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In vitro time–kill analysis of oritavancin against clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to daptomycin
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Diagnostic Microbiology and Infectious Disease 71 (2011) 470 – 473 www.elsevier.com/locate/diagmicrobio
In vitro time–kill analysis of oritavancin against clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to daptomycin☆,☆☆ Céline Vidaillac a, 1 , Jorge Parra-Ruiz a, 2 , Michael Joseph Rybak a, b, c,⁎ a
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA b School of Medicine, Wayne State University, Detroit, MI 48201, USA c Detroit Receiving Hospital, Detroit, MI 48201, USA Received 24 June 2011; accepted 2 September 2011
Abstract Oritavancin exhibited lower MIC50 values (0.03 and 0.5 mg/L) than comparators against methicillin-resistant Staphylococcus aureus (MRSA, n = 50) and vancomycin-intermediate SA strains (n = 60). At subtherapeutic concentrations, oritavancin demonstrated rapid (within 9 h) and concentration-dependent bactericidal activity against daptomycin nonsusceptible (DNS) MRSA. Further investigations are warranted to determine the therapeutic potential of oritavancin against DNS MRSA. © 2011 Elsevier Inc. All rights reserved. Keywords: Oritavancin; Susceptibility; Daptomycin nonsusceptible MRSA
The utility of vancomycin as a primary therapy for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been compromised by the slow emergence of vancomycin-intermediate S. aureus (VISA, MIC greater than 2 mg/L) and vancomycin-resistant S. aureus (VRSA, MIC greater than 8 mg/L) strains (Jones, 2008). The reliability of this agent is also further questioned by the increased prevalence of heterogeneous VISA (hVISA) associated with poor treatment outcomes and therapeutic failure despite vancomycin MIC values that are usually recorded in the susceptible range (Rong and Leonard, 2010). Daptomycin and linezolid are considered as alternative ☆
Funding: This study was funded by a research grant from The Medicines Company, Parsippany, NJ, USA. ☆☆ A portion of this work was presented at the 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, April 10–13, 2010, Poster P937. ⁎ Corresponding author. Tel.: +1-313-577-4376; fax: +1-313-577-8915. E-mail address: [email protected] (M.J. Rybak). 1 Present address: Molecular Microbiology Laboratory, UMR 7565, CNRS, Nancy University, Nancy, France. 2 Permanent address: Infectious Diseases Unit, HU San Cecilio, Granada, Spain. 0732-8893/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2011.09.002
therapies for MRSA infections (Jones, 2008; Liu et al., 2011), but resistance to these agents has already emerged (b1% in MRSA isolates) (Leach et al., 2011; Rossolini et al., 2010). Oritavancin is a novel lipoglycopeptide derivative of chloroeremomycin that exhibits activity against Grampositive isolates including MRSA strains. Like daptomycin but in contrast to vancomycin, bactericidal activity of oritavancin occurs under static and exponential phases of growth secondary to a complex mechanism that includes membrane permeabilization and alteration of the cell wall (Domenech etal., 2010). Cross resistance with other antimicrobials, including vancomycin and daptomycin, has not been reported yet, suggesting that oritavancin may represent a promising antimicrobial candidate to treat multidrug-resistant S. aureus (Bouza and Burillo, 2010). In an effort to understand the therapeutic interest of oritavancin to treat infections due to daptomycin nonsusceptible MRSA (DNS, MIC N1 mg/L), we assessed and compared its in vitro activity compared to those of relevant anti-MRSA agents. Two hundred and twenty clinical MRSA isolates characterized for the SCCmec cassette by polymerase chain reaction (PCR) (Zhang et al., 2005), including 50 MRSA fully susceptible to vancomycin, 100 hVISA isolates, 60
C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
