Le Infezioni in Medicina

ISSN 1124-9390 LE INFEZIONI IN MEDICINA

Supplemento 2018

SCIENTIFIC EVIDENCES ON MICROBIOLOGICAL EFFICACY, PHARMACOKINETIC/ PHARMACODYNAMIC (PK/PD) AND CLINICAL PROFILE OF DALBAVANCIN LE INFEZIONI IN MEDICINA Rivista trimestrale di eziologia, epidemiologia, diagnostica, clinica e terapia delle patologie infettive

Supplemento 2018 O SOMMARIO

Edizioni Internazionali srl Divisione EDIMES Edizioni Medico-Scientifiche - Pavia

Via Riviera 39 - 27100 Pavia Tel. 0382/526253 Fax 0382/423120 3 Introduction e-mail: [email protected]

Registrazione 4 In vitro activity of dalbavancin Trib. di Milano n. 506 against gram-positive cocci del 6/9/2007 – In vitro activity of dalbavancin against staphylococci isolates Direzione e Redazione – In vitro activity of dalbavancin Dipartimento di Medicina e Chirurgia against enterococcal isolates Università degli Studi di Salerno Via Allende, Baronissi, Salerno - Italy – In vitro activity of dalbavancin Tel. 0039 (089) 672420 against streptococci isolates e-mail: [email protected] – In vitro activity of dalbavancin www.infezmed.it against uncommon isolates – In vitro activity of dalbavancin against Direttore responsabile different pathogens isolates P.E. Zoncada 10 Synergistic effect of dalbavancin Pubblicato nel mese di dicembre 2018 with other antimicrobial agents

11 Microbiological activity of dalbavancin against biofilm

12 PK/PD and clinical profile of dalbavancin

15 Conclusions

15 References LE INFEZIONI IN MEDICINA THE OFFICIAL JOURNAL OF THE ITALIAN SOCIETY OF INFECTIOUS AND TROPICAL DISEASES A quarterly journal covering the etiological, epidemiological, diagnostic, clinical and therapeutic aspects of infectious diseases

Editor in chief Co-editors Editorial assistant Esposito S. Andreoni M., Di Perri G., Galli M. Noviello S., Esposito I.

ASSOCIATE EDITORS d’Arminio Monforte A. (Milan, Italy) Dos Santos V.M. (Brasília, Brazil) HIV/AIDS Dryden M. (Winchester, UK) Antinori A., Cauda R. Ece G. (Izmir, Turkey) Viral hepatitis Filice G. (Pavia, Italy) Gaeta G. B., Taliani G. Garau J. (Barcelona, Spain) Fungal infections Gazzerro P. (Salerno, Italy) Viale P., Viscoli C. Gentile I. (Naples, Italy) Bacterial infections Giacometti A. (Ancona, Italy) Bassetti M., De Rosa F.G. Giamarellou H. (Athens, Greece) Gollapudi S. (Los Angeles, USA) Infections in the Gould I. (Aberdeen, UK) immunocompromised host Grossi P. (Varese, Italy) Grossi P., Tavio M. Gyssens I. (Nijmegen, The Netherlands) CNS infections Heisig P. (Hamburg, Germany) Pagliano P. Karamanou M. (Athens, Greece) Emerging infectious diseases Kazama I. (Sendai Miyagi, Japan) Ippolito G., Rezza G. Lakatos B. (Budapest, Hungary) Mycobacterial infections Lari R. (Teheran, Iran) Parrella R., Sanduzzi A. Lipsky B.A. (Seattle, USA) Sexually transmitted diseases Lye D. (Singapore) Matteelli A. Marinis A. (Piraeus, Greece) Marvaso A. (Naples, Italy) Tropical diseases Mastroianni C. (Rome, Italy) Antinori S., Castelli F. Meletis G. (Thessaloniki, Greece) Anthropozoonoses Menichetti F. (Pisa, Italy) Cascio A., Iaria C. Milkovich G. (Richmond, USA) History of infectious diseases Nava A. (Milan, Italy) Contini C. Novelli A. (Florence, Italy) Papadopoulos A. (Athens, Greece) EDITORIAL BOARD Paparizos V. (Athens, Greece) Parvizi J. (Philadelphia, USA) Angarano G. (Bari, Italy) Pea F. (Udine, Italy) Anyfantakis D. (Chania, Crete, Greece) Pisaturo M.A (Naples, Italy) Atalay M.A. (Kayseri, Turkey) Reitan J.F. (Crown Point, USA) Biçer S. (Istanbul, Turkey) Saeed K. (Southempton, UK) Bifulco M. (Naples, Italy) Sanduzzi A. (Naples, Italy) Boccazzi A. (Milan, Italy) Scaglione F. (Milan, Italy) Bonnet E. (Tolouse, France) Scotto G. (Foggia, Italy) Borgia G. (Naples, Italy) Segreti J. (Chicago, USA) Bouza E. (Madrid, Spain) Sganga G. (Rome, Italy) Bouza J.M.E. (Valladolid, Spain) Soriano A. (Barcelona, Spain) Brancaccio G. (Padua, Italy) Stefani S. (Catania, Italy) Camporese A. (Pordenone, Italy) Tambic A.A. (Zagreb, Croatia) Concia E. (Verona, Italy) Tumbarello M. (Rome, Italy) Coppola N. (Naples, Italy) Ünal S. (Ankara, Turkey) Corcione S. (Turin, Italy) Vullo V. (Rome, Italy) Dal T. (Ankara, Turkey) Yalcin A.D. (Antalya, Turkey) de Araújo Filho J.A. (Goiânia, Brazil) Yalcin N. (Antalya, Turkey) Le Infezioni in Medicina 2018 s2 3

Scientific evidences on microbiological efficacy, pharmacokinetic/ pharmacodynamic (PK/PD) and clinical profile of dalbavancin

Floriana Campanile1, Marco Falcone2 1Department of Biomedical and Biotechnological Sciences (BIOMETEC), Medical Molecular Microbiology and Antibiotic Resistance laboratory (MMARLab), University of Catania; 2Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa

ABSTRACT Dalbavancin, a novel second-generation semi-synthet- teria. In Europe, dalbavancin is indicated for the treat- ic lipoglycopeptide, has recently been approved for the ment of ABSSSIs in adults. treatment of severe skin infections sustained by Gram- Two dalbavancin treatment regimens have been ap- positive multi-drug resistant (MDR) pathogens. More proved for adults with ABSSSI: single-dose regimen specifically, it is indicated for the treatment of adult pa- (1500 mg) in patients with normal renal function, tients with ABSSSIs, caused by Gram-positive patho- shows to be equally effective and well tolerated with gens: S. aureus (including methicillin-susceptible and respect to the two-dose regimen (1000 mg followed by methicillin-resistant strains), Streptococcus pyogenes, S. 500 mg), in terms of prompt clinical response (48-72 h) agalactiae, S. dysgalactiae, S. anginosus group (including and low rates of adverse outcome. S. anginosus, S. intermedius, S. constellatus) and Entero- This paper will review the scientific evidence of coccus faecalis (vancomycin susceptible strains). To re- the microbiological efficacy of dalbavancin against duce the development of drug-resistant bacteria and Gram-positive and rare isolates, its synergistic activ- maintain the effectiveness of dalbavancin, FDA recom- ity in combination with other drugs, and the pharma- mends this drug only to treat infections that are proven cokinetic/pharmacodynamic (PK/PD) and clinical or strongly suspected to be caused by susceptible bac- profile.

