Abstract
Telavancin had MIC50, MIC90, and MIC100 values of 0.03, 0.06, and 0.12 μg/ml, respectively, against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and non-multidrug-resistant (non-MDR) and MDR subsets. MRSA with elevated MIC values for vancomycin (2 to 4 μg/ml) or daptomycin (1 to 2 μg/ml) had telavancin MIC50 (0.06 μg/ml) values 2-fold higher than those of isolates with lower MIC results (MIC50, 0.03 μg/ml). However, telavancin had MIC90 and MIC100 results of 0.06 and 0.12 μg/ml (100% susceptible), respectively, regardless of the MRSA subset.
TEXT
Methicillin-resistant Staphylococcus aureus (MRSA) has remained a major public health problem worldwide and challenges the management of infections caused by this pathogen (1). Multiple factors have been implicated with this therapeutic challenge, including the dynamic epidemiology of MRSA lineages (2). Infection rates of MRSA rise and fall in epidemic waves, with several waves occurring in the past decades and the emergence of community-acquired (CA) MRSA being the latest and one of the still-present waves (2). CA-MRSA isolates, primarily those associated with the USA300 lineage, are responsible for the vast majority of skin and skin structure infections (SSSIs) in the United States (3). Moreover, the emergence of CA-MRSA is reflected in the nosocomial epidemiology of S. aureus, and the USA300 clone has also been implicated as a cause of invasive infections among hospitalized patients (4–6).
The treatment of invasive MRSA infections has relied significantly on vancomycin. However, several studies have reported increased treatment failures against isolates displaying elevated vancomycin MIC results (i.e., 2 μg/ml) but still considered susceptible based on current breakpoints (7). Interestingly, recent investigations have identified treatment failures in infections caused by both MRSA and methicillin-susceptible S. aureus (MSSA) isolates exhibiting elevated MIC values for vancomycin, regardless of treatment with vancomycin or another β-lactam agent (8–10). This suggests that increasing vancomycin MICs may reflect a yet-to-be-identified marker of host or organism. Recent consensus guidelines recommend alternative therapeutic agents for the management of infections due to MRSA strains with reduced susceptibility to vancomycin (11, 12).
Telavancin is a lipoglycopeptide antibiotic with potent in vitro bactericidal activity against Gram-positive bacteria, including MSSA, MRSA, vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (hVISA), and multidrug-resistant (MDR) streptococci and enterococci (13, 14). Early in 2014, the Food and Drug Administration (FDA) approved a revised broth microdilution susceptibility testing method for telavancin that was published in a labeling supplement for a package insert for a commercially produced formulation of telavancin (Vibativ) (15). This revised method was also published in the Clinical and Laboratory Standards Institute (CLSI) M100-S24 document (16) Briefly, this revised method follows the current CLSI guidelines for water-insoluble agents and includes the addition of polysorbate-80 (P-80; 0.002%) to the test medium (15–17). The latter constitutes an approach similarly used for other members of the lipoglycopeptide class (18, 19). These modifications were shown to improve the drug solubility during panel preparation and drug availability in the 96-well plastic plates, resulting in a more accurate in vitro assessment of telavancin MIC determinations (17). This study was conducted to assess and update the activity of telavancin against a recent (2011 to 2013) collection of S. aureus clinical isolates and resistant subsets collected from U.S. medical centers using the recently approved broth microdilution method.
As part of the SENTRY Antimicrobial Surveillance Program for the United States, a total of 9,610 S. aureus clinical isolates collected from 28 U.S. sites were included in this analysis. These isolates were recovered from blood (1,937 isolates; 20.2%) and SSSI (4,851; 50.5%) and from patients with hospital-acquired bacterial pneumonia (2,283; 23.8%), urinary tract infections (163; 1.7%), and other less prevalent or undetermined infection sources (376; 3.9%). Isolates were determined to be clinically significant based on local guidelines and submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA). Isolates were initially identified by the participating laboratory, and identification was confirmed by the reference monitoring laboratory by standard algorithms and supported by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) (Bruker Daltonics, Bremen, Germany).