VISA, and 10 VRSA were evaluated in this study. Heteroresistant VISA isolates were characterized by MacroEtest (BioMerieux, Durham, NC) and confirmed by modified population analysis profile using the reference strain Mu3 as described elsewhere (Wootton et al., 2001). VISA and VRSA isolates were selected on the basis of their MIC values determined by broth microdilution following CLSI guidelines (CLSI, 2009). All strains were selected from the AntiInfective Research Laboratory (ARL, Detroit, MI, USA) and the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) collections. MICs of oritavancin, vancomycin, teicoplanin, daptomycin cefoxitin, and oxacillin were determined in duplicate by broth microdilution, according to the CLSI M7-A8 guidelines (CLSI, 2009). Time–kill experiments (TK) were performed in triplicate using a starting inoculum of 10 6 CFU/mL based on NCCLS M26A recommendations (NCCLS, 1999). Four DNS MRSA were tested and included, including 1 hVISA (R3489) (Vidaillac et al., 2010a), 1 VISA (R5995), 1 VRSA (VRSA-2), and 1 vancomycin-susceptible MRSA (SA-684) (Rose et al., 2007). Mueller-Hinton broth II (Difco, Detroit, MI, USA) was used to perform the MIC determination and TK. According to CLSI M7-A8 guidelines, the broth was supplemented with calcium (final concentration of 50 mg/ L) for daptomycin, Tween 80 (0.002%) for oritavancin, or sodium chloride (final concentration of 4%) for oxacillin and cefoxitin. Quality control was performed using S. aureus ATCC 29213 for all experiments (MIC determination and TK analysis). Bactericidal activity of oritavancin, vancomycin, teicoplanin, and daptomycin was investigated and compared in TK at 4× and 8× MIC. Viable count samples (100 μL) were taken at 0, 1, 2, 4, 8, and 24 h. Except for TK assays performed with oritavancin, samples were diluted in normal saline prior to plating (75–100 μL) onto Tryptic Soy Agar (TSA, Difco) plates using an automatic spiral-plating device
471
(WASP; DW Scientific, West Yorkshire, United Kingdom). Antibiotic carryover was accounted for using vacuum filtration. Samples collected from oritavancin regimens were drop-plated onto TSA plates after treatment with activated charcoal (25 g/L) to remove the drug from the samples, as described previously (Arhin et al., 2009). Plates were then incubated at 35 °C for 18–24 h prior to colony counting. TK curves were constructed by plotting mean colony counts (log10 CFU/mL) versus time, and bactericidal activity was defined as a ≥3 log10 CFU/mL (99.9%) reduction from the starting inoculum. Both sampling methods allowed for a limit of detection of 1 log10 CFU/mL. Susceptibility values are reported in Table 1. Consistent with previous studies, we found that oritavancin had the lowest MIC50 and MIC90 values compared to other agents for the MRSA collection (0.03 and 0.06 mg/L, respectively, versus 0.5 and 0.5 mg/L for daptomycin) (Saravolatz et al., 2010). Oritavancin MIC50 and MIC90 values were similar to daptomycin for the hVISA and VISA groups, but the range of oritavancin MICs was lower than the MIC range of daptomycin. Consistent with the literature, a shift toward higher MICs was observed in the VISA collection (but not in the MRSA, hVISA, and VRSA groups) for daptomycin (Saravolatz et al., 2010). Similarly and although this has not been reported previously, cross resistance between oritavancin and vancomycin was also observed in the VISA collection (but not in the other groups). This phenomenon has been already described for daptomycin and explained by an increased cell wall thickness and changes in the surface charges of VISA isolates (Cui et al., 2006). The lack of cross resistance in the VRSA group suggests that the same mechanism may contribute for the potential cross resistance of vancomycin and oritavancin in VISA isolates. Further investigations are warranted to confirm this hypothesis. Of interest, a shift
Table 1 Oritavancin and comparator MICs (mg/L) against clinical isolates of HA-MRSA, hVISA, VISA, and VRSA Species/isolate no.
MRSA (n = 50)
SA-684 hVISA (n = 100)
3489 VISA (n = 60)
5995 VRSA (n = 11)
VRSA-2
Antimicrobial agent
MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC
ORI
DAP
VAN
TEC
OXA
CFX
0.03 0.06 0.015–0.25 0.25 0.25 0.5 0.03–1 0.125 0.5 2 0.125–4 1 0.5 1 0.25–2 0.254
0.5 0.5 0.125–2 2 0.25 0.5 0.125–1 2 1 2 0.5–2 2 0.25 1 0.25–2 4
1 1 0.5–2 2 1 2 0.5–2 1 4 4 4–8 4 256 512 64–1024 1024
0.25 0.5 0.125–1 2 1 2 0.25–4 2 2 4 1–8 2 64 1024 32–1024 8
128 256 8–256 ND 128 512 4–512 ND 128 256 1–512 ND 64 128 64–128 ND
128 256 16–256 ND 128 256 8–512 ND 128 512 8–512 ND 32 256 32–256 ND
ORI = Oritavancin; DAP = daptomycin; VAN = vancomycin; TEC = teicoplanin; OXA = oxacillin; CFX = cefoxitin; ND = not determined. The highest concentrations tested were 32 mg/L for oritavancin and 1024 mg/L for the other agents.