n INTRODUCTION neous array of disorders, recently, the Food and Drug Administration (FDA) introduced Acute bacterial skin and skin structure in- the definition of ABSSSIs, which allowed a fections (ABSSSIs), previously named skin standardization and the introduction of more and soft-tissue infections (SSTIs), are among comparable endpoints in registration phase the most common bacterial infections and II-III clinical trials [1, 2]. can occur with variable clinical presenta- The common source of pathogens is the en- tion, from mild to serious life-threatening dogenous flora of the patient skin or mucous infections. Since SSTIs represent a heteroge- membranes. Consequently, the etiological agents are frequently Gram-positive cocci, generally residents on the skin, or anaerobic Corresponding Author bacteria and Gram-negative aerobes when Floriana Campanile incisions are made near the perineum or [email protected] groin [3]. 4 F. Campanile, M. Falcone

According to the National Nosocomial Infec- dose regimen). This dosage is also approved tion Surveillance system reports, Gram-posi- for patients on regular hemodialysis. In pa- tive cocci (particularly Staphylococcus aureus, tients with glomerular renal function < 30 coagulase-negative staphylococci and Entero- mL/min or in those not on regular hemo- coccus spp.), followed by Escherichia coli, Pseu- dialysis the single dose regimen expects the domonas aeruginosa and Enterobacter spp., are administration of 1125 mg of the drug, while the most commonly encountered pathogens the two-dose regimen the administration of in ABSSSIs [4]. 750 mg followed one week later by 375 mg Methicillin-resistant Staphylococcus aureus [7, 8]. (MRSA) continues to be a major public health Long-acting antibiotics such as dalbavancin problem, causing significant morbidity and may represent a significant innovation, that mortality and elevated health care costs [5]. improves the process of care of complex or MRSA is the most important pathogen in- frail patients admitted to acute-care hospi- volved in ABSSSIs, and several new drugs tals. Elderly or frail patients nowadays con- with anti-MRSA activity have been devel- stitute a large proportion of hospital popu- oped in the last years for their use in the set- lation. Frail patients have usually multiple ting of ABSSSIs [2], to increase the efficacy comorbidities, need frequent hospitalization against resistant isolates, but also to over- due to exacerbation of underlying diseases, come the main disadvantages of old drugs and receive multiple medications [2]. In these and to open the way to modern approach to cases, the presence of an infection like ABSS- clinical management of patients, including SI could result in a worsening of a baseline the early discharge or outpatient manage- condition, because of infection itself, side ef- ment [6]. fects of antimicrobials, risk of drug-to-drug Dalbavancin is a second-generation semi- interactions, prolonged hospitalization, and synthetic lipoglycopeptide, belonging to the subsequent risk of clinical failure or death. same class of vancomycin, that binds to the Under these circumstances, the availabili- C terminal D-alanyl-D-alanine subgroup of ty of easy to deliver single dose drugs, with the stem pentapeptide in nascent cell wall minimal drug interactions and possibly pro- peptidoglycan and inhibits the late stages moting a fast discharge of the patient from of bacterial cell wall synthesis by prevent- the hospital is crucial to optimize the process ing transglycosylation and transpeptidation of care. of the peptidoglycan chain. In addition, the lipid radical allows dalbavancin to form a n IN VITRO ACTIVITY OF DALBAVANCIN long lipophilic side chain that firmly anchors AGAINST GRAM-POSITIVE COCCI the compound to the cellular membrane, in- creasing its antimicrobial activity against Food and Drug Administration (FDA) sug- Gram-positive cocci by improving its affin- gested an interpretative susceptible break- ity for the terminal D-Ala-D-Ala, and pro- point of ≤0.25 µg/mL for dalbavancin against longs its half-life, allowing for once-week- S. aureus [including MRSA and methicil- ly dosing. In fact, two treatment regimens lin-susceptible S. aureus (MSSA)], Streptococ- have been approved for dalbavancin: in cus pyogenes, S. agalactiae, S. dysgalactiae, S. patients with normal renal function dalba- anginosus group [including S. anginosus, S. vancin should be administrated at the dos- intermedius and S. constellatus], and Enterococ- age of 1500 mg (single dose regimen) or 1000 cus faecalis [vancomycin-susceptible strains mg followed one week later by 500 mg (two- only] [7]. The European Committee on An- Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 5

timicrobial Susceptibility Testing (EUCAST) In vitro activity of dalbavancin susceptible breakpoint against Staphylococcus against staphylococci isolates spp., β-haemolytic streptococci of Groups A, Dalbavancin demonstrated potent in vitro ac- B, C and G, and S. anginosus group is ≤0.125 tivity against Staphylococcus spp. (including µg/mL, with the specification that S. aureus methicillin-resistant isolates). In vitro activity isolates susceptible to vancomycin can be re- has also been demonstrated against hetero- ported susceptible to dalbavancin [9]. geneous vancomycin-intermediate S. aureus The reference method suggested by all inter- (hVISA), vancomycin intermediate S. aureus national guidelines is the broth microdilution (VISA; 0.5-2 mg/L) and other MDR-MRSA method (BMD) according to ISO standard isolates, including those with decreased sus- 20776-1, although a study comparing dalba- ceptibility to daptomycin. vancin MIC values determined by gradient Table 1 and Table 2 show the microbiological test and reference BMD validated the former activity of dalbavancin against S. aureus and as an accurate procedure [10]. coagulase-negative staphylococci (CoNS) iso-

Table 1 - Microbiological activity of dalbavancin against Staphylococcus aureus isolates. MSSA MRSA Study N. of isolates MIC (mg/L) MIC (mg/L)

Range MIC50 MIC90 Range MIC50 MIC90 Streit JM et al., 2992 ≤0.015-0.25 0.06 0.06 ≤0.015–0.5 0.06 0.06 2004 [11] (1815 MSSA, 1177 MRSA) Gales AC et al., 536 ≤ 0.008-0.25 0.06 0.06 0.016–0.12 0.06 0.06 2004 [23] (393 MSSA, 143 MRSA) Lin G et al., 72 ≤0.015-0.125 0.06 0.06 ≤0.015–0.125 0.03 0.06 2005 [48] (43 MSSA, 29 MRSA) Jones RN et al., 3417 - 0.03 0.06 - 0.03 0.06 2005 [20] (2441 MSSA, 976 MRSA) Jones RN et al., 2102 - 0.06 0.06 - 0.06 0.06 2006 [24] (1041 MSSA, 1061 MRSA) * Biedenbach DJ et al., 1771 - 0.064 0.125 - 0.064 0.19 2007 [13] (1009 MSSA, 762 MRSA) Biedenbach DJ et al., 46773 ≤0.03-0.25 0.06 0.06 ≤0.03–0.5 0.06 0.06 2009 [22] (27052 MSSA, 19721 MRSA) Karlowsky JA, 2611 ≤0.03-0.25 0.06 0.06 ≤0.03–0.12 0.06 0.06 2011 [14] (1980 MSSA, 631 MRSA) Jones RN et al., 1036 ≤0.03-0.25 0.06 0.06 ≤0.03–0.12 0.06 0.06 2013 [30] (514 MSSA, 522 MRSA) McCurdy et al., 62195 ≤0.008- 0.5 0.06 0.06 ≤0.008- 0.5 0.06 0.06 2015 [47] (35220 MSSA, 26975 MRSA) Huband M et al., 9303 - 0.06 0.06 ≤0.03–0.25 0.06 0.06 2016 [26] (6832 MSSA, 2471 MRSA) Pfaller MA et al., 14319 ≤0.002-0.25 0.03 0.03 ≤0.002–0.12 0.03 0.03 2018 [12] (9111 MSSA, 5208 MRSA) Pfaller MA et al., 801 - ≤0.03 0.06 - 0.06 0.06 2018 [27] (534 MSSA, 267 MRSA) *Dalbavancin MIC values were obtained by reference BMD method in all studies, except for Biedenbach DJ et al, 2007 [13], where MICs were obtained by gradient test (AB BIODISK). 6 F. Campanile, M. Falcone

Table 2 - Microbiological activity of dalbavancin against coagulase-negative staphylococci. Methicillin-S Methicillin-R Study N. of isolates MIC (mg/L) MIC (mg/L)

