthesis of inhibitors of the resistance mechanismsas a slow infusion over at least 1 hour.[108-110] Withto be administered in combination with unmodifiedthese precautions, vancomycin can be safely used,glycopeptides.causing only relatively mild and self-limiting gener-

al toxicity.[111,112] However, the dose should be2.1 Semisynthetic Modification ofcorrected in the case of renal insufficiency. TheNatural Glycopeptidesmain adverse effects are phlebitis at the site of

injection as well as nephrotoxicity and ototoxicity,2.1.1 Modification of the Binding Pocketthe latter remaining the most problematic because it

can be irreversible.[64] Both nephro- and ototoxicity Binding studies have shown that five sites on theare aggravated by the concomitant use of aminog- peptidic backbone of glycopeptides are involved in


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HO OHOH

HN

HOOC

NH

HN

O

ONH

O

CONH2O

HN

HN

ONHCH3

OCI

O O

CIO

HO

O OH

HOHO

OO

H3C

HO

CH3H2N

Acylation:↑ activity

Alkylation:↑↑ activity

Amino sugar:↑ dimer formation

Carboxamide: ↑ activity

(Staphylococcusepidermidis)

CI:↑ dimer formation

Vancomycin

HO OHOH

Membrane anchoringInhibition of transglycosylase

Dimerisation

HN

NH

HOOC

O

O

O

Cl

O

HN

O

NH

OHN

NH

OCONH2 O

NHCH 3

HO

O

O OHHO

HO

O

HOH3C

CH3H2N

CI

Binding to D-Ala-D-Ala

6 5 4

3

2

1

HO OOH

HN

NH

O

HOOC

HN

O

NH

OHN

O

NH

O

NH2

HO

OH

OCI

O O

O CI

O

NHAc

OHO

HO

OH

OHO

HO

HN CO

HO

O

OHOH

OH

OH

O

Teicoplanin

Sugar: ↑ activity

staphylococci↓ activity VanA

COOH: ↑ activity Gram-negative

↓ activity VanA

Sugar:↑ activity

Alkyl:↑ half-life↑ activity↓ VanB induction

CI:↑ activity

Basic amide:↑ activity

↑ activity Gram-negative

Acylation:↑ activitystaphylococci

Fig. 3. Structure-activity relationship (SAR) of glycopeptides derived from vancomycin and teicoplanin. Upper panel: current view of the parts of the molecules involved in thevarious modes of action proposed for glycopeptides. Lower panel: most salient SARs that can be drawn for vancomycin (left) or teicoplanin (right) derivatives. ↑ indicates increased;↓ indicates decreased.


the interaction with the D-Ala-D-Ala termini (figure to cross their outer membrane.[118] Esterification3). Efforts have been made to change these amino with hydrophobic alcohols also leads to marginalacid residues, with the aim to generate compounds activity on Gram-negative bacteria. Similarly, basicwith increased affinity for both dipeptide and dep- amides of the A40,926 derivative of teicoplaninsipeptide termini. These have included trimming or (which lacks the N-acetylglucosamine sugar; figureenlarging the heptapeptide backbone, epimerisation 1) show increased activity against staphylococciof the C3 chiral centre (in teicoplanin only), or (particularly coagulase-negative) and streptococci.substitution of amino acids 1 and 3.[116] Unfortunate- The most active compounds also show moderately, most of these modifications have resulted in a activity against VanA enterococci.[119,120] At the N-reduction of antibacterial activity. Nevertheless, the terminus, acylation or alkylation causes either apossibility of obtaining active compounds by this slight increase or no modification in activity. An-type of approach remains open, based on the obser- other important modification in the teicoplaninvation that substitution of the Asn at position 3 by a backbone is the introduction of chlorine atoms,hydrophobic amino acid enhances the affinity of which increase both target affinity and antibacterialvancomycin for D-Ala-D-Lac precursors.[117] activity.[116]

2.1.3 Alteration of Sugars2.1.2 Modification or Addition ofFunctional Groups Despite their location apparently far from the

binding pocket, sugars play a determinant role inA few functional groups can be modified out ofglycopeptide activity, since aglycones of both van-the binding pocket, essentially causing changes incomycin and teicoplanin are systematically less ac-physicochemical properties. These studies have gen-tive than their parent compounds.[116,121] Substitut-erated useful knowledge in SAR and have alloweding these sugars can actually have a considerablechanges in the natural compounds to be proposed.impact on glycopeptide pharmacological properties.