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C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
toward the susceptible range was also noticed for cefoxitin and, to a greater degree, for oxacillin. Three of the VISA isolates exhibited an oxacillin MIC ≤4 mg/L (data not shown) (Vidaillac et al., 2010b). PCR confirmed that these 3 VISA isolates still carried the SCCmec cassette (data not shown), suggesting a see-saw effect. This phenomenon seems to be a characteristic of VISA strains and occurs secondary to vancomycin exposure and selection of subpopulations that are more susceptible to beta-lactams (Sieradzki et al., 2003). The interest of such observation has been further evaluated in different studies looking at the antibacterial activity of vancomycin in association with oxacillin (Domaracki et al., 2000; Joukhadar et al., 2010). In one of these studies, authors reported potential synergistic effect of vancomycin plus oxacillin against non-hVISA/VISA MRSA (Domaracki et al., 2000). Recent investigations performed in our laboratory revealed synergy of vancomycin plus oxacillin against VISA but not against hVISA and MRSA isolates (Vidaillac et al., 2010b). This phenomenon might be the result of the activity of oxacillin against subpopulations with increased glycopeptide MICs and decreased oxacillin MICs. In TK, oritavancin demonstrated rapid concentrationdependent bactericidal activity against the DNS MRSA SA684 and hVISA R3489. At 4× and 8× MIC, bactericidal activity was achieved at 8 and 4 h against SA-684 and at 9
and 5 h against R3489. In contrast, against VRSA-2 and the VISA isolate R5995, time to achieve 3 log10 kill was similar at 4× (data not shown) and 8× MIC (Fig. 1). Daptomycin also demonstrated concentration-dependent activity and rapid bactericidal activity (within 8 h) against the same isolates (Fig. 1). At 8× MIC, vancomycin and teicoplanin achieved a maximum of 2.7, 2.6, and 2.9 log10 CFU/mL decrease against the DNS MRSA (SA-684), VRSA-2, and hVISA R3489, whereas they achieved 3 log10 kill between 16 and 19 h against the VISA isolate R5995 (Fig. 1). Further discussion of these results should, however, take into consideration the in vivo concentrations of each agent after standard therapies. Concentrations of oritavancin tested in this study were above the predicted free peak and trough concentrations observed after the administration of 1200 mg intravenously (24 and 3 mg/L, respectively) (McKay et al., 2009). In contrast, all daptomycin concentrations tested were below the free peak and trough concentrations observed in patients after the administration of 4 mg/kg daily dose intravenously (3.61 and 0.45 mg/L, respectively) (Cha et al., 2003). And concentrations of vancomycin and teicoplanin were within or below the free peak and trough concentrations observed in vivo (McKay et al., 2009; Stevens et al., 2005). Additional investigations, especially under dynamic conditions and/or in the presence of albumin, may be of interest to further clarify the therapeutic interest of
Fig. 1. In vitro activity of oritavancin, vancomycin, teicoplanin, and daptomycin at 8× MIC against 4 clinical daptomycin nonsusceptible MRSA isolates. Results are presented as time–kill curves at 8× MIC for (A) isolate R3489 (hVISA), (B) isolate SA-684 (MRSA), (C) isolate R5995 (VISA), and (D) VRSA-2. Legend: Growth control, filled square; oritavancin, filled circle; daptomycin, opened inversed triangle; teicoplanin, opened triangle; vancomycin, opened circle.
