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Home , Lipoglycopeptide, Telavancin

and activity against resistant strains after ISTITUTO NAZIONALE PER LE MALATTIE INFETTIVE "LAZZARO SPALLANZANI“ resistance selection in vitro IRCCS, ROMA Taglietti F, Principe L, Bordi E, Di Caro A, Di Bella S, Musso M, Petrosillo N. National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy

ABSTRACT Subsequently multistep resistance selection was performed, increasing the Methicillin resistant Staphylococcus aureus represent a major threat world- vancomycin MIC of all MRSA to 2 µg/ml value. At this time all the 19 strains were wide and there are still several concerns regarding its treatment. Although vancomycin is tested again using Sensititre plates against , vancomycin, daptomycin and the drug of choice, clinical failures in patients with serious gram-positive infections have telavancin. Results were read after 24 and 48 h of incubation. Four (21%) of the initial been increasingly reported in the last years with an higher risk with increasing MRSA strains returned oxacillin susceptible with a MIC 0.5 µg/ml at 24 and 48 h. vancomycin MICs, well within the susceptible range. Moreover, it has been reported an This result was confirmed with a Kirby Bauer test. association between reduced susceptibility to daptomycin and to vancomycin in S. At 24 h, 13 (68.4%) and 6 (31.6%) strains showed a telavancin MIC 0.5 µg/ml and 1 aureus. Telavancin is a semi-syntetic that has a dual mechanism of µg/ml respectively. At 48 h, 4 strains more increased the televancin MIC to 1 µg/ml. action and it is active against MRSA, VISA and VRSA strains. Objective of our study is No one exceeded this value. At 24 h for daptomycin, only one strain (5.3%) was to evaluate the in vitro activity of telavancin and daptomycin against MRSA strains with confirmed with a MIC 0.25 µg/ml; 3 (15.8%) resulted with a MIC 0.5 µg/ml and the a vancomycin MIC ≤ 0.5 µg/ml and against MRSA strains after induction of remaining 15 strains (78.9%) showed a MIC 1 µg/ml. Daptomycin’s MIC after 48 h vancomycin MIC 2 µg/ml. of incubation showed the same results as 24 h. Full susceptibility results are shown in Table 2. Eighteen patients were cured using glycopeptides. One patient died for septic Introduction shock occurred during vancomycin treatment. Of note, Sensititre plates method in the Methicillin resistant Staphylococcus aureus (MRSA) infections represent a major threat S. aureus strain isolated from the died patient, revealed as baseline value, a world-wide and there are still several concerns regarding its treatment. Although vancomycin MIC 2 µg/ml not detected by VITEK system. vancomycin is the drug of choice, clinical failure has been reported in the last years especially in those with vancomycin MIC 2 µg/ml (1-4). Daptomycin has good activity Discussion against MRSA, VISA and VRSA. (5-6) The emergence of S. aureus strains with a The treatment of MRSA infections requires the administration of a fully active agent. daptomycin MIC at the upper range of susceptibility, and sometimes above, has been Strains of S. aureus exhibiting decreased susceptibility or resistance to vancomycin reported during treatment. Moreover, it has been reported an association between reduced severely compromise the patients’ outcome. In the present study we demonstrate that susceptibility to daptomycin and to vancomycin in S. aureus. No definitive daptomycin in vitro activity of both, telavancin and daptomycin, maintains a MIC range within resistance mechanism has been identified; the development of increasing daptomycin MIC 0.25 µg/ml and 1 µg/ml against MRSA with induced MIC increased to vancomycin. values has been sporadically reported after prolonged daptomycin and/or vancomycin All S. aureus strains with the induced vancomycin MIC 2 µg/ml examinated by the treatment (7). It has been demonstrated that a thickened is a common electron microscopy showed a cell-wall thickening (Figure 1). In conclusion, characteristic of VISA strains (8-10). Telavancin is a semi-syntetic lipoglycopeptide with a daptomycin and telavancin seems to represented a good alternative for the treatment of smaller size than daptomycin (11). It has a dual , including inhibition MRSA infections with a vancomycin MIC 2 µg/ml. of cell wall synthesis and disruption of membrane barrier function, resulting in bacterial References death (12-13). Telavancin is active against MRSA, VISA and VRSA (14-16). Objective of 1.Jones RN. Microbiological features of vancomycin in the 21st century: minimum inhibitory concentration creep, bactericidal/static activity, and applied breakpoints to predict clinical outcomes or detect resistant strains. Clin Infect Dis 2006; 42:S13-24. our study is to evaluate the in vitro activity of telavancin and daptomycin against MRSA 2.Petrosillo N, Capone A, Di Bella S, Taglietti F. Management of resistance in the intensive care unit setting. Expert Rev Anti Infect Ther 2010; 8:289– strains with a vancomycin MIC ≤ 0.5 µg/ml and against MRSA strains after induction of 302. 