Modification of VancomycinModification of VancomycinAs stated earlier, the affinity of vancomycin forBesides the beneficial addition of a 4-epi-its target is increased by its capacity to dimerise.

vancosamine on the benzylic function of residueThis process is facilitated by the addition of an6,[122] substitution of the vancosamine sugar by hy-amino sugar to residue 6 and by the presence of adrophobic substituents proved mostly useful, prob-chlorine atom in meta on the aromatic substituent ofably by somehow mimicking the lipophilic sideresidue 2.[10,13,116] Other modifications at the extre-chain of teicoplanin derivatives. N-alkyl derivativesmities of the peptidic backbone have also broughtwere found to be more active than N-acyl products,significant pieces of information. Thus, replacementparticularly against enterococci, streptococci andof the free carboxylate terminus by a carboxamidestaphylococci.[116] When combined with the addi-increases the activity on Staphylococcus epider-tional 4-epi-vancosamine (as in LY264826; see fig-midis, whereas D-amino acids at the N-terminusure 1), an alkyl side chain confers to the molecule anappear more active than their corresponding L-iso-unexpectedly rapid, concentration-dependent bacte-mers.[116]ricidal activity, including against VanA- and VanB-

Modification of Teicoplanin type resistant enterococci.[123-125] The activity ofAs for vancomycin, structure-activity studies of these hydrophobic derivatives on resistant strains

teicoplanin have examined the influence of substi- has been proposed to result from the combination oftuting the extremities of the peptidic backbone. At a facilitation of the binding to the peptidoglycanthe C-terminus, substitution by a basic, positively precursors due to their anchoring in the mem-charged amide considerably increases activity on brane[9,11] and of a direct inhibition of transglycosy-staphylococci and also confers moderate activity on lases.[15,126] Recent studies also suggest that some ofGram-negative bacteria, because of improved ability these derivatives may act as inhibitors not only of



cell wall synthesis but also of phospholipid synthe- linkers and various linkage positions.[130,131] Im-sis.[127] Acidic and hydrophilic substituents have proved activity has been observed against Gram-also been added on the resorcinol in alpha of the free positive organisms, including GISA and VREcarboxylate of lipidated analogues of vancomycin, strains, opening promising lines of investigation inwith favourable consequences on distribution and this area. Secondly, taking into account the possibil-safety profiles, without negative effect on activity ity of a dual target for glycopeptides, namely theagainst MRSA or vancomycin-resistant enterococci dipeptide termini of peptidoglycan precursors, and(VRE).[128] the enzymes involved in the transglycosylation step,

vancomycin derivatives have been prepared whereModification of Teicoplanin

the aglycone is separated from the sugars by linkers,The impact of sugars on the activity is em-

with the aim to correctly position each part of thephasised by the fact that the removal of N-acyl-

molecule.[132] This approach could now be extendedglucosamine reduces activity, particularly against

to other glycopeptides in which both the aglyconestreptococci and enterococci, whereas removal of N-

and the carbohydrate moieties would be individuallyacetylglucosamine decreases the activity against

optimised for interaction with their own target, so asstaphylococci but may confer activity against Gram-

to generate very active compounds.negative as well as VanA-type enterococci. This isespecially true for derivatives that also have a basic

2.3 Inhibitors of Resistance Mechanismsamide substitution of the C-terminus.[116]

Substituents on sugars also play important roles.In the same way as clavulanic acid or sulbactam

As mentioned in the previous section, lipophilichave been designed to restore the activity of β-

substituents are of major interest for vancomycinlactam agents against β-lactamase-producing organ-

activity. Teicoplanin contains naturally a lipophilicisms, inhibitors of glycopeptide resistance mechan-

side chain that is responsible for its prolonged half-isms could be considered to specifically circumvent

life. This side chain is also important for activity,the mechanisms of resistance developed by entero-

since deacylated derivatives are only weak antibio-cocci (which, as described in section 1.2, may also

tics.[116] The acyl chain has been proposed not onlyapply to the recently described highly resistant S.