C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
oritavancin against MRSA strains with reduced susceptibility to glycopeptides and/or daptomycin. Acknowledgments The authors are grateful to The Medicines Company for their financial support and valuable contribution to the manuscript. References Arhin FF, McKay GA, Beaulieu S, Sarmiento I, Parr Jr TR, Moeck G (2009) Impact of human serum albumin on oritavancin in vitro activity against Staphylococcus aureus. Diagn Microbiol Infect Dis 65:207–210. Bouza E, Burillo A (2010) Oritavancin: a novel lipoglycopeptide active against Gram-positive pathogens including multiresistant strains. Int J Antimicrob Agents 36:401–407. Cha R, Grucz Jr RG, Rybak MJ (2003) Daptomycin dose-effect relationship against resistant Gram-positive organisms. Antimicrob Agents Chemother 47:1598–1603. Clinical and Laboratory Standards Institute (2009) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. 9th ed. Wayne, PA: CLSI. Cui LZ, Tominaga E, Neoh HM, Hiramatsu K (2006) Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus. Antimicrob Agents Chemother 50:1079–1082. Domaracki BE, Evans AM, Venezia RA (2000) Vancomycin and oxacillin synergy for methicillin-resistant staphylococci. Antimicrob Agents Chemother 44:1394–1396. Domenech O, Dufrene YF, Van Bambeke F, Tukens PM, Mingeot-Leclercq MP (2010) Interactions of oritavancin, a new semi-synthetic lipoglycopeptide, with lipids extracted from Staphylococcus aureus. Biochim Biophys Acta 1798:1876–1885. Jones RN (2008) Key considerations in the treatment of complicated staphylococcal infections. Clin Microbiol Infect 14(Suppl 2):3–9. Joukhadar C, Pillai S, Wennersten C, Moellering Jr RC, Eliopoulos GM (2010) Lack of bactericidal antagonism or synergism in vitro between oxacillin and vancomycin against methicillin-susceptible strains of Staphylococcus aureus. Antimicrob Agents Chemother 54:773–777. Leach KL, Brickner SJ, Noe MC, Miller PF (2011) Linezolid, the first oxazolidinone antibacterial agent. Ann N Y Acad Sci 1222:49–54. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF (2011) Clinical practice guidelines by the IDSA for the treatment of MRSA infections in adults and children. Clin Infect Dis 52:1–38.
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McKay GA, Beaulieu S, Arhin FF, Belley A, Sarmiento I, Parr Jr T, Moeck G (2009) Time-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. J Antimicrob Chemother 63:1191–1199. NCCLS (1999) Methods for determining bactericidal activity of antimicrobial agents. Approved guideline. NCCLS document M26-A. Wayne, PA: NCCLS. Rong SL, Leonard SN (2010) Heterogeneous vancomycin resistance in Staphylococcus aureus: a review of epidemiology, diagnosis, and clinical significance. Ann Pharmacother 44:844–850. Rose WE, Rybak MJ, Kaatz GW (2007) Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies. J Antimicrob Chemother 60:334–340. Rossolini GM, Mantengoli E, Montagnani F, Pollini S (2010) Epidemiology and clinical relevance of microbial resistance determinants versus antiGram-positive agents. Curr Opin Microbiol 13:582–588. Saravolatz LD, Pawlak J, Johnson LB (2010) In vitro activity of oritavancin against community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA) and daptomycin-non-susceptible S. aureus (DNSSA). Int J Antimicrob Agents 36:69–72. Sieradzki K, Leski T, Dick J, Borio L, Tomasz A (2003) Evolution of a vancomycin-intermediate Staphylococcus aureus strain in vivo: multiple changes in the antibiotic resistance phenotypes of a single lineage of methicillin-resistant S. aureus under the impact of antibiotics administered for chemotherapy. J Clin Microbiol 41:1687–1693. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC (2005) Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 41:1373–1406. Vidaillac C, Leonard SN, Rybak MJ (2010a) In-Vitro activity and aminoglycoside synergy of ceftaroline against hospital-acquired (HA) methicillin-resistant Staphylococcus aureus (MRSA) isolates. Sous presse. Int J Antimicrob Agents 35:527–530. Vidaillac C, Murray K, Rybak M (2010b) Evaluation of vancomycin and oxacillin combination against mecA positive vancomycin-intermediate Staphylococcus aureus (VISA) and heterogenous VISA (hVISA) with varying oxacillin susceptibility. Program and abstract of the 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, 10–13th April 2010 (O38). Wootton M, Howe RA, Hillman R, Walsh TR, Bennett PM, MacGowan AP (2001) A modified population analysis profile (PAP) method to detect hetero-resistance to vancomycin in Staphylococcus aureus in a UK hospital. J Antimicrob Chemother 47:399–403. Zhang K, McClure JA, Elsayed S, Louie T, Conly JM (2005) Novel multiplex PCR assay for characterization and concomitant subtyping of staphylococcal cassette chromosome mec types I to V in methicillinresistant Staphylococcus aureus. J Clin Microbiol 43:5026–5033.