Range MIC50 MIC90 Range MIC50 MIC90 Streit JM et al., 2004 [11] 774 ≤0.015-0.25 0.03 0.06 ≤0.015-0.5 0.03 0.06 (157 MS, 617 MR) Gales AC et al., 2004 [23] 251 ≤0.008-0.12 0.03 0.06 ≤0.008-1 0.03 0.12 (58 MS, 192 MR) Lin G et al., 2005 [48] 74 ≤0.015-0.06 0.03 0.06 ≤0.015-0.25 0.03 0.06 (38 MS, 36 MR) Jones RN et al., 2005 [20] 1231 - 0.03 0.06 - 0.03 0.06 (295 MS, 936 MR) Jones RN et al., 2006 [24] 255 - 0.03 0.12 - 0.03 0.06 (46 MS, 209 MR) *Biedenbach DJ et al., 2007 [13] 240 - 0.047 0.125 - 0.064 0.19 (58 MS, 182 MR) Biedenbach DJ et al., 2009 [22] 12308 ≤0.03-1 ≤0.03 0.06 ≤0.03-2 ≤0.03 0.12 (2836 MS, 9472 MR) Karlowsky JA, 2011 [14] 236 ≤0.03-1 ≤0.03 0.06 ≤0.03-0.06 ≤0.03 0.06 (202 MS, 34 MR) Jones RN et al., 2013 [30] 115║ ≤0.03–0.25║ ≤0.03║ 0.06║ - - - Pfaller MA et al., 2018 [12] 1992║ ≤0.002 to >.0.25║ 0.03║ 0.06║ - - - Pfaller MA et al., 2018 [27] 160║ - ≤0.03║ 0.06║ - - - *Dalbavancin MIC values were obtained by reference BMD method in all studies, except for Biedenbach DJ et al, 2007 [13], where MICs were obtained by gradient test (AB BIODISK). ║ all strains, not distinguished based on methicillin-susceptibility

lates, respectively [11, 12]. MIC values have and from 16 to 32-fold more active than van- been distinguished based on resistance pro- comycin against S. aureus and CoNS, respec- files, when the categorization was provided. tively [13]. Similarly, among clinical isolates In all studies, dalbavancin exerted its activity from the Canadian Ward Surveillance Study against 90% of S. aureus isolates at 0.06 mg/L, (CANWARD), dalbavancin showed a poten- regardless of the presence or methicillin-re- cy higher than that of vancomycin and tela- sistance. The unique exception was reported vancin, both among S. aureus and S. epider- in the study of Biedenbach DJ, in which MICs midis [14]. were evaluated by gradient test [13]. Further considerations are needed for van- Compared with the most frequently used an- comycin-intermediate S. aureus (VISA) and ti-Gram-positive drugs, dalbavancin showed vancomycin-resistant S. aureus (VRSA). a potent in vitro antibacterial efficacy. The Against VISA isolates, dalbavancin showed most recent study of Pfaller et al, evaluating a higher in vitro activity than vancomycin

antimicrobial activity of dalbavancin against (dalbavancin MIC90 2 mg/L versus van-

clinical isolates from USA and Europe comycin MIC90 4 mg/L), and comparable showed that against MRSA, dalbavancin was MIC values against VRSA strains (MIC >16 16-fold more potent than daptomycin and mg/L) [15]. Recently, Sader and coauthors 32-fold more potent than vancomycin and tested dalbavancin against a large collection linezolid [12]. In a large collection of staph- of S. aureus isolates, including isolates with ylococcal isolates, dalbavancin was 16-fold decreased susceptibility to the most antimi- Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 7

crobial agents used to treat severe S. aureus against vancomycin-susceptible E. faecium infections [16]. Overall, 1141 isolates showed isolates. Vancomycin-susceptible enterococ- decreased susceptibility to vancomycin (MIC ci (VSE) showed dalbavancin MIC values ≥2 mg/L), 143 isolates to teicoplanin (MIC lower than the susceptibility breakpoint es- ≥4 mg/L) and 52 isolates to telavancin (MIC tablished by FDA (MIC ≤0.25 mg/L) [7]. In ≥0.12 mg/L); 48 isolates were non-suscepti- all studies, dalbavancin was also analyzed ble to daptomycin (MIC ≥2 mg/L), and 25 among vancomycin-resistant enterococci isolates were resistant to linezolid (MIC ≥8 (VRE) strains, showing expected higher MIC mg/L). Dalbavancin retained its in vitro an- values (MIC50 >4 mg/L) (Table 3). Among tibacterial activity against 99.3% of isolates VRE isolates, variable MIC values were ob- with vancomycin MIC ≥2 mg/L and was served, with respect to the Van phenotype active against isolates with decreased sus- expressed by the VRE isolates. Dalbavancin ceptibility to the other drugs; only 8 strains was found to be inactive against VanA ente- (0.01%) were found dalbavancin non-suscep- rococci. In the studies in which a distinction tible (MIC ≥0.25 mg/L) [16]. As part of a mul- between Van phenotypes was performed, ticenter Italian study, the in vitro antibacterial 50% of VanB isolates were inhibited at 0.03 and bactericidal activity of dalbavancin was mg/L, while VanA isolates from >4 to 32 also demonstrated against clinically relevant mg/L [20, 21]. In the study conducted by S. aureus isolates, including heterogeneous Jones et al, only 6/54 VanB isolates showed vancomycin-intermediate (hVISA), dapto- dalbavancin MIC ≥1 mg/L [20]. Biedenbach mycin non-susceptible (DNS) and rifampic- and coauthors reported dalbavancin MIC in resistant (RIF-R). In this study, the RIF-R values >0.25 mg/L among 29.8% of E. fae- strains showed the highest percentage of iso- calis and 22.4% of E. faecium isolates with a lates with reduced susceptibility (n. 11, 22%), VanB phenotype [22]. While, in the study of considering that some rpoB mutations have Neudorfer et al., all VRE isolates, including been already associated with the emergence all vanA, vanB1 and vanB2/3 positive, had of vancomycin intermediate-resistance [17]. MIC values >16 μg/mL [21]. In support of these in vitro findings, studies In conclusion, dalbavancin is considered ac- conducted in murine thigh infection models tive against VSE isolates, but only partially showed that dalbavancin has potent in vivo against VRE. In particular, it did not exert activity against S. aureus strains, including any activity against isolates showing VanA those exhibiting a VISA phenotype [18]. phenotype and only partially against VanB Finally, the activity of dalbavancin against isolates. This characteristic limits its use in clinical isolates of S. aureus has been demon- infections sustained by VRE isolates. strated also in the randomized clinical trial (DISCOVER 1 and DISCOVER 2), in which In vitro activity of dalbavancin the MIC90 of dalbavancin was 0.06 mg/L for against streptococci isolates the 511 S. aureus isolates [19]. Dalbavancin is broadly active against streptococci. Penicillin and ceftriaxone-resistant S. In vitro activity of dalbavancin against pneumoniae strains were inhibited at very low enterococcal isolates concentrations of dalbavancin with MIC90 Dalbavancin has been indicated only for in- values ranging from 0.016 to 0.03 mg/L [11- fections sustained by vancomycin suscepti- 14, 20, 22-27]. ble E. faecalis isolates [7], although it exhib- Dalbavancin was also active against viridans its a good in vitro antibacterial activity also group streptococci (VGS) and β-hemolytic 8 F. Campanile, M. Falcone

Table 3 - Microbiological activity of dalbavancin against Enterococcus spp isolates. VSE VRE Study Type of isolates N. of isolates MIC (mg/L) MIC (mg/L)