to favour anchoring in the membrane, and thereforeaureus strains). This goal has been achieved by

the interaction with the target,[11] but also to circum-designing small molecules such as ε-aminopenta-

vent VanB induction,[129] explaining teicoplanin ac-noylated prolinol,[133] which are able to selectively

tivity against resistant strains of the VanB-type. Oncleave the ester linkage of the D-Ala-D-Lac dep-

the other hand, the replacement of the N-acetyl-sipeptide of resistant bacteria. Concomitant admin-

glucosamine by an N-acylglucuronic acid (as inistration of this compound and vancomycin in-

A40926, see figure 1) has a detrimental effect oncreases the activity of the glycopeptide in vitro

activity against VanA enterococci but improvesagainst VanA-type enterococci, without affecting its

anti-Gram-negative activity.[116]activity against susceptible strains. However, ac-tivity remains globally low, probably because VanX2.2 Hybrid and Multivalent Glycopeptideshydrolyses the D-Ala-D-Ala dipeptide, so that there

On the basis of current knowledge on the mode of is no pentapeptide left for binding glycopeptides.action of glycopeptides, more innovative strategies These inhibitors will, therefore, need to be com-have been explored to optimise activity against both bined with inhibitors of the VanX D-D-pepti-susceptible and resistant strains. First, considering dase.[134,135] They have been obtained with inhibito-the potential cooperative binding occurring in multi- ry potencies in the micromolar range, but microbio-valent drugs, as well as the enhanced activity of logical data are still lacking to demonstrate theglycopeptides capable of self-association, dimers of interest of combining these inhibitors with vanco-vancomycin have been prepared using different mycin.



3. Properties of the Ideal Glycopeptide cosaminyl moiety of vancomycin by a lipophilicside chain resulted in enhanced activity and in some

Based on an examination of the limitations of the cases restored activity towards vancomycin-resis-current molecules and also on the promising proper- tant enterococci.[121,137]ties of some of the semisynthetic derivatives de-scribed in section 2, we delineate in table VI the 4.1.1 Microbiological andmain desirable characteristics expected from new Pharmacological Propertiesglycopeptides for future clinical development. Twomolecules, oritavancin and dalbavancin, fulfil these Spectrum of Activity and Resistanceconditions in various ways and are currently in The activity of oritavancin (table II) is similar tophase II/III of clinical development. that of vancomycin against staphylococci, with

MICs ranging between 0.03 and 8 mg/L; no4. Glycopeptides Undergoing differences are seen between methicillin-susceptibleClinical Evaluation and -resistant stains. Against enterococci, orita-

vancin is more active than vancomycin or teico-planin, with MICs consistently lower than 1 mg/L.4.1 OritavancinRemarkably, it is as active against glycopeptide-resistant strains as against glycopeptide-susceptibleOritavancin (LY333328) was discovered at Eliisolates. Oritavancin is also very potent againstLilly (Indianapolis, IN, USA) but is now developedpneumococci (both penicillin-susceptible and -resis-by InterMune (Brisbane, CA, USA)[136] [see figure 1tant). It shows low MICs against other Gram-posi-for structure]. This molecule was obtained by

reductive alkylation with 4′-chloro-biphenyl-car- tive species including other streptococci, Listeriaboxaldehyde of A82846B (chloroeremomycin; spp., Clostridium spp. and corynebacteria,[50] but isLY264826), a natural glycopeptide that differs from not active against Gram-negative bacteria, includingvancomycin by the addition of a 4-epi-vancosamine Haemophilus influenzae. Resistance of S. aureus tosugar and the replacement of the vancosamine of the oritavancin has so far not been described in clinicaldisaccharide moiety by an epi-vancosamine.[122] The isolates,[51,52,138] including VISA strains. In contrast,design of this drug was based on previous observa- enterococci with reduced susceptibility to orita-tions that chloroeremomycin was more potent than vancin (MIC 8–16 mg/L) have been obtained invancomycin because of its stronger tendency to self- vitro, using strains harbouring the vanA or the vanBassociate,[3] and that substitution of the van- gene clusters.[139] Three mechanisms seem to