Isolates were tested for susceptibility by broth microdilution following CLSI guidelines (20). Telavancin was tested using dry-form panels manufactured by Thermo Fisher Scientific (Cleveland, Ohio, USA). These panels provide telavancin MIC results (dilution range applied, 0.015 to 2 μg/ml) equivalent to those approved by the FDA (15) and published by the CLSI (16, 17). The quality of the MIC values was ensured by concurrent testing of S. aureus (ATCC 29213) and Enterococcus faecalis (ATCC 29212). Telavancin MIC interpretations for S. aureus applied the recently approved breakpoint criterion (≤0.12 μg/ml for susceptible) appropriate for the revised testing method (15, 21). CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint criteria were applied for comparator agents (16, 21). MRSA isolates were categorized according to the vancomycin MIC (≤1 versus 2 to 4 μg/ml) and daptomycin MIC (≤0.5 versus 1 to 2 μg/ml) results, and group of isolates with MIC values at the upper end of the MIC distributions were compared with those having lower MIC values (10, 22). In addition, S. aureus strains showing a phenotype of resistance to methicillin and at least additional three classes of antimicrobial agents were defined as multidrug resistant (MDR).
Overall, telavancin demonstrated MIC50 and MIC90 values of 0.03 and 0.06 μg/ml against S. aureus (100.0% susceptible), respectively, and equivalent values were observed against the MSSA, MRSA, non-MDR and MDR subsets (Table 1). Tested against the MRSA subset displaying vancomycin MIC results of 2 to 4 μg/ml or daptomycin MIC values of 1 to 2 μg/ml, the telavancin MIC50 value (0.06 μg/ml) was 2-fold higher than that (MIC50, 0.03 μg/ml) obtained from MRSA isolates with lower MIC values for vancomycin (≤1 μg/ml) or daptomycin (≤0.5 μg/ml). All MRSA subsets had potent telavancin MIC90 results (0.06 μg/ml). In vitro activity comparison analysis resulted in telavancin (MIC50/90, 0.03/0.06 μg/ml) showing MIC values 8-fold lower than the values for daptomycin (MIC50/90, 0.25/0.5 μg/ml) and 16-fold to 32-fold lower than the values for vancomycin (MIC50/90, 1/1 μg/ml) or linezolid (MIC50/90, 1/1 μg/ml) against MSSA, the overall MRSA group, and the MDR subset (Table 2). Gentamicin, tetracycline, and trimethoprim-sulfamethoxazole also had antimicrobial coverage (>90.0% susceptible) in tests against MRSA, while these agents and clindamycin were active against MSSA.
TABLE 1.
Antimicrobial activity and MIC distribution for telavancin against a contemporary (2011 to 2013) U.S. collection of S. aureus clinical isolates using a recently approved and revised susceptibility testing method
| S. aureus categorya (no. of isolates tested) | MIC (μg/ml) |
No. (cumulative %) of isolates inhibited by telavancin at indicated MIC (μg/ml)b |
||||
|---|---|---|---|---|---|---|
| 50% | 90% | ≤0.015 | 0.03 | 0.06 | 0.12 | |
| All (9,610) | 0.03 | 0.06 | 364 (3.8) | 6,210 (68.4) | 3,012 (99.8) | 24 (100.0) |
| MSSA (4,959) | 0.03 | 0.06 | 242 (4.9) | 3,272 (70.9) | 1,437 (99.8) | 8 (100.0) |
| MRSA (4,651) | 0.03 | 0.06 | 122 (2.6) | 2,938 (65.8) | 1,575 (99.7) | 16 (100.0) |
| Vancomycin MIC, ≤1 μg/ml (4,561) | 0.03 | 0.06 | 119 (2.6) | 2,930 (66.8) | 1,502 (99.8) | 10 (100.0) |
| Vancomycin MIC, 2–4 μg/ml (90) | 0.06 | 0.06 | 3 (3.3) | 8 (12.2) | 73 (93.3) | 6 (100.0) |
| Daptomycin MIC, ≤0.5 μg/ml (4,607) | 0.03 | 0.06 | 122 (2.6) | 2,928 (66.2) | 1,545 (99.7) | 12 (100.0) |
| Daptomycin MIC, 1–2 μg/ml (43) | 0.06 | 0.06 | 0 (0.0) | 9 (20.9) | 30 (90.7) | 4 (100.0) |
| MDR (1,371) | 0.03 | 0.06 | 37 (2.7) | 749 (57.3) | 574 (99.2) | 11 (100.0) |
| Non-MDR (3,280) | 0.03 | 0.06 | 85 (2.6) | 2,189 (69.3) | 1,001 (99.8) | 5 (100.0) |
MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; MDR, multidrug resistant.
Data representing modal MICs are shown in bold.
TABLE 2.