Range MIC50 MIC90 Range MIC50 MIC90 Streit JM et al., E. faecalis 606 ≤0.015-4 0.03 0.06 ≤0.015->32 4 32 2004 [11] (586 VSE, 20 VRE) E. faecium 128 ≤0.015-4 0.06 0.12 ≤0.03->32 8 32 (77 VSE, 51 VRE) Gales AC et al., Enterococcus spp 157 ≤0.008-0.25 0.03 0.06 0.06 to >16 16 - 2004 [23] (148 VSE, 9 VRE) Streit JM et al., E. faecalis 14 - - - 0.12->32 32 32 2004 [11] (All VRE)1 E. faecium 73 ≤0.016- 0.12 0.06 0.12 0.03->32 16 32 (29 VSE, 44 VRE) Jones RN et al., Enterococcus spp 1905 - 0.03 0.06 - 4⌠ >16 2005 [24] (1424 VSE, 481 VRE)2 Biedenbach DJ E. faecalis 10374 ≤0.03-0.5 ≤0.03 0.06 ≤0.03->4 >4 >4 et al., 2009 [22] (10025 VSE, 374 VRE)3 E. faecium 4754 ≤0.03-2 0.06 0.12 ≤0.03–>4 >4 >4 (2578 VSE, 2176 VRE)3 Jones RN et al., Enterococcus spp 54 ≤0.03-0.12 ≤0.03 0.06 0.25->4 >4 >4 2013 [30] (30 VSE, 24 VRE)4 Neudorfer K E. faecalis 58 ≤0.016-0.125 0.03 0.125 >16 >16 >16 et al., 2018 [21] (52 VSE, 8 VRE)5 E. faecium 25 ≤0.016-0.125 0.03 0.125 >16 >16 >16 (4 VSE, 21 VRE)5 Pfaller MA et al., E. faecalis 2022 ≤0.015-0.25 0.03 0.06 - - - 2018 [12] (all VSE) E. faecium 531 ≤0.015-0.25 0.06 0.12 - - - (all VSE) Pfaller MA et al., E. faecalis║ 82║ - 0.06║ 0.12║ - - - 2018, [27]

1 2 Referred only to vanA positive enterococci. 11 isolates of vanB positive Enterococcus spp had MIC50 0.03 mg/L and MIC90 0.12 mg/L; Referred to vanA, vanB and vanC VRE. Forty-eight (889%) of the 54 VanB isolates had MIC values ≤0.25 mg/L, while 317 (94.6%) of the 335 vanA isolates had MIC values ≥1 mg/L; 3Referred to all VRE isolates, including vanA and vanB. Overall, 230 VanA and 84 VanB E. faecalis, 1744 VanA and 134 VanB E. faecium have been included in the study. Among these, 70.2% of 84 E. faecalis isolates with a VanB phenotype and 77.6% of 134 E. faecium isolates with 4 a VanB phenotype had dalbavancin MIC values ≤0.25 mg/L; Referred only to VanA enterococci, 2 VanB E. faecium isolates had MIC50 ≤0.03 mg/L; 5all VRE isolates, including all vanA, vanB1 and vanB2/3 isolates tested.

⌠ MIC50 8 µg/mL for VRE isolates from North America; ║ all strains, not distinguished based on vancomycin-susceptibility.

streptococci with all MICs <0.12 mg/L. With higher when compared to S. pyogenes data

regards to VGS, they were very susceptible to (MIC90 ≤0.03 μg/mL) (Table 4) [25, 29]. dalbavancin that inhibits all strains at ≤0.12 mg/L, regardless of resistance phenotype. In vitro activity of dalbavancin

Moreover, dalbavancin MIC90 values were at against uncommon isolates least 16-fold lower than those obtained for Dalbavancin has been tested against uncom- comparator agents against VGS, both MDR mon isolates of streptococci, such as sero-

and non-MDR isolates [28]. The MIC90 value group C, F and G of β- hemolytic streptococ- for S. agalactiae (0.12 mg/L) was somewhat ci, uncommon VGS (S. anginosus, S. milleri, Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 9

Table 4 - Microbiological activity of dalbavancin against streptococci. Penicillin-S Penicillin-R Study Type of isolates N. of isolates MIC (mg/L) MIC (mg/L)

Range MIC50 MIC90 Range MIC50 MIC90 Streit JM et al., S. pneumoniae 1396 (996 PS, ≤0.015-0.06 ≤0.015 0.03 ≤0.015–0.25 ≤0.015 0.03 2004 [11] 400 PR) Viridans streptoocci 134 (104 PS, ≤0.015-0.06 ≤0.015 0.03 ≤0.015–0.03 ≤0.015 0.03 30 PR) β-haemolytic 234 ≤0.015-0.25 ≤0.015 0.06 - - - streptococci Gales AC et al., S. pneumoniae 208 (152 PS, ≤0.008-0.06 0.016 0.016 ≤0.008–0.06 0.016 0.016 2004 [23] 27PI, 29PR) Viridans streptoocci 13 ≤ 0.008-0.03 0.016 0.016 - - - β-haemolytic streptococci 53 ≤ 0.008-0.06 ≤0.008 0.06 - - - Jones RN et al., S. pneumoniae 682 (452 PS, - 0.016 0.03 - 0.016 0.016 2005 [20] 107 PI, 123 PR) Viridans streptoocci 140║ - 0.016⌠ 0.03 - - - β-haemolytic 342 - ≤0.008 0.016⌠⌠ - - - streptococci Jones RN et al., S. pneumoniae 678 (416 PS, - 0.016 0.03 - 0.016 0.016 2006 [24] 135 PI, 127 PR) Viridans streptoocci 46 - ≤0.008 0.03 - - - β-haemolytic 241 - 0.016 0.03 - - - streptococci *Biedenbach DJ β-haemolytic 479 - 0.016 0.047 - - - et al., 2007 [13] streptococci Biedenbach DJ Viridans streptoocci 2148 ≤0.03-0.12 ≤0.03 ≤ 0.03 - - - et al., 2009 [22] β-haemolytic 5316 ≤0.03-0.25 ≤0.03 ≤0.03 - - - streptococci Karlowsky JA, S. pneumoniae 893 (739 PS, ≤0.03-0.12 ≤0.03 ≤0.03 ≤0.03 ≤0.03 ≤0.03 2011 [14] 120 PI, 34 PR) S. pyogenes 220 ≤0.03-0.06 ≤0.03 ≤0.03 - - - Jones RN et al., Viridans streptoocci 40 ≤0.03-0.12 ≤0.03 0.06 - - - 2013 [30] S. pyogenes 155 ≤0.03-0.12 ≤0.03 ≤0.03 - - - S. agalactiae 153 ≤0.03-0.25 ≤0.03 0.12 - - - Huband M et al., Viridans streptoocci 135║ ≤0.03-0.12 0.03 0.06 - - - 2016 [26] β-haemolytic 125║ ≤0.03-0.12 ≤0.03 0.06 - - - streptococci Pfaller MA et al., S. pneumoniae 3487║ ≤0.002-0.06 0.015 0.015 - - - 2018 [12] Viridans streptoocci 1063║ ≤0.002-0.25 0.08 0.03 - - - β-haemolytic streptococci 3269 ≤0.002-0.12 0.015 0.03 - - - Pfaller MA et al., Viridans streptoocci 45 - ≤0.03 ≤0.03 - - - 2018 [27] β-haemolytic streptococci 164 - ≤0.03 ≤0.03 - - -

⌠ MIC50 ≤0.08 µg/mL for isolates from North America. *Dalbavancin MIC values were obtained by reference BMD method in all studies, except for Biedenbach DJ et al, 2007 [13], where MICs were obtained by gradient test (AB BIODISK).