operate:[139] (i) the complete elimination of D-Ala-ending precursors by overexpression of the vanAgene cluster or by reduced expression of the host D-Ala:D-Ala ligase; (ii) mutations in the VanSB sensorof the vanB cluster (which can occur in clinicalisolates[140]); or (iii) the expression of VanZ, a pro-tein encoded by a gene present in the resistancetransposon but the precise function of which is stillunknown. A clinical strain of oritavancin-dependentEnterococcus faecalis has also been isolated but theunderlying mechanism should be different from thatconferring dependence to vancomycin and teico-planin, since the growth of this strain is not restoredin the presence of D-Ala-D-Ala precursors.[141]

Table VI. Properties of an ideal glycopeptide

Microbiological properties

High intrinsic activity against Gram-positive organisms, includingmethicillin-resistant Staphylococcus aureus, vancomycin-resistantenterococci and glycopeptide-resistant S. aureus

Pharmacodynamic properties

Rapid and concentration-dependent bactericidal activity

Pharmacokinetic properties

Area under the concentration/time curve and peak plasmaconcentration for free fraction adequate to cover minimuminhibitory concentration of target pathogens

Prolonged half-life (once daily administration)

High diffusibility in tissues, including in the CNS

Safety profile

Lower incidence of adverse effects than current molecules



Pharmacodynamic Properties in Relation to the the other glycopeptides. Like teicoplanin, orita-Mode of Action vancin is characterised by high protein binding toOritavancin is bactericidal in vitro, with MBCs albumin, which explains its prolonged retention in

only 1- to 8-fold higher than the corresponding mammals, but also reduces the rate and extent of itsMICs against most of the covered microorga- bactericidal activity and shortens the postantibioticnisms.[50] Killing curve experiments have revealed a effect.[146,148] This could be important when serumstriking difference between vancomycin and orita- levels become close to the MIC for the infectingvancin concerning the rate of killing and its concen- organism. Further studies should address pharmaco-tration-dependent character. Oritavancin indeed kinetic-pharmacodynamic relationships for theseshows very rapid and highly concentration-depen- drugs, but we may anticipate, on the basis of itsdent bactericidal activity (3-log reduction in bacter- concentration-dependent bactericidal activity inial counts after 1–8 hours) in conditions where van- vitro, that high serum levels or AUC relative to MICcomycin requires at least 8–24 hours to reach the will correlate with optimal efficacy. Studies on cul-same effect.[50,142] However, oritavancin acts more tured cells also show that oritavancin accumulates inslowly against VRE.[143] These properties suggest eukaryotic cells to exceptional levels (the apparentthat oritavancin could have another mode of action cellular concentration reaching values as high as 400than conventional glycopeptides. The current view times the extracellular ones), which may be an ad-is that oritavancin combines the advantages of a vantage for the eradication of intracellular infec-high capacity to dimerise and to interact with the tions.[149]membrane, and therefore may cooperatively bind topeptidoglycan residues of both susceptible and re- Models of Infectionsistant strains. It may also directly perturb the mem- The promising in vitro activity of oritavancin hasbrane properties and inhibit transglycosylation reac- prompted evaluation of its activity in models oftions.[125] difficult-to-treat infections. As anticipated, orita-

Oritavancin also displays a concentration-depen- vancin given once daily is as effective as vancomy-dent postantibiotic effect, increasing from ~2 hours cin given every 8 hours against MRSA rabbit endo-at 1 × MIC to 4 hours against VRE and 8 hours carditis[150] and is bactericidal against S. pneu-against MRSA.[143] As with vancomycin, the combi- moniae rabbit meningitis,[151,152] even though thenation of oritavancin with gentamicin is synergis- drug penetration in the CSF reaches only 5% of thetic.[143-145] The combination with ampicillin en- serum concentration.[152] Oritavancin activity hashances the bactericidal activity of oritavancin, with- also been studied in models of infections byout being truly synergistic. It also prolongs its glycopeptide-resistant enterococci. While orita-postantibiotic effect against VRE from 18 to 23 vancin was effective in a model of rat central venoushours at 10 × MIC.[146] catheter infection,[153] its activity was more limited