3.Neoh HM, Hori S, Komatsu M, Oguri T, Takeuchi F, Cui L, Hiramatsu K. Impact of reduced vancomycin susceptibility on the therapeutic outcome of MRSA vancomycin MIC 2 µg/ml. bloodstream infections. Ann Clin Microbiol Antimicrob 2007; 6:13. 4.Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering Jr RC, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of MRSA bacteremia. J Clin Microbiol 2004;42:2398-2402. 5.Jung D, Rozek A, Okon M, Hancock RE. Structural transitions as determinants of the action of the calcium dependent antibiotic daptomycin. Chem Biol 2004; Material and methods 11: 949-957. Nineteen MRSA strains with a vancomycin MIC ≤ 0.5 µg/ml, already tested with VITEK 6.Hobbs JK, Miller K, O’neill AJ, Chopra I. Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus. J Antimicrob Chemother 2008; 62: 1003-1008. system, isolated from patients with bloodstream (9 patients), skin and soft skin infections 7.Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007; 45: 601-608. 8.Gander S, Kinnaird A, Finch R. Telavancin: in vitro activity against staphylococci in a biofilm model. J Antimicrob Chemother 2006; 56: 337-343. (6 patients) and osteomyelitis (4 patients), were considered. First, all the strains were 9.Cui L, J Lian, H Neoh, P Ethel, and K Hiramatsu. DNA microarray-based identification of genes associated with glycopeptides resistance in Staphylococcus aureus. Antmicrob Agents Chemother 2005;49:3404-3413. tested again, utilizing Sensititre plates, for susceptibility against oxacillin, vancomycin, 10.Cui L, X Ma, K Sato, et al. Cell wall thickening is a common feature of vancomycin resistance in Staphylococcus aureus. J Clin Microbiol 2003; 41: 5-14. 11.Barcia-Macay M, Mouaden F, Mingeot-Leclerq MP, Tulkens PM, Van Bambeke F. Cellular of telavancin, a novel lipoglycopeptide daptomycin and telavancin. Sensititre plates were provided by the Astellas Pharma spa. antibiotic, and analysis of lysosomal changes in cultured eukaryotic cells (J774 mouse macrophages and rat embryonic fibroblasts). J Antimicrob Chemother 2008; 61: 1288-94. After the first evaluation, multistep resistance selection was performed using the broth 12.Kanafani ZA. Telavancin: a new lipoglycopeptide with multiple mechanism of action. Expert Rev Anti Infect Ther 2006; 4: 743-749. 13.Draghi DC, Benton BM, Krause KM, Thornsberry C, Pillar C, Sahm DF. Comparative surveillance study of telavancin activity against recently collected macrodilution method. Serial passages were performed daily in Mueller-Hinton broth for gram-positive clinical isolates from across the United States. Antimicrob Agents Chemother 2008; 52: 2383-8. each strain in subinhibitory concentrations of vancomycin until generating stable strains 14.Pace JL, Krause K, Johnston D, et al. In vitro activity of TD-6424 against Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47: 3602-3604. 15.King A, Phillips I, Kaniga K. Comparative in vitro activity of telavancin (TD-6424), a rapidly bactericidal, concentration-dependent anti-infective with with a vancomycin MIC 2 µg/ml. At this time, all the MRSA strains were tested again for multiple mechanism of action against Gram-positive bacteria. J Antimicrob Chemother 2004; 53: 797-803. 16.Leuthner KD, Cheung CM, Rybak MJ. Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 susceptibility to oxacillin, telavancin and daptomycin using the Sensititre plates. Results glycopeptide non susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother 2006; 58: 338-43. were read after 24 and 48 h of incubation. Broth microdilution methods used for MIC testing were determined according to the Clinical and Laboratory Standards Institute methodology. Cell-wall thickening was demonstrated by electron microscopy. Figure 1.