║ all strains, not distinguished based on penicillin-susceptibility; ⌠⌠ MIC90 0.03 µg/mL for isolates from North America. 10 F. Campanile, M. Falcone

S. dysgalactiae, S. mitis, S. mutans, S. salivari- regulatory authorities. Dalbavancin has been us/S. vestibularis group) and, finally, against evaluated against a total of 801 S. aureus, 160 Corynebacterium spp, L. monocytogenes, Mic- CoNS, 164 β-haemolytic streptococci, 82 E. rococcus spp [30]. S. anginosus and so-called faecalis and 45 VGS causing BJI from differ- S. milleri were the most susceptible strep- ent sites in Europe and US from 2011 and

tococci (MIC90 ≤0.03 mg/L), while S. mitis 2016 [27]. Dalbavancin showed lower MIC90 group and S. salivarius/vestibularis group iso- values of 0.06 mg/L against S. aureus from

lates had higher recorded results (MIC50/90, the US and European countries, irrespective ≤0.03/0.06 mg/L) [30]. Dalbavancin was very of the methicillin susceptibility and resulted

active against Corynebacterium spp. (MIC50/90, 8-fold more potent than daptomycin and 16-

0.06/0.12 mg/L), L. monocytogenes (MIC50/90, fold more potent than vancomycin and line- 0.06/0.12μg/mL), and Micrococcus spp. zolid [27]. Similar results have been obtained

(MIC50/90, ≤0.03/≤0.03 mg/L) [30]. against CoNS (S. epidermidis and S. lugdun-

ensis) with MIC50 and MIC90 values of <0.03 In vitro activity of dalbavancin against and 0.06 mg/L respectively, β-haemolytic different pathogens isolates streptococci and VGS (100.0% susceptible). Dalbavancin has been tested in vitro against As expected, all E. faecalis with the exception isolates responsible for DFIs, both aerobes of vanA carrying strains, were susceptible to (MSSA, MRSA, CoNS, S. agalactiae, β-hemo- dalbavancin [27]. lytic streptococci, Corynebacterium spp. C. amycolatum), and anaerobes (Clostridium spp, n SYNERGISTIC EFFECT Peptoniphilus asaccharolyticus, Finegoldia mag- OF DALBAVANCIN WITH OTHER na, Anaerococcus prevotii) [31]. As expected, ANTIMICROBIAL AGENTS dalbavancin was at least two-fold more active than vancomycin and daptomycin and Combination therapy has a distinct advan- fourfold more active than linezolid against tage over monotherapies because the relat- MRSA, MSSA, and CoNS isolates [31]. How- ed synergistic effect and the prevention of ever, the MIC values of dalbavancin for the emergence of drug resistance. In a study one of three strains of S. haemolyticus was 2 in which dalbavancin was tested in com- mg/L. Moreover, dalbavancin results active bination with other 9 drugs (clindamycin, against C. perfringens, other clostridia, P. asac- daptomycin, gentamicin, levofloxacin, lin- charolyticus, F. magna, and A. prevotii, with ezolid, oxacillin, quinupristin/dalfopristin,

MIC90 of ≤0.125 mg/L [31]. These in vitro data rifampicin, vancomycin) synergistic effect demonstrated that dalbavancin could be ac- was found only with oxacillin, and no an- tive against isolates from patients with DFIs tagonist effect was observed [32]. Howev- and could be a basis for further evaluation in er, several studies recently highlighted the some specific populations of patients. As a synergistic activity of dalbavancin in combi- matter of fact, for DFIs, who often were man- nation with other antimicrobials. More spe- aged as outpatients, an antimicrobial agent cifically, dalbavancin seems to have a good with a long half-life, especially one adminis- synergistic effect when used in combination tered once weekly, could be advantageous. with β-lactams (cefazolin, cefepime, ceftaro- Dalbavancin has been evaluated against clin- line, ertapenem and oxacillin) [33], linezolid ical isolates from patients with bone and joint and daptomycin [43]. Finally, in an in vivo infections (BJI), an infection for which this model of foreign-body infection, the use of drug has not yet obtained the approval from dalbavancin in combination with rifampicin Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 11

was shown to prevent the emergence of ri- bloodstream isolates, collected from patients fampicin resistance [34]. in the General Hospital of Vienna between Even if combination therapies could mitigate 2012 and 2015 [36]. Recently, Fernández J the main advantage of dalbavancin, which is and coworkers demonstrated the activity of the possibility of once weekly or single ad- dalbavancin against staphylococcal biofilms ministration, involving the use of some drugs associated with prosthetic joint infections, in available as oral formulation, could strength- both planktonic and biofilm states [37]. The en its efficacy in patients with infections sus- minimum biofilm bactericidal concentrations tained by resistant microorganisms. Further (MBBC50) for S. aureus and S. epidermidis was clinical research involving dalbavancin com- 1 mg/L independently from methicillin-sus- binations is warranted. ceptibility, while the MBBC90 was 2 μg/mL for MRSA and MSSA and 4 mg/L for MRSE and methicillin susceptible S. epidermidis n MICROBIOLOGICAL ACTIVITY (MSSE). If compared with data about vanco- OF DALBAVANCIN AGAINST BIOFILM mycin (MBBC50 and MBBC90 ≥128 mg/L) and

Biofilms can potentially form on any foreign tedizolid (MBBC50 and MBBC90 were both object inserted into the human body, such >32 mg/L) [37], these findings appear very as implants or catheters, and the number of promising for the use of dalbavancin in in- infections in which biofilms are involved is fections sustained by biofilm. Similar results growing each year. For clinicians, the ability have been obtained when dalbavancin was of biofilm bacteria to withstand the actions of tested against biofilm of VSE isolates, but not antibiotics and the host defense represents a for VRE strains [21]. For E. faecalis and E. fae- substantial challenge. Thus, the assessment cium, dalbavancin MBBCs (both MBBC50 and of the activity of a drug against biofilms is a MBBC90) were ≤4 mg/L for vancomycin-sus- crucial point in the evaluation process of the ceptible, but >16 mg/L for VRE isolates [38]. new antibiotics. Moreover, in the setting of However, it has to be considered that van- antibiotics acting against Gram-positive coc- comycin MBBCs were >128 mg/L for all ci, the activity against biofilm appears to be isolates, and daptomycin MBBC90 values for an essential property because S. aureus and both species were 128 mg/L [21]. These find- S. epidermidis are among the most common ings are in line with in vitro studies of dalba- pathogens involved with surface-associated vancin activity against enterococcal isolates. infections, as a result of the capability of pro- In an in vivo study, 12 rabbits underwent a sub- ducing biofilm [2, 35]. The open-label study cutaneous implantation of catheter segments design and the small sample size did not al- in their back, inoculated with S. aureus [38]. low the generalizability of these results, but Animals were randomized in three groups, these findings suggested a potential role of in relation of having received a pre-implan- dalbavancin in the eradication of biofilms. tation, itravenous injections of dalbavancin, Several preclinical studies specifically eval- vancomycin or normal saline (control). There uated the activity of dalbavancin against was a trend toward a lower rate of device col- biofilms. In vitro data showed promising onization in the rabbits pre-treated with dal- anti-biofilm activity of dalbavancin against bavancin compared with the vancomycin and Gram-positive isolates belonging to differ- control groups. However, probably due to the ent species. Dalbavancin successfully re- low number of animals used in this study, no duced biofilms obtained from 10 MRSA and statistically significant differences among the 10 methicillin-resistant S. epidermidis (MRSE) 3 groups were observed [38]. 12 F. Campanile, M. Falcone