Oritavancin activity is negatively affected by in a rabbit endocarditis model, causing a reductionlarge inocula,[143] but not by acid pH or by the in the number of bacteria in the vegetations butgrowth phase of the bacteria.[147] However, as point- failing to sterilise them.[154] Increasing serum con-ed out by Mercier et al.,[147] activity might be slight- centrations to values as high as 80 mg/L did notly reduced against VRE in stationary growth phase, provide significant improvement and did not pre-as observed in animal model infective endocarditis vent the selection of resistant mutants, probablyor in acidic foci of infection. because of the heterogeneous distribution of the

drug in the vegetations. Yet combination with genta-micin proved synergistic and bactericidal, and pre-Pharmacokinetic Profile and Relationship with

Pharmacodynamic Properties vented the emergence of resistant mutants.[155] Intra-The pharmacokinetic properties of oritavancin cellular bactericidal activity of oritavancin has been

are presented in table III in comparison with those of demonstrated in in vitro models of polymorphonu-



clear leucocytes infected by vancomycin-resistant terminal methylamino group.[164] In dalbavancin, aenterococci[156] or by MRSA[157] as well as in macro- 3,3-dimethylaminopropylamide replaces the peptidephages infected by S. aureus.[158] Taken together, carboxy group of A40926.[165] SAR studies of teico-these data suggest a definite clinical interest for this planin indicated an improvement in activity bydrug, provided it can reach the infected compart- derivatisation of its carboxy group, and improvedment at sufficiently high concentrations. Efficacy activity against VanA-type enterococci is expectedagainst infections occurring in less accessible com- to occur when removing the acetyl-partments as well as against intracellular organisms glucosamine.[48] The most active compound in theneeds, therefore, to be examined in the light of the series was actually the 6β-decarboxy-6β-hydrox-tissue distribution of the drug in vivo. ymethyl amide of A40926,[165] but development of

this compound was halted because of its poor tolera-4.1.2 Clinical Studies bility in animals (causing adverse effects typical ofOritavancin is currently in phase III develop- histamine release, which have been ascribed to its

ment, with two studies completed in the treatment of basic character[48]). Unfortunately, most data onpatients with complicated skin and skin structure dalbavancin have been published only as abstractsinfection caused by Gram-positive pathogens in- or as short quotations in review papers. This makescluding MRSA.[159] The intent-to-treat analysis of an in-depth comparison of dalbavancin withone of these, a double-blind, randomised study, has oritavancin difficult.been presented as an abstract[160] and showed equi-valent clinical success with oritavancin at 1.5 or 4.2.1 Microbiological and3 mg/kg for 3–7 days versus vancomycin (15 mg/kg Pharmacological Propertiestwice daily for 3–7 days followed by oral cephalexinfor up to 10–14 days in the vancomycin group). Spectrum of Activity and Resistance

In general (table II), dalbavancin is more potent4.1.3 Safety Profilethan vancomycin, teicoplanin and, to some extent,The only published data available so far are thoseoritavancin against staphylococci (with MICsof the phase I studies, in which oritavancin was wellranging from


trough concentrations of dalbavancin are above the with clindamycin, ceftriaxone, vancomycin orcurrent MIC of the targeted microorganisms. cefazolin) for the treatment of deep skin and soft

tissue infections caused by methicillin-susceptiblePharmacodynamic Properties in Relation to the S. aureus or MRSA.Mode of ActionLike oritavancin, dalbavancin is bactericidal, 4.2.3 Safety Profile

with MBC/MIC ratios close to 1, even in the pres- Preclinical studies in rats and dogs show thatence of 30% serum.[66] It is synergic with ampicillin, dalbavancin is well tolerated after intravenous bolusincluding against VanA-type enterococci. administration at doses several times higher than

those expected to be used in humans.[48] Phase I orPharmacokinetic Profile and Relationship with

phase II clinical trials have not reported major ad-Pharmacodynamic Propertiesverse effects in the range of concentrations whereThe pharmacokinetic profile of dalbavancin isdalbavancin is effective.[66,169] No dosage adjust-compared with that of the other glycopeptides inments are necessary in case of mild renal insuffi-table III. Phase I studies have used higher dosages,ciency.[170]providing higher AUC values. However, when