Antimicrobial activity of telavancin and comparator agents tested against a contemporary (2011 to 2013) U.S. collection of clinical isolates using a recently approved and revised susceptibility testing method
| Organism categorya (no. tested) and antimicrobial agent | MIC (μg/ml) |
% susceptible/% intermediate/% resistantb |
|||
|---|---|---|---|---|---|
| 50% | 90% | FDA | CLSI | EUCAST | |
| MSSA (4,959) | |||||
| Telavancin | 0.03 | 0.06 | 100.0/-c/- | -/-/- | -/-/- |
| Vancomycin | 1 | 1 | 100.0/0.0/0.0 | 100.0/0.0/0.0 | |
| Daptomycin | 0.25 | 0.5 | >99.9/-/- | >99.9/0.0/<0.1 | |
| Linezolid | 1 | 1 | >99.9/0.0/<0.1 | >99.9/0.0/<0.1 | |
| Levofloxacin | 0.25 | 4 | 88.8/0.9/10.3 | 88.8/0.9/10.3 | |
| Erythromycin | 0.25 | >16 | 65.6/3.7/30.7 | 66.0/1.3/32.7 | |
| Clindamycin | ≤0.25 | ≤0.25 | 95.2/0.1/4.7 | 94.8/0.4/4.8 | |
| Gentamicin | ≤1 | ≤1 | 99.2/0.2/0.6 | 99.0/0.0/1.0 | |
| Tetracycline | ≤0.25 | ≤0.25 | 96.2/0.7/3.1 | 95.3/0.2/4.5 | |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 99.5/0.0/0.5 | 99.5/0.1/0.4 | |
| MRSA (4,651) | |||||
| Telavancin | 0.03 | 0.06 | 100.0/-/- | -/-/- | 100.0/-/- |
| Vancomycin | 1 | 1 | >99.9/<0.1/0.0 | >99.9/0.0/<0.1 | |
| Daptomycin | 0.25 | 0.5 | >99.9/-/- | >99.9/0.0/<0.1 | |
| Linezolid | 1 | 1 | 99.9/0.0/0.1 | 99.9/0.0/0.1 | |
| Levofloxacin | 4 | >4 | 31.3/2.2/66.5 | 31.3/2.2/66.5 | |
| Erythromycin | >16 | >16 | 10.4/1.9/87.7 | 10.6/0.5/88.9 | |
| Clindamycin | ≤0.25 | >2 | 70.5/0.1/29.4 | 70.2/0.3/29.5 | |
| Gentamicin | ≤1 | ≤1 | 96.8/0.1/3.1 | 96.5/0.0/3.5 | |
| Tetracycline | ≤0.25 | 1 | 94.9/0.4/4.7 | 92.6/2.0/5.4 | |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 97.8/0.0/2.2 | 97.8/0.2/2.0 | |
| MRSA with vancomycin MIC 2–4 μg/ml (4,651) | |||||
| Telavancin | 0.06 | 0.06 | 100.0/-/- | -/-/- | 100.0/-/- |
| Vancomycin | 2 | 2 | 98.9/1.1/0.0 | 98.9/0.0/1.1 | |
| Daptomycin | 0.5 | 1 | 97.8/-/- | 97.8/0.0/2.2 | |
| Linezolid | 1 | 2 | 98.9/0.0/1.1 | 98.9/0.0/1.1 | |
| Levofloxacin | >4 | >4 | 14.4/0.0/85.6 | 14.4/0.0/85.6 | |
| Erythromycin | >16 | >16 | 5.6/1.1/93.3 | 5.6/1.1/93.3 | |
| Clindamycin | >2 | >2 | 36.7/0.0/63.3 | 36.7/0.0/63.3 | |
| Gentamicin | ≤1 | 2 | 91.1/0.0/8.9 | 88.9/0.0/11.1 | |
| Tetracycline | ≤0.25 | 2 | 95.6/1.1/3.3 | 88.9/6.7/4.4 | |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 97.8/0.0/2.2 | 97.8/1.1/1.1 | |
| MDR MRSA (1,371) | |||||
| Telavancin | 0.03 | 0.06 | 100.0/-/- | -/-/- | 100.0/-/- |
| Vancomycin | 1 | 1 | 99.9/0.1/0.0 | 99.9/0.0/0.1 | |
| Daptomycin | 0.25 | 0.5 | 99.9/-/- | 99.9/0.0/0.1 | |
| Linezolid | 1 | 1 | 99.7/0.0/0.3 | 99.7/0.0/0.3 | |
| Levofloxacin | >4 | >4 | 0.9/0.3/98.8 | 0.9/0.3/98.8 | |
| Erythromycin | >16 | >16 | 0.5/0.4/99.1 | 0.5/0.1/99.4 | |
| Clindamycin | >2 | >2 | 6.3/0.0/93.7 | 6.3/0.0/93.7 | |
| Gentamicin | ≤1 | 4 | 90.2/0.2/9.6 | 89.9/0.0/10.1 | |
| Tetracycline | ≤0.25 | >8 | 88.6/0.2/11.2 | 82.4/6.1/11.5 | |
| Trimethoprim-sulfamethoxazole | ≤0.5 | ≤0.5 | 93.9/0.0/6.1 | 93.9/0.7/5.4 | |
MSSA, methicillin-susceptible S. aureus; MRSA, methicillin-resistant S. aureus; MDR, multidrug resistant.