The activity of dalbavancin, alone and in ter feature confers to this antibiotic a unique combination with rifampicin, was inves- characteristic: the possibility of once-a-week tigated in a MRSA foreign-body infection dosage. model in guinea pigs [34]. More specifically, In healthy adult volunteers, dalbavancin ex- 4 sterile polytetrafluoroethylene cylindrical hibits linear, dose-proportional PK [40]: fol- cages were subcutaneously implanted in the lowing administration of multiple 30-min in- flanks of the guinea pigs under aseptic con- travenous infusion doses, mean dalbavancin ditions. Cages were infected by percutane- concentrations in plasma increase propor- ous injection of MRSA strains (Day 0). Anti- tionally with dose and decline in a log-linear

microbial treatment with dalbavancin, alone manner [39]. Conversely, the T1/2, clearance or in combination with rifampicin, was in- and volume of distribution at steady state re- itiated 3 days after infection. Two weeks main essentially unchanged. Similar system- after surgery, the sterility of the cages was ic exposures (expressed as Area Under Curve checked by culture of aspirated cage fluid. [AUC] values) of dalbavancin were seen be- Dalbavancin at high dose (60 mg/kg and 80 tween subjects with normal renal function mg/kg) reduced planktonic MRSA in cage and those with mild renal impairment, while fluid, but failed to eradicate biofilm MRSA slightly higher AUC values were observed in from cages. At 80 mg/kg (corresponding those with moderate renal impairment [40]. to 1000 mg in humans) and in combination Instead, patients with severe renal impair- with rifampicin, dalbavancin eradicated ment had a marked increase in exposure that only one-third of cage-associated MRSA in- would require dose adjustment. Dalbavancin fections [34]. exposure is not affected by hepatic insuffi- The discrepancies of in vitro and in vivo stud- ciency [40]. ies could have different explanation. First of The penetration of dalbavancin in specific all, in vitro studies evaluated the specific mi- tissues has been also investigated. A phase crobiological activity of dalbavancin against I study evaluated dalbavancin distribution different isolates in a highly controlled arti- in the bone, skin, and articular tissue [41]. ficial environment but independently from Dalbavancin concentration in cortical bone the host response to the infection. Moreover, was 6.3 µg/g, 12 h after infusion of a single pharmacokinetic and pharmacodynamic fac- 1000-mg intravenous and 4.1 µg/g 2 weeks tors could influence the success in animal later [17]. In skin, dalbavancin concentrations models. after 12 h and 2 weeks were 19.4 µg/g and In conclusion, although dalbavancin demon- 13.8 µg/g, respectively [41]. In synovial tis- strated to possess a potent in vitro activity sue, they were 25.0 µg/g and 15.9 µg/g [41]. against biofilm, future studies are needed to Thus, in these compartments dalbavancin evaluate the in vivo efficacy of dalbavancin distributes at concentrations that are expect- alone and in combinations with other antimi- ed to exceed the MIC for S. aureus for extend- crobials, in biofilm-related infections. ed periods. Excretion of the drug is very slow; with the majority of drug excreted in the urine (33% n PK/PD AND CLINICAL unchanged, 12% metabolite) in 42 days and, PROFILE OF DALBAVANCIN to a lesser degree, in feces (20%) in 70 days Dalbavancin requires intravenous admin- [42]. PK parameters of dalbavancin in chil- istration, has a high protein binding and dren are slightly different from those ob- long half-life (up to 8.5 days) [39]. This lat- served in adult patients. In pediatric subjects Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 13

(12-17 years) who received 1000 mg of dalba- 500 mg on day 8) or linezolid (600 mg given vancin, median values of T1/2 were 216 hours intravenously or intravenously/orally every and in those who received dalbavancin at the 12 h for 14 days) [44]. MRSA was identified dose of 15 mg/kg, median T1/2 was 219 hours. in 51% of patients from whom it was possi- Of note, 9 of the 10 subjects still had detecta- ble to isolate a pathogen at baseline. Among ble dalbavancin in plasma samples (>0.5 μg/ patients who were clinically evaluable at the mL) 1320 hours (55 days) after dosing [43]. TOC visit, 88.9% in the dalbavancin arm and Moreover, the AUC exposures were approx- 91.2% in the linezolid arm achieved clinical imately 30% less than those documented in success, defined as improvement of signs adults. It can be due to the enhanced renal and symptoms of infection. Moreover, both and/or hepatic elimination usually docu- treatments yielded successful microbiologi- mented in healthy adolescents compared cal response in excess of 85% among mi- with adults [43]. crobiologically evaluable patients at end of Table 5 summarizes phase III clinical trials of therapy [44]. dalbavancin in patients with ABSSSIs. The Safety and efficacy of dalbavancin in clinical first clinical study evaluating the efficacy of setting have been further demonstrated in dalbavancin in infected patients goes back two double blind, non-inferiority phase III to 2005. A total of 854 patients with com- clinical trials, DISCOVER 1 and DISCOVER plicated SSTIs, including infections known 2, conducted from 2011 to 2012 [19]. Patients or suspected to involve MRSA, were rand- with ABSSSIs, defined accordingly with the omized 2:1 to receive dalbavancin (1000 mg FDA definitions [1], having one or more sys- given intravenously on day 1, followed by temic signs of infection within 24 hours and

Table 5 - Phase 3 clinical trials on efficacy of dalbavancin in patients with ABSSSIs. Related adverse Study Inclusion criteria Intervention Comparator N. of patients Clinical efficacy events Jauregui LE Suspected Dalbavancin Linezolid Total: 854 pts 88.9% 25.4% et al., 2005 or confirmed 2-dose regimen 600 mg q12h Pts clinically (dalbavancin) (dalbavancin) [44] SSSI due to evaluable at the versus 91.2% versus 32.2% gram-positive TOC visit: 660 (comparator) (linezolid) pathogens Most frequent: nausea, diarrhea Boucher H Patients with Dalbavancin Vancomycin Total: 1312 pts 79.7% 32.8% et al., 2014 ABSSSIs 2-dose regimen 1 g (or 15 mg/kg) (659 versus (dalbavancin) (dalbavancin) [19] needed iv q12h, eventually 653 comparator) versus 79.8% versus 37.9% therapy de-escalated (comparator), comparator, DISCOVER to linezolid Weighted p=0.05 1 and 2 600 mg q12h difference - 0.1% Most frequent: (95% CI, -4.5 nausea, to 4.2 diarrhea Dunne MW Patients with Dalbavancin Dalbavancin Total: 698 pts 84.2% (2-dose 19.9 (2-dose et al., 2016 ABSSSIs 2-dose regimen single-dose (349 2-dose regimen) versus regimen) versus [45] needed iv regimen regimen versus 81.4% (single 20.1% (single therapy 349 single dose dose regimen) dose regimen) regimen) Absolute Most frequent: difference - 2.9% nausea (95% CI -8.5, 2.8) ABSSSI: Acute bacterial skin and skin structure infections; Pts: patients. 14 F. Campanile, M. Falcone