Results All of 19 S. aureus strains tested (100%) were resistant to oxacillin and were susceptible to vancomycin with a MIC ≤ 0.5 µg/ml using the VITEK system. Sensititre plates method confirmed that all S. aureus strains were resistant to oxacillin, while only 2 strains (10.5%) confirmed a vancomycin MIC 0.5 µg/ml, 11 strains (57.9%) showed a vancomycin MIC 1 µg/ml, and 6 strains (31.6%) showed a vancomycin MIC 2 µg/ml. In the same microbiological passage we tested for telavancin and daptomycin. For telavancin, 2 strains (10.5%) had a MIC 0.25 µg/ml, 16 strains MIC 0.5 µg/ml (84.2%), and only one (5.3%) with a telavancin MIC 1 µg/ml; this latter MRSA had an initial vancomycin MIC 2 µg/ml. Results regarding daptomycin were: 3 strains with a MIC 0.25 µg/ml (15.8%), 7 (36.8%) with MIC 0.5 µg/ml, 9 (47.4%) with a MIC 1 µg/ml; all of these 9 strains had an initial vancomycin MIC range within 1 µg/ml and 2 µg/ml (Table 1).

Table 1. Table 2.

STRAINS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 STRAINS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 VITEK 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 TELAVANCIN MIC 1 0.5 0.5 0.5 0.5 0.5 0.5 1 0.5 0.5 0.5 1 0.5 1 0.5 1 0.5 1 0.5 VANCOMYCIN (VANCO MIC 2/24H) VANCOMYCIN 1 1 1 2 1 2 1 1 1 1 2 0.5 2 2 1 1 2 1 0.5 TELAVANCIN MIC 1 0.5 0.5 0.5 1 0.5 1 1 1 1 0.5 1 0.5 1 0.5 1 0.5 1 0.5 SENSITITRE (VANCO MIC 2/48H) TELAVANCIN 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 1 0.25 0.5 0.5 0.5 0.25 DAPTOMYCIN MIC 1 1 1 1 1 1 1 1 1 1 0.5 1 0.25 1 1 1 0.5 1 0.5 SENSITITRE (VANCO MIC 2/24H) (1ST PASSAGE) OXACILLIN >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 DAPTOMYCIN MIC 1 1 1 1 1 1 1 1 1 1 0.5 1 0.25 1 1 1 0.5 1 0.5 SENSITITRE (VANCO MIC 2/48H) (1ST PASSAGE) OXACILLIN MIC >4 0.5 0.5 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 >4 0.5 >4 >4 0.5 >4 DAPTOMYCIN 0.5 1 1 1 0.5 1 0.5 0.5 1 0.5 0.5 0.25 0.25 1 1 1 0.5 1 0.5 (VANCO MIC 2/48H) SENSITITRE (1ST PASSAGE)

Dr. Fabrizio Taglietti 2nd Infectious Diseases Division, National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense, 292- 00149 Rome, Italy. Phone: +39 0655170294 Fax: +39 0655170315. e-mail: [email protected]