Telavancin breakpoint criteria for S. aureus according to the labeling supplement for the product (Vibativ) and EUCAST (MRSA only) at ≤0.12 μg/ml for susceptibility.
-, breakpoint not available.
Daptomycin MIC results (MIC50/90, 0.5/1 μg/ml) obtained against MRSA isolates with elevated vancomycin MIC values (2 to 4 μg/ml) were 2-fold higher than those obtained against MRSA with vancomycin MIC data points at ≤1 μg/ml (MIC50/90, 0.25/0.5 μg/ml; data not shown). Daptomycin (MIC50/90, 0.5/1 μg/ml) and linezolid (MIC50/90, 1/2 μg/ml) remained active (97.8% to 98.9% susceptible) against MRSA isolates with vancomycin MIC values of 2 to 4 μg/ml; however, telavancin had MIC results 8-fold to 32-fold lower than the MIC results determined for these comparators. Gentamicin, tetracycline, and trimethoprim-sulfamethoxazole also remained active in vitro against the MRSA subset showing vancomycin MIC values of 2 to 4 μg/ml, whereas gentamicin and trimethoprim-sulfamethoxazole exhibited in vitro activity against the MDR subset.
In this in vitro study, telavancin exhibited potent activity against S. aureus, including isolates with decreased susceptibility to comparator agents, maintaining MIC90 and MIC100 results of 0.06 and 0.12 μg/ml, respectively, regardless of the MRSA subset (100.0% susceptible). In addition, the telavancin potency observed was at least 8-fold greater than that seen with the tested comparators. These results confirm the telavancin activity against a recent collection of S. aureus clinical isolates and also update the drug activity with respect to applying a recently approved broth microdilution susceptibility testing method. Moreover, these results confirm the more potent activity of telavancin compared with that seen in previous studies (13, 14, 23), which underestimated the potency of drug due to solubility and availability issues during susceptibility testing (17).
ACKNOWLEDGMENTS
This surveillance study was sponsored by an educational/research grant from Theravance Biopharma Antibiotics, Inc., via the SENTRY Antimicrobial Surveillance Program platform. JMI Laboratories also received compensation fees for services with regard to manuscript preparation, which was funded by Theravance Biopharma Antibiotics, Inc. Theravance Biopharma Antibiotics, Inc., had no involvement in the collection, analysis, or interpretation of data.
REFERENCES
- 1.Rodvold KA, McConeghy KW. 2014. Methicillin-resistant Staphylococcus aureus therapy: past, present, and future. Clin Infect Dis 58(Suppl 1):S20–S27. doi: 10.1093/cid/cit614. [DOI] [PubMed] [Google Scholar]
- 2.Chatterjee SS, Otto M. 2013. Improved understanding of factors driving methicillin-resistant Staphylococcus aureus epidemic waves. Clin Epidemiol 5:205–217. doi: 10.2147/CLEP.S37071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Talan DA, Krishnadasan A, Gorwitz RJ, Fosheim GE, Limbago B, Albrecht V, Moran GJ. 2011. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis 53:144–149. doi: 10.1093/cid/cir308. [DOI] [PubMed] [Google Scholar]
- 4.Mendes RE, Deshpande LM, Smyth DS, Shopsin B, Farrell DJ, Jones RN. 2012. Characterization of methicillin-resistant Staphylococcus aureus strains recovered from a phase IV clinical trial for linezolid versus vancomycin for the treatment of nosocomial pneumonia. J Clin Microbiol 50:3694–3702. doi: 10.1128/JCM.02024-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Seybold U, Kourbatova EV, Johnson JG, Halvosa SJ, Wang YF, King MD, Ray SM, Blumberg HM. 2006. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis 42:647–656. doi: 10.1086/499815. [DOI] [PubMed] [Google Scholar]
- 6.Popovich KJ, Weinstein RA, Hota B. 2008. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis 46:787–794. doi: 10.1086/528716. [DOI] [PubMed] [Google Scholar]
- 7.van Hal SJ, Lodise TP, Paterson DL. 2012. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 54:755–771. doi: 10.1093/cid/cir935. [DOI] [PubMed] [Google Scholar]