requiring at least 3 days of intravenous ther- receive dalbavancin as either a single intra- apy were included in the study [19]. Patients venous infusion of 1500 mg of dalbavancin who received previous antibiotic therapy over 30 minutes or in 2 doses as 1000 mg within the immediate 14 days were exclud- intravenously over 30 minutes, followed by ed. They were randomized 1:1 to receive 500 mg intravenously one week later. For pa- dalbavancin at a dose of 1 g intravenous- tients with a creatinine clearance of <30 mL/ ly followed by 500 mg on day 8 (two-dose minute the single-dose regimen was 1000 mg regimen) or vancomycin 1 g (or 15 mg per as a single infusion while the 2-dose regimen kilogram of body weight) every 12 hours for 750 mg intravenously followed 1 week later at least 3 days, with an option to switch to by 375 mg intravenously. To maintain the oral linezolid, at a dose of 600 mg every 12 blinding, patients randomized to the single hours, to complete a course of 10 to 14 days dose received a placebo infusion on day 8. of therapy [19]. A total of 1312 adults with Metronidazole and aztreonam were allowed ABSSSI were finally included in the studies. in both treatment groups for infection with Of note, approximately 15% of the patients suspected anaerobic gram-negative patho- had a history of recent or current intrave- gens, respectively. Clinical response (defines nous drug use, and 13% had diabetes mel- as the achievement of a ≥20% reduction in the litus. DISCOVER 1 included more patients size of the erythema and no need of rescue with major abscesses, while DISCOVER 2 antibacterial therapy in the 48-72 hours from included more with patients affected by the start of therapy) was observed in 81.4% cellulitis. Analysis of the primary endpoint of those randomized to the single-dose reg- (early clinical response, requiring the cessa- imen vs 84.2% in the 2-dose regimen (abso- tion of spread of infection-related erythema lute difference -2.9 [95% CI, -8.5%, 2.8%]), and the absence of fever at 48 to 72 hours) demonstrating the non-inferiority of the sin- showed non-inferiority of dalbavancin com- gle-dose compared to the 2-dose regimen. pared to vancomycin in both DISCOVER 1 Moreover, no differences in terms of adverse and DISCOVER 2 [19]. In the pooled anal- events were observed between the two study ysis 79.7% in the dalbavancin group and groups [45]. 79.8% in the vancomycin-linezolid group Dalbavancin is usually well tolerated. In a had cessation of spread of infection-related pooled analysis of patients, participating in erythema and absence of fever at 48 to 72 h phase 2 and 3 clinical trials, the 85% of pa- (weighted difference, -0.1 percentage point; tients completed the course of therapy. The 95% CI, -4.5 to 4.2). Moreover, similar rates most commonly identified reasons for dis- of reduction in the size of the infected area continuation are similarly distributed among of at least 20% at 48 to 72 hours were detect- worsening clinical status, lost to follow-up, ed [19]. occur of an adverse event, and withdrawal Dunne and coworkers, conducted a rand- of consent [46]. The most common adverse omized, double-blind trial in patients with events during dalbavancin course were gas- ABSSSIs to assess the safety and efficacy of trointestinal disturbances, while serious ad- a single intravenous infusion of 1500 mg verse events were progression of cellulitis, of dalbavancin compared to the standard leukopenia and an anaphylactoid reaction. 2-dose regimen [45]. Patients with catheter The rate of adverse events and the its time of infection, infected devices, diabetic foot ul- onset were similar between dalbavancin and ceration, perirectal abscess, or decubitus ulcer comparators group used in the whole clinical were excluded. They were randomized 1:1 to development [46]. Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 15

n CONCLUSIONS ria and distinction from community-acquired pneumonia. Int J Infect Dis.15, e545-50, 2011. In conclusion, dalbavancin represents an ef- [7] DALVANCE (dalbavancin) for injection, for in- fective choice, alternative to established ther- travenous use Initial U.S. Approval: 2014. Available apies with the conventional anti-Gram-posi- at: https://www.accessdata.fda.gov/drugsatfda_ tive drugs commonly used for the treatment docs/label/2016/021883s003lbl.pdf. Accessed on Oct, 20th 2018. of ABSSSIs in adults. [8] Xydalba. Summary of product characteristics. Its broad antimicrobial spectrum of activity Available at: https://www.ema.europa.eu/docu- against MDR Gram-positive pathogens, ad- ments/product-information/xydalba-epar-prod- vantageous pharmacokinetic benefits, long uct-information_en.pdf. Accessed on: Oct 17th 2018. half-life and excellent tissue penetration [9] The European Committee on Antimicrobial Sus- make this drug a suitable treatment option ceptibility Testing. Breakpoint tables for interpreta- for clinicians. Moreover, the single-dose ad- tion of MICs and zone diameters. Version 8.1, valid from 2018-05-15. Available at: http://www.eucast. ministration, effective as conventional ther- org/fileadmin/src/media/PDFs/EUCAST_files/ apies, without requiring prolonged hospital Breakpoint_tables/v_8.1_Breakpoint_Tables.pdf. stay, could be significantly advantageous for Accessed on Oct, 20th 2018. patients and the overall health care system. [10] Fritsche, T. R., R. P. Rennie, B. P. Goldstein, and R. N. Jones. Comparison of dalbavancin MIC values Acknowledgments determined by Etest (AB BIODISK) and reference dilution methods using gram-positive organisms. J. The authors thank Dr. Giusy Tiseo for provid- Clin. Microbiol. 44, 2988-2990, 2006. ing medical writing support/editorial sup- [11] Streit JM, Fritsche TR, Sader HS, Jones RN. port, which was funded by Angelini S.p.A. Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates. Diagn n Microbiol Infect Dis. 48:137-43, 2004. REFERENCES [12] Pfaller MA, Mendes RE, Duncan LR, Flamm RK, [1] US Food and Drug Administration. Guidance Sader HS. Activity of dalbavancin and comparator for industry. Acute bacterial skin and skin structure agents against Gram-positive cocci from clinical in- infections: developing drugs for treatment. 2013. fections in the USA and Europe 2015-16. J Antimicrob Available at: https://www.fda.gov/downloads/ Chemother. 73, 2748-2756, 2018. Drugs/Guidances/ucm071185.pdf. Last access: 02nd [13] Biedenbach DJ1, Ross JE, Fritsche TR, Sader HS, Nov, 2018. Jones RN. Activity of dalbavancin tested against [2] Falcone M, Concia E, Giusti M et al. Acute bac- Staphylococcus spp. and beta-hemolytic Streptococcus terial skin and skin structure infections in internal spp. isolated from 52 geographically diverse med- medicine wards: old and new drugs. Intern Emerg ical centers in the United States. J Clin Microbiol. Med. 11, 637-48, 2016. 45:998-1004, 2007. [3] Esposito S, Bassetti M, Concia E et al. Diagnosis [14] Karlowsky JA, Adam HJ, Poutanen SM, Hoban and management of skin and soft-tissue infections DJ, Zhanel GG; Canadian Antimicrobial Resistance (SSTI). A literature review and consensus statement: Alliance (CARA). In vitro activity of dalbavancin an update. J Chemother. 29, 197-214, 2017. and telavancin against staphylococci and strepto- [4] National Nosocomial Infections Surveillance cocci isolated from patients in Canadian hospitals: (NNIS). System report, data summary from January results of the CANWARD 2007-2009 study. Diagn 1992 through June 2004. Am J Infect Control. 32, 470- Microbiol Infect Dis. 69, 342-7, 2011. 85, 2004. [15] Weshnoweski B, Vashisht R, Tailor F, DeCorby [5] Khan A, Wilson B, Gould IM et al. Current and M, Zhanel GG Langner S, Hoban DJ (2008) Activi- future treatment options for community-associated ty of dalbavancin against S. aureus, S. epidermidis, S. MRSA infection. Expert Opin Pharmacother. 19, 457- pneumoniae, and Enterococcus spp. isolated from Ca- 470, 2018. nadian hospitals: CANWARD 2007. Presented at the [6] Falcone M, Shindo Y, Venditti M, Kollef MH. 48th Interscience Conference on Antimicrobial Agents Healthcare associated pneumonia: diagnostic crite- and Chemotherapy, Washington, D.C. 25-28, 2008. 16 F. Campanile, M. Falcone

