Abstract
Oritavancin exhibited potent activity against vancomycin-susceptible (MIC50 and MIC90, 0.015/0.03 μg/ml) and vanB-carrying E. faecalis isolates (MIC50 and MIC90, 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC50s and MIC90s for vanA-harboring E. faecalis were noted (MIC50 and MIC90, 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤0.5 μg/ml. Vancomycin-susceptible and vanB-carrying E. faecium strains (MIC50 and MIC90, ≤0.008 and ≤0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC50 and MIC90, 0.03 and 0.06 μg/ml). Oritavancin exhibited good in vitro potency against this collection of organisms, including vancomycin-resistant enterococci.
TEXT
Enterococcus species have become important nosocomial pathogens and currently represent the third most frequent pathogens responsible for health care-associated infections in the United States (10), with Enterococcus faecium isolates eliciting greater concern, as they are often resistant to commonly used antimicrobial agents, such as ampicillin, aminoglycosides, and glycopeptides (14). Enterococcus faecalis and E. faecium account for approximately 90% of nosocomial enterococcal infections and may acquire various types of glycopeptide resistance determinants (vanA, -B, -D, -E, -G, and -N) (5, 12). Among these elements, vanA and vanB are the most prevalent in clinically relevant species (9, 21). Although the rate of vancomycin resistance among E. faecalis strains causing bloodstream infections (BSI) has been stable over the last decade, the rate in E. faecium has escalated to 30% and 79% in Europe and the United States, respectively (10, 19).
There is growing evidence demonstrating that nosocomial enterococci possess specific characteristics, such as the presence of antimicrobial resistance determinants and pathogenicity traits, which enable them to rapidly adapt to the hospital environment and cause a broad range of invasive infections (11, 16, 17). The ability to acquire, retain, and express genetic elements further enhances the propensity of enterococci to sustain selective pressure (9). As infections caused by resistant bacteria usually begin with colonization of mucosal surfaces, in particular the intestinal epithelium, broad-spectrum antimicrobial therapy depletes the intestinal microbiota, which plays an important role in the production of antimicrobial proteins by stimulating the immune system (2). An individual with a compromised mucosal innate immune defense is more prone to bacterial colonization, which eventually progresses to an infectious episode (2). In fact, it has been demonstrated that intestinal domination by vancomycin-resistant enterococci (VRE) precedes bloodstream infections (18).
Oritavancin is a semisynthetic bactericidal lipoglycopeptide in late stage of clinical development for treatment of severe infections caused by Gram-positive organisms. This drug has demonstrated potent activity against Gram-positive pathogens, including multidrug-resistant (MDR) enterococci (VRE), staphylococci, and streptococci (1). This study describes the activity of oritavancin compared to other antimicrobial agents against a contemporary (2009-2010) collection of enterococcal clinical isolates causing BSI in U.S. and European hospitals, including VRE strains with molecularly characterized glycopeptide resistance determinants.
A total of 2,260 enterococci (1,312 E. faecalis, 869 E. faecium, 24 E. gallinarum, and 15 E. casseliflavus isolates) were collected from 29 medical institutions in the United States and 27 centers in 13 European countries, including Turkey and Israel. Strains included in this study were those recovered from blood in a prevalence mode design following established protocols as part of the SENTRY Antimicrobial Surveillance Program (i.e., the first 20 unique and consecutive blood isolates collected each month for 12 months per medical site). Isolates were submitted to a central monitoring laboratory (JMI Laboratories, North Liberty, IA) and had the bacterial species identification confirmed by an automated system (Vitek2; bioMérieux, Hazelwood, MO) or conventional biochemical algorithms, as required.