Diagnostic Microbiology and Infectious Disease 71 (2011) 470 – 473 www.elsevier.com/locate/diagmicrobio
In vitro time–kill analysis of oritavancin against clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to daptomycin☆,☆☆ Céline Vidaillac a, 1 , Jorge Parra-Ruiz a, 2 , Michael Joseph Rybak a, b, c,⁎ a
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA b School of Medicine, Wayne State University, Detroit, MI 48201, USA c Detroit Receiving Hospital, Detroit, MI 48201, USA Received 24 June 2011; accepted 2 September 2011
Abstract Oritavancin exhibited lower MIC50 values (0.03 and 0.5 mg/L) than comparators against methicillin-resistant Staphylococcus aureus (MRSA, n = 50) and vancomycin-intermediate SA strains (n = 60). At subtherapeutic concentrations, oritavancin demonstrated rapid (within 9 h) and concentration-dependent bactericidal activity against daptomycin nonsusceptible (DNS) MRSA. Further investigations are warranted to determine the therapeutic potential of oritavancin against DNS MRSA. © 2011 Elsevier Inc. All rights reserved. Keywords: Oritavancin; Susceptibility; Daptomycin nonsusceptible MRSA
The utility of vancomycin as a primary therapy for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has been compromised by the slow emergence of vancomycin-intermediate S. aureus (VISA, MIC greater than 2 mg/L) and vancomycin-resistant S. aureus (VRSA, MIC greater than 8 mg/L) strains (Jones, 2008). The reliability of this agent is also further questioned by the increased prevalence of heterogeneous VISA (hVISA) associated with poor treatment outcomes and therapeutic failure despite vancomycin MIC values that are usually recorded in the susceptible range (Rong and Leonard, 2010). Daptomycin and linezolid are considered as alternative ☆
Funding: This study was funded by a research grant from The Medicines Company, Parsippany, NJ, USA. ☆☆ A portion of this work was presented at the 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, Austria, April 10–13, 2010, Poster P937. ⁎ Corresponding author. Tel.: +1-313-577-4376; fax: +1-313-577-8915. E-mail address: [email protected] (M.J. Rybak). 1 Present address: Molecular Microbiology Laboratory, UMR 7565, CNRS, Nancy University, Nancy, France. 2 Permanent address: Infectious Diseases Unit, HU San Cecilio, Granada, Spain. 0732-8893/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2011.09.002
therapies for MRSA infections (Jones, 2008; Liu et al., 2011), but resistance to these agents has already emerged (b1% in MRSA isolates) (Leach et al., 2011; Rossolini et al., 2010). Oritavancin is a novel lipoglycopeptide derivative of chloroeremomycin that exhibits activity against Grampositive isolates including MRSA strains. Like daptomycin but in contrast to vancomycin, bactericidal activity of oritavancin occurs under static and exponential phases of growth secondary to a complex mechanism that includes membrane permeabilization and alteration of the cell wall (Domenech etal., 2010). Cross resistance with other antimicrobials, including vancomycin and daptomycin, has not been reported yet, suggesting that oritavancin may represent a promising antimicrobial candidate to treat multidrug-resistant S. aureus (Bouza and Burillo, 2010). In an effort to understand the therapeutic interest of oritavancin to treat infections due to daptomycin nonsusceptible MRSA (DNS, MIC N1 mg/L), we assessed and compared its in vitro activity compared to those of relevant anti-MRSA agents. Two hundred and twenty clinical MRSA isolates characterized for the SCCmec cassette by polymerase chain reaction (PCR) (Zhang et al., 2005), including 50 MRSA fully susceptible to vancomycin, 100 hVISA isolates, 60
C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