[16] Sader HS, Mendes RE, Duncan LR, Pfaller MA, [27] Pfaller MA, Flamm RK, Castanheira M, Sader Flamm RK. Antimicrobial Activity of Dalbavancin HS, Mendes RE. Dalbavancin in-vitro activity ob- against Staphylococcus aureus with decreased suscep- tained against Gram-positive clinical isolates caus- tibility to glycopeptides, daptomycin, and/or line- ing bone and joint infections in US and European zolid from U.S. Medical Centers. Antimicrob Agents hospitals (2011-2016). Int J Antimicrob Agents. 51, Chemother. 62, e02397-17, 2018. 608-611, 2018. [17] Campanile F, Bongiorno D, Rizzo M, Stefani S. [28] Mendes RE, Sader HS, Streit JM, Farrell DJ, in vitro antibacterial and bactericidal activity of dal- Jones RN. Sustained potent activity of dalbavancin bavancin against different multidrug resistant (MDR) when tested against multidrug-resistant staphylo- Staphylococcus aureus strains. (Abs. n. 3857). 28th EC- coccal and streptococcal isolates responsible for doc- CMID congress Madrid, Spain, 21-24 April 2018. umented infection in European sites (2011-2013). 25th [18] Lepak A, Marchillo K, VanHecker J, Andes D. ECCMID congress, Copenhagen, Denmark, 25 - 28 Impact of glycopeptide resistance in Staphylococcus April 2015. aureus on the dalbavancin in vivo pharmacodynamic [29] Scott LJ. Dalbavancin: A Review in Acute Bac- target. Antimicrob Agents Chemother. 59, 7833-6, 2015. terial Skin and Skin Structure Infections. Drugs. 75, [19] Boucher HW, Wilcox M, Talbot GH, Puttagunta 1281-91, 2015. S, Das AF, Dunne MW. Once-weekly dalbavancin [30] Jones RN, Stilwell MG. Comprehensive up- versus daily conventional therapy for skin infection. date of dalbavancin activity when tested against N Engl J Med. 370, 2169-79, 2014. uncommonly isolated streptococci, Corynebacteri- [20] Jones RN, Fritsche TR, Sader HS, Goldstein um spp., Listeria monocytogenes, and Micrococcus BP. Antimicrobial spectrum and potency of dalba- spp. (1357 strains). Diagn Microbiol Infect Dis. 76, vancin tested against clinical isolates from Europe 239-40, 2013. and North America (2003): initial results from an [31] Goldstein EJ, Citron DM, Warren YA, Tyrrell international surveillance protocol. J Chemother. 17, KL, Merriam CV, Fernandez HT. In vitro activities 593-600, 2005. of dalbavancin and 12 other agents against 329 aer- [21] Neudorfer K, Schmidt-Malan SM, Patel R. Dal- obic and anaerobic gram-positive isolates recovered bavancin is active in vitro against biofilms formed from diabetic foot infections. Antimicrob Agents by dalbavancin-susceptible enterococci. Diagn Mi- Chemother. 50, 2875-9, 2006. crobiol Infect Dis. 90, 58-63, 2018. [32] Johnson DM, Fritsche TR, Sader HS, Jones RN. [22] Biedenbach DJ, Bell JM, Sader HS, Turnidge JD, Evaluation of dalbavancin in combination with Jones RN. Activities of dalbavancin against a world- nine antimicrobial agents to detect enhanced or an- wide collection of 81,673 gram-positive bacterial iso- tagonistic interactions. Int J Antimicrob Agents. 27, lates. Antimicrob Agents Chemother. 53, 1260-3, 2009. 557-60, 2006. [23] Gales AC, Sader HS, Jones RN. Antimicrobial [33] Xhemali X, Smith JR, Kebriaei R, et al. Evalua- activity of dalbavancin tested against Gram-positive tion of dalbavancin alone and in combination with clinical isolates from Latin American medical cen- β-lactam antibiotics against resistant phenotypes of tres. Clin Microbiol Infect. 11, 95-100, 2005. Staphylococcus aureus. J Antimicrob Chemother. 2018 [24] Jones RN, Stilwell MG, Sader HS, Fritsche TR, [Epub ahead of print]. Goldstein BP. Spectrum and potency of dalbavancin [34] Baldoni D, Furustrand Tafin U, et al. Activity tested against 3322 Gram-positive cocci isolated in of dalbavancin, alone and in combination with ri- the United States Surveillance Program (2004). Di- fampicin, against meticillin-resistant Staphylococcus agn Microbiol Infect Dis. 54, 149-53, 2006. aureus in a foreign-body infection model. Int J Anti- [25] Jones RN, Sader HS, Flamm RK. Update of dal- microb Agents. 42, 220-5, 2013. bavancin spectrum and potency in the USA: report [35] Donlan RM. Biofilms and device-associated in- from the SENTRY Antimicrobial Surveillance Pro- fections. Emerg Infect Dis. 7, 277-281, 2001. gram (2011). Diagn Microbiol Infect Dis. 75, 304-7, 2013. [36] Knafl D, Tobudic S, Cheng SC, Bellamy DR, Thal- [26] Huband MD, Castanheira M, Farrell DJ, et al. In hammer F. Dalbavancin reduces biofilms of methicil- vitro activity of dalbavancin against multidrug-re- lin-resistant Staphylococcus aureus (MRSA) and methi- sistant Staphylococcus aureus and streptococci from cillin-resistant Staphylococcus epidermidis (MRSE). Eur patients with documented infections in Europe and J Clin Microbiol Infect Dis. 36, 677-680, 2017. surrounding regions (2011-2013). Int J Antimicrob [37] Fernández J, Greenwood-Quaintance KE, Patel Agents. 47, 495-9, 2016. R. In vitro activity of dalbavancin against biofilms Microbiological efficacy, pharmacokinetic/pharmacodynamic and clinical profile of dalbavancin 17

of staphylococci isolated from prosthetic joint infec- dren 12-17 Years of age. Pediatr Infect Dis J. 34, 748- tions. Diagn Microbiol Infect Dis. 85, 449-51, 2016. 52, 2015. [38] Darouiche RO, Mansouri MD. Dalbavancin [44] Jauregui LE, Babazadeh S, Seltzer E, et al. Ran- compared with vancomycin for prevention of Staph- domized, double-blind comparison of once-weekly ylococcus aureus colonization of devices in vivo. J In- dalbavancin versus twice-daily linezolid therapy for fect. 50, 206-9, 2005. the treatment of complicated skin and skin structure [39] Leighton A, Gottlieb AB, Dorr MB, et al. Tolera- infections. Clin Infect Dis. 41, 1407-15, 2005. bility, pharmacokinetics, and serum bactericidal ac- [45] Dunne MW, Puttagunta S, Giordano P, Krievins tivity of intravenous dalbavancin in healthy volun- D, Zelasky M, Baldassarre J. A Randomized clinical teers. Antimicrob Agents Chemother. 48, 940-5, 2004. trial of single-dose versus weekly dalbavancin for [40] Marbury T, Dowell JA, Seltzer E, Buckwalter M. treatment of acute bacterial skin and skin structure Pharmacokinetics of dalbavancin in patients with infection. Clin Infect Dis. 62, 545-51, 2016. renal or hepatic impairment. J Clin Pharmacol. 49, [46] Dunne MW, Talbot GH, Boucher HW, Wilcox 465-76, 2009. M, Puttagunta S. Safety of dalbavancin in the treat- [41] Dunne MW, Puttagunta S, Sprenger CR, Rubi- ment of skin and skin structure infections: a pooled no C, Van Wart S, Baldassarre J. Extended-duration analysis of randomized, comparative studies. Drug dosing and distribution of dalbavancin into bone Saf. 39, 147-57, 2016. and articular tissue. Antimicrob Agents Chemother. 59, [47] McCurdy SP, Jones RN, Mendes RE, Puttagun- 1849-55, 2015. ta S, Dunne MW. In vitro activity of dalbavancin [42] Tatarkiewicz J, Staniszewska A, Bujalska-Za- against drug-resistant Staphylococcus aureus isolates drożny M. New agents approved for treatment of from a Global Surveillance Program. Antimicrob acute staphylococcal skin infections. Arch Med Sci. Agents Chemother. 59, 5007-92, 015. 12, 1327-1336, 2016. [48] Lin G, Credito K, Ednie LM, Appelbaum PC. [43] Bradley JS, Puttagunta S, Rubino CM, Blumer Antistaphylococcal activity of dalbavancin, an ex- JL, Dunne M, Sullivan JE. Pharmacokinetics, safety perimental glycopeptide. Antimicrob Agents Chem- and tolerability of single dose dalbavancin in chil- other. 49, 770-2, 2005. bianca bianca ISSN 1124-9390 LE INFEZIONI IN MEDICINA

Supplemento 2018

SCIENTIFIC EVIDENCES ON MICROBIOLOGICAL EFFICACY, PHARMACOKINETIC/ PHARMACODYNAMIC (PK/PD) AND CLINICAL PROFILE OF DALBAVANCIN