Isolates were tested for susceptibility by broth microdilution following Clinical and Laboratory Standards Institute (CLSI) recommendations (3). Oritavancin susceptibility testing was performed using dry-form panels (TREK Diagnostic Systems, Cleveland, OH), which provide results equivalent to those of the CLSI-approved broth microdilution method supplemented with 0.002% polysorbate-80 (3). Quality assurance was performed by concurrent testing of the CLSI-recommended strains E. faecalis ATCC 29212 and Staphylococcus aureus ATCC 29213 (4). Interpretation of comparator MICs was in accordance with published CLSI (4) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria (7). Isolates with vancomycin MICs of ≥8 μg/ml were screened for vanA and vanB in a multiplex PCR assay (6). The identification of E. casseliflavus and E. gallinarum was confirmed by PCR for the presence of vanC1, -2, and -3 (6).
Of the 2,260 enterococcal strains recovered from blood, the majority were E. faecalis (1,312; 58.1%), followed by E. faecium (869; 38.5%). E. faecium represented the vast majority (486/523; 93.0%) of vancomycin-resistant strains (Table 1). The vanA genotype was by far the most prevalent, accounting for 73.0% (27/37) and 96.7% (470/486) of E. faecalis and E. faecium strains, respectively. All vanA-carrying enterococci showed a VanA phenotype (i.e., vancomycin and teicoplanin MICs, >16 and >8 μg/ml, respectively), except for two U.S. E. faecium isolates that exhibited teicoplanin MICs of ≤1 and 4 μg/ml (Table 2). Enterococcal strains carrying the vanB gene demonstrated vancomycin and teicoplanin MICs of ≥8 and ≤2 μg/ml, respectively.
Table 1.
Antimicrobial activity of oritavancin against vancomycin-susceptible and vancomycin-resistant enterococcal clinical isolates causing bloodstream infections in U.S. and European hospitals
| Organism and resistance (no. tested) | MIC (μg/ml) |
Numbera (cumulative %) inhibited at MIC (μg/ml) ofa: |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| 50% | 90% | ≤0.008 | 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | |
| E. faecalis (1,312) | |||||||||
| Vancomycin susceptible (1,275) | 0.015 | 0.03 | 435 (34.1) | 575 (79.2) | 211 (95.8) | 43 (99.1) | 7 (99.7) | 3 (99.9) | 1 (100.0) |
| vanA (27) | 0.25 | 0.5 | 0 (0.0) | 1 (3.7) | 3 (14.8) | 3 (25.9) | 0 (25.9) | 15 (81.5) | 5 (100.0) |
| vanB (10) | 0.015 | 0.015 | 1 (10.0) | 8 (90.0) | 0 (90.0) | 1 (100.0) | − | − | − |
| E. faecium (869) | |||||||||
| Vancomycin susceptible (383) | ≤0.008 | ≤0.008 | 374 (97.7) | 7 (99.5) | 2 (100.0) | − | − | − | − |
| vanA (470) | 0.03 | 0.06 | 76 (16.2) | 74 (31.9) | 146 (63.0) | 133 (91.3) | 37 (99.1) | 4 (100.0) | − |
| vanB (16) | ≤0.008 | ≤0.008 | 16 (100.0) | − | − | − | − | − | − |
| E. casseliflavus (15) and E. gallinarum (24) | |||||||||
| vanC (39) | ≤0.008 | 0.015 | 34 (87.2) | 5 (100.0) | − | − | − | − | − |
Modal MICs are in bold.
Table 2.