VISA, and 10 VRSA were evaluated in this study. Heteroresistant VISA isolates were characterized by MacroEtest (BioMerieux, Durham, NC) and confirmed by modified population analysis profile using the reference strain Mu3 as described elsewhere (Wootton et al., 2001). VISA and VRSA isolates were selected on the basis of their MIC values determined by broth microdilution following CLSI guidelines (CLSI, 2009). All strains were selected from the AntiInfective Research Laboratory (ARL, Detroit, MI, USA) and the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) collections. MICs of oritavancin, vancomycin, teicoplanin, daptomycin cefoxitin, and oxacillin were determined in duplicate by broth microdilution, according to the CLSI M7-A8 guidelines (CLSI, 2009). Time–kill experiments (TK) were performed in triplicate using a starting inoculum of 10 6 CFU/mL based on NCCLS M26A recommendations (NCCLS, 1999). Four DNS MRSA were tested and included, including 1 hVISA (R3489) (Vidaillac et al., 2010a), 1 VISA (R5995), 1 VRSA (VRSA-2), and 1 vancomycin-susceptible MRSA (SA-684) (Rose et al., 2007). Mueller-Hinton broth II (Difco, Detroit, MI, USA) was used to perform the MIC determination and TK. According to CLSI M7-A8 guidelines, the broth was supplemented with calcium (final concentration of 50 mg/ L) for daptomycin, Tween 80 (0.002%) for oritavancin, or sodium chloride (final concentration of 4%) for oxacillin and cefoxitin. Quality control was performed using S. aureus ATCC 29213 for all experiments (MIC determination and TK analysis). Bactericidal activity of oritavancin, vancomycin, teicoplanin, and daptomycin was investigated and compared in TK at 4× and 8× MIC. Viable count samples (100 μL) were taken at 0, 1, 2, 4, 8, and 24 h. Except for TK assays performed with oritavancin, samples were diluted in normal saline prior to plating (75–100 μL) onto Tryptic Soy Agar (TSA, Difco) plates using an automatic spiral-plating device
471
(WASP; DW Scientific, West Yorkshire, United Kingdom). Antibiotic carryover was accounted for using vacuum filtration. Samples collected from oritavancin regimens were drop-plated onto TSA plates after treatment with activated charcoal (25 g/L) to remove the drug from the samples, as described previously (Arhin et al., 2009). Plates were then incubated at 35 °C for 18–24 h prior to colony counting. TK curves were constructed by plotting mean colony counts (log10 CFU/mL) versus time, and bactericidal activity was defined as a ≥3 log10 CFU/mL (99.9%) reduction from the starting inoculum. Both sampling methods allowed for a limit of detection of 1 log10 CFU/mL. Susceptibility values are reported in Table 1. Consistent with previous studies, we found that oritavancin had the lowest MIC50 and MIC90 values compared to other agents for the MRSA collection (0.03 and 0.06 mg/L, respectively, versus 0.5 and 0.5 mg/L for daptomycin) (Saravolatz et al., 2010). Oritavancin MIC50 and MIC90 values were similar to daptomycin for the hVISA and VISA groups, but the range of oritavancin MICs was lower than the MIC range of daptomycin. Consistent with the literature, a shift toward higher MICs was observed in the VISA collection (but not in the MRSA, hVISA, and VRSA groups) for daptomycin (Saravolatz et al., 2010). Similarly and although this has not been reported previously, cross resistance between oritavancin and vancomycin was also observed in the VISA collection (but not in the other groups). This phenomenon has been already described for daptomycin and explained by an increased cell wall thickness and changes in the surface charges of VISA isolates (Cui et al., 2006). The lack of cross resistance in the VRSA group suggests that the same mechanism may contribute for the potential cross resistance of vancomycin and oritavancin in VISA isolates. Further investigations are warranted to confirm this hypothesis. Of interest, a shift
Table 1 Oritavancin and comparator MICs (mg/L) against clinical isolates of HA-MRSA, hVISA, VISA, and VRSA Species/isolate no.