- 8.Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O'Sullivan MV, Anderson TL, Roberts SA, Gao W, Christiansen KJ, Coombs GW, Johnson PD, Howden BP. 2011. Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations. J Infect Dis 204:340–347. doi: 10.1093/infdis/jir270. [DOI] [PubMed] [Google Scholar]
- 9.Aguado JM, San-Juan R, Lalueza A, Sanz F, Rodríguez-Otero J, Gómez-Gonzalez C, Chaves F. 2011. High vancomycin MIC and complicated methicillin-susceptible Staphylococcus aureus bacteremia. Emerg Infect Dis 17:1099–1102. doi: 10.3201/eid/1706.101037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Castón JJ, González-Gasca F, Porras L, Illescas S, Romero MD, Gijón J. 19 August 2014. High vancomycin minimum inhibitory concentration is associated with poor outcome in patients with methicillin-susceptible Staphylococcus aureus bacteremia regardless of treatment. Scand J Infect Dis doi: 10.3109/00365548.2014.931596. [DOI] [PubMed] [Google Scholar]
- 11.Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP. 2009. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 66:82–98. doi: 10.2146/ajhp080434. [DOI] [PubMed] [Google Scholar]
- 12.Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, Rybak MJ, Talan DA, Chambers HF. 2011. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52:285–292. doi: 10.1093/cid/cir034. [DOI] [PubMed] [Google Scholar]
- 13.Hegde SS, Skinner R, Lewis SR, Krause KM, Blais J, Benton BM. 2010. Activity of telavancin against heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) in vitro and in an in vivo mouse model of bacteraemia. J Antimicrob Chemother 65:725–728. doi: 10.1093/jac/dkq028. [DOI] [PubMed] [Google Scholar]
- 14.Mendes RE, Sader HS, Farrell DJ, Jones RN. 2012. Worldwide appraisal and update (2010) of telavancin activity tested against a collection of Gram-positive clinical pathogens from five continents. Antimicrob Agents Chemother 56:3999–4004. doi: 10.1128/AAC.00011-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Theravance. 2014. Vibativ package insert. http://www.vibativ.com.
- 16.Clinical and Laboratory Standards Institute. 2014. Performance standards for antimicrobial susceptibility testing: 24th informational supplement M100-S24. Wayne, PA. [Google Scholar]
- 17.Farrell DJ, Mendes RE, Rhomberg PR, Jones RN. 2014. Revised reference broth microdilution method for testing telavancin: effect on MIC results and correlation with other testing methodologies. Antimicrob Agents Chemother 58:5547–5551. doi: 10.1128/AAC.03172-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Rennie RP, Koeth L, Jones RN, Fritsche TR, Knapp CC, Killian SB, Goldstein BP. 2007. Factors influencing broth microdilution antimicrobial susceptibility test results for dalbavancin, a new glycopeptide agent. J Clin Microbiol 45:3151–3154. doi: 10.1128/JCM.02411-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Arhin FF, Sarmiento I, Belley A, McKay GA, Draghi DC, Grover P, Sahm DF, Parr TR Jr, Moeck G. 2008. Effect of polysorbate 80 on oritavancin binding to plastic surfaces: implications for susceptibility testing. Antimicrob Agents Chemother 52:1597–1603. doi: 10.1128/AAC.01513-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Clinical and Laboratory Standards Institute. 2012. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard M07-A9: ninth edition. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 21.EUCAST. 2014. Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014 http://www.eucast.org/clinical_breakpoints/ Accessed 2 January 2014.
- 22.Kullar R, Davis SL, Kaye KS, Levine DP, Pogue JM, Rybak MJ. 2013. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 33:3–10. doi: 10.1002/phar.1220. [DOI] [PubMed] [Google Scholar]
- 23.Farrell DJ, Krause KM, Benton BM. 2011. In vitro activity of telavancin and comparator antimicrobial agents against a panel of genetically defined staphylococci. Diagn Microbiol Infect Dis 69:275–279. doi: 10.1016/j.diagmicrobio.2010.09.017. [DOI] [PubMed] [Google Scholar]