corrected for the free fraction, the AUC/MIC and 5. New Glycopeptides in the Clinics: forCmax/MIC ratios of dalbavancin are in the same Which Indications?order of magnitude as those of teicoplanin. Plasmadalbavancin concentrations still exceed the MBC The improved pharmacological properties of newvalues for staphylococci 1 week after administration glycopeptides make them very potent agents, withof a single dose of 1000mg but free serum concen- potentially large clinical indications. However, theirtrations are close to the MIC.[66,67] use should be as restricted as that of conventional

glycopeptides if one wishes to avoid the rapid emer-Models of Infection

gence of resistance.The activity of dalbavancin has been assessed in

The advantages of oritavancin that should provemodels of infections by glycopeptide-susceptibleto be useful in clinical practice include: (i) its fastGram-positive organisms and by GISA. Preliminaryrate of bacterial killing, its spectrum of activity,reports indicate a reduction in bacterial load after awhich covers VRE, methicillin-resistant staphylo-single-dose administration in models of penicillin-cocci and to some extent the GISA strains; (ii) itsresistant S. pneumoniae pneumonia or of MRSA ratactivity against intracellular forms of enterococcipouch infection.[48,167] Its activity is superior to thatand staphylococci; and (iii) its prolonged half-life.of conventional glycopeptides in models of endocar-For dalbavancin, the main improvement seems to beditis due to MRSA or GISA, and of acute septicae-its pharmacokinetic profile, which should allowmia caused by staphylococci, streptococci or entero-once-weekly administration. Microbiological prop-cocci.[66,168]erties of dalbavancin are less favourable than those

4.2.2 Clinical Studies of oritavancin, since VRE are not covered.No clinical data have been published so far but On the basis of these properties, and also in view

phase II/III clinical trials are ongoing to evaluate the of the results from animal models, oritavancin mayefficacy and safety of dalbavancin for the treatment become a drug of interest for infections caused byof complicated skin and soft tissue infections caused VRE, while both oritavancin and dalbavancin couldby Gram-positive organisms or the use of dalba- be considered for severe infections by multiresistantvancin in a once-a-week mode of administration for organisms, such as methicillin-resistant staphylo-other Gram-positive hospital infections.[66] In a first cocci or S. pneumoniae. In the latter case, however,report of a phase II study,[169] administration of two other alternatives such as fluoroquinolones (moxi-doses (1000mg on day 1 and 500mg on day 8) was floxacin or gatifloxacin) should be examined first.found to be as effective as comparators (7–21 days In some countries resistance to fluoroquinolones has



already reached alarming levels (15% in Southeast 6. ConclusionAsia [Hong Kong, South Korea[171]]). There are also

Oritavancin, and to a lesser extent dalbavancin,situations such as CNS infections in which fluoro- offer considerable possibilities for improvementquinolones are poorly efficient.[172,173] Oritavancin over vancomycin and teicoplanin, essentially inand dalbavancin could, therefore, prove very useful terms of pharmacokinetic and pharmacodynamicin these ‘niche’ but important indications. Finally, properties, as well as of activity against resistanttheir activity against GISA strains appears limited strains (for oritavancin). Whether these properties

can translate into improved clinical efficacy awaits(table II), which could be a deterrent to recom-completion of clinical studies. Should these mole-mending them in these situations. However, synergycules soon become approved for clinical use, it ishas been demonstrated for dalbavancin when com-vital that they are used rationally and prudently tobined with β-lactam agents.[57] Encouraging resultsprotect against the rapid emergence of resistancehave also been obtained in animal models,[168] whichand extend their useful life.

should stimulate further testing of this moleculeagainst GISA infections. Acknowledgements

Therefore, reasonable indications could include F. Van Bambeke is Chercheur Qualifié of the Belgianthe following: (i) nosocomial septicaemia or infec- Fonds National de la Recherche Scientifique. The authors

have provided no information on sources of funding or ontions of deep organs caused by MRSA or VREconflicts of interest directly relevant to the content of this

(oritavancin only); (ii) severe and recurrent skin and review.soft tissue infections caused by MRSA (in relationwith activity against both extra- and intracellular References

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