MRSA (n = 50)
SA-684 hVISA (n = 100)
3489 VISA (n = 60)
5995 VRSA (n = 11)
VRSA-2
Antimicrobial agent
MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC MIC50 MIC90 Range MIC
ORI
DAP
VAN
TEC
OXA
CFX
0.03 0.06 0.015–0.25 0.25 0.25 0.5 0.03–1 0.125 0.5 2 0.125–4 1 0.5 1 0.25–2 0.254
0.5 0.5 0.125–2 2 0.25 0.5 0.125–1 2 1 2 0.5–2 2 0.25 1 0.25–2 4
1 1 0.5–2 2 1 2 0.5–2 1 4 4 4–8 4 256 512 64–1024 1024
0.25 0.5 0.125–1 2 1 2 0.25–4 2 2 4 1–8 2 64 1024 32–1024 8
128 256 8–256 ND 128 512 4–512 ND 128 256 1–512 ND 64 128 64–128 ND
128 256 16–256 ND 128 256 8–512 ND 128 512 8–512 ND 32 256 32–256 ND
ORI = Oritavancin; DAP = daptomycin; VAN = vancomycin; TEC = teicoplanin; OXA = oxacillin; CFX = cefoxitin; ND = not determined. The highest concentrations tested were 32 mg/L for oritavancin and 1024 mg/L for the other agents.
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C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
toward the susceptible range was also noticed for cefoxitin and, to a greater degree, for oxacillin. Three of the VISA isolates exhibited an oxacillin MIC ≤4 mg/L (data not shown) (Vidaillac et al., 2010b). PCR confirmed that these 3 VISA isolates still carried the SCCmec cassette (data not shown), suggesting a see-saw effect. This phenomenon seems to be a characteristic of VISA strains and occurs secondary to vancomycin exposure and selection of subpopulations that are more susceptible to beta-lactams (Sieradzki et al., 2003). The interest of such observation has been further evaluated in different studies looking at the antibacterial activity of vancomycin in association with oxacillin (Domaracki et al., 2000; Joukhadar et al., 2010). In one of these studies, authors reported potential synergistic effect of vancomycin plus oxacillin against non-hVISA/VISA MRSA (Domaracki et al., 2000). Recent investigations performed in our laboratory revealed synergy of vancomycin plus oxacillin against VISA but not against hVISA and MRSA isolates (Vidaillac et al., 2010b). This phenomenon might be the result of the activity of oxacillin against subpopulations with increased glycopeptide MICs and decreased oxacillin MICs. In TK, oritavancin demonstrated rapid concentrationdependent bactericidal activity against the DNS MRSA SA684 and hVISA R3489. At 4× and 8× MIC, bactericidal activity was achieved at 8 and 4 h against SA-684 and at 9
and 5 h against R3489. In contrast, against VRSA-2 and the VISA isolate R5995, time to achieve 3 log10 kill was similar at 4× (data not shown) and 8× MIC (Fig. 1). Daptomycin also demonstrated concentration-dependent activity and rapid bactericidal activity (within 8 h) against the same isolates (Fig. 1). At 8× MIC, vancomycin and teicoplanin achieved a maximum of 2.7, 2.6, and 2.9 log10 CFU/mL decrease against the DNS MRSA (SA-684), VRSA-2, and hVISA R3489, whereas they achieved 3 log10 kill between 16 and 19 h against the VISA isolate R5995 (Fig. 1). Further discussion of these results should, however, take into consideration the in vivo concentrations of each agent after standard therapies. Concentrations of oritavancin tested in this study were above the predicted free peak and trough concentrations observed after the administration of 1200 mg intravenously (24 and 3 mg/L, respectively) (McKay et al., 2009). In contrast, all daptomycin concentrations tested were below the free peak and trough concentrations observed in patients after the administration of 4 mg/kg daily dose intravenously (3.61 and 0.45 mg/L, respectively) (Cha et al., 2003). And concentrations of vancomycin and teicoplanin were within or below the free peak and trough concentrations observed in vivo (McKay et al., 2009; Stevens et al., 2005). Additional investigations, especially under dynamic conditions and/or in the presence of albumin, may be of interest to further clarify the therapeutic interest of
Fig. 1. In vitro activity of oritavancin, vancomycin, teicoplanin, and daptomycin at 8× MIC against 4 clinical daptomycin nonsusceptible MRSA isolates. Results are presented as time–kill curves at 8× MIC for (A) isolate R3489 (hVISA), (B) isolate SA-684 (MRSA), (C) isolate R5995 (VISA), and (D) VRSA-2. Legend: Growth control, filled square; oritavancin, filled circle; daptomycin, opened inversed triangle; teicoplanin, opened triangle; vancomycin, opened circle.
C. Vidaillac et al. / Diagnostic Microbiology and Infectious Disease 71 (2011) 470–473
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