Antimicrobial activity of oritavancin and comparator agents against vancomycin-susceptible and vancomycin-resistant enterococcal clinical isolates causing bloodstream infections in U.S. and European hospitals
| Organism (no. tested) and antimicrobial agent | MIC (μg/ml) |
% Susceptible/% resistanta |
|||
|---|---|---|---|---|---|
| Range | 50% | 90% | CLSI | EUCAST | |
| Vancomycin-susceptible E. faecalis (1,275) | |||||
| Oritavancin | ≤0.008–0.5 | 0.015 | 0.03 | −/− | −/− |
| Ampicillin | ≤1–8 | ≤1 | 2 | 100.0/0.0 | 99.8/0.0 |
| Vancomycin | 0.25–4 | 1 | 2 | 100.0/0.0 | 100.0/0.0 |
| Teicoplanin | ≤2–4 | ≤2 | ≤2 | 100.0/0.0 | 99.9/0.1 |
| Daptomycin | 0.12–4 | 1 | 2 | 100.0/− | −/− |
| Linezolid | 0.25–>8 | 1 | 2 | 99.9/0.1 | 99.9/0.1 |
| Quinupristin-dalfopristin | ≤0.5–>2 | >2 | >2 | 0.5/95.0 | 0.5/89.0 |
| Levofloxacin | ≤0.5–>4 | 1 | >4 | 69.0/30.4 | −/− |
| Tetracycline | ≤2–>8 | >8 | >8 | 23.2/76.5 | −/− |
| vanA E. faecalis (27) | |||||
| Oritavancin | 0.015–0.5 | 0.25 | 0.5 | −/− | −/− |
| Ampicillin | ≤1–>16 | ≤1 | 2 | 96.3/3.7 | 96.3/3.7 |
| Vancomycin | >16 | >16 | >16 | 0.0/100.0 | 0.0/100.0 |
| Teicoplanin | >8 | >8 | >8 | 3.7/96.3 | 0.0/100.0 |
| Daptomycin | 0.5–2 | 1 | 2 | 100.0/− | −/− |
| Linezolid | 1–2 | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| Quinupristin-dalfopristin | 2–>2 | >2 | >2 | 0.0/96.3 | 0.0/96.3 |
| Levofloxacin | 2–>4 | >4 | >4 | 3.7/96.3 | −/− |
| Tetracycline | ≤2–>8 | >8 | >8 | 3.7/96.3 | −/− |
| vanB E. faecalis (10) | |||||
| Oritavancin | ≤0.008–0.06 | 0.015 | 0.015 | −/− | −/− |
| Ampicillin | ≤1–2 | ≤1 | 2 | 100.0/0.0 | 100.0/0.0 |
| Vancomycin | 8–>16 | >16 | >16 | 0.0/80.0 | 0.0/100.0 |
| Teicoplanin | ≤2 | ≤2 | ≤2 | 100.0/0.0 | 100.0/0.0 |
| Daptomycin | ≤0.06–2 | 0.5 | 1 | 100.0/− | −/− |
| Linezolid | 0.5–2 | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| Quinupristin-dalfopristin | >2 | >2 | >2 | 0.0/100.0 | 0.0/100.0 |
| Levofloxacin | >4 | >4 | >4 | 0.0/100.0 | −/− |
| Tetracycline | ≤2–>8 | ≤2 | >8 | 50.0/50.0 | −/− |
| Vancomycin-susceptible E. faecium (383) | |||||
| Oritavancin | ≤0.008–0.03 | ≤0.008 | ≤0.008 | −/− | −/− |
| Ampicillin | ≤1–>8 | >8 | >8 | 14.4/85.6 | 14.1/85.6 |
| Vancomycin | 0.25–4 | 1 | 1 | 100.0/0.0 | 100.0/0.0 |
| Teicoplanin | ≤2–4 | ≤2 | ≤2 | 100.0/0.0 | 99.7/0.3 |
| Daptomycin | 0.12–>8 | 2 | 4 | 99.7/− | −/− |
| Linezolid | 0.5–>8 | 1 | 2 | 99.2/0.8 | 99.2/0.8 |
| Quinupristin-dalfopristin | ≤0.5–>2 | ≤0.5 | >2 | 72.1/15.7 | 72.1/11.7 |
| Levofloxacin | ≤0.5–>4 | >4 | >4 | 15.4/77.5 | −/− |
| Tetracycline | ≤2–>8 | ≤2 | >8 | 56.7/42.8 | −/− |
| vanA E. faecium (470) | |||||
| Oritavancin | ≤0.008–0.25 | 0.03 | 0.06 | −/− | −/− |
| Ampicillin | >8 | >8 | >8 | 0.0/100.0 | 0.0/100.0 |
| Vancomycin | >16 | >16 | >16 | 0.0/99.6 | 0.0/100.0 |
| Teicoplanin | ≤1–>8 | >8 | >8 | 0.6/96.2 | 0.2/99.8 |
| Daptomycin | 0.12–4 | 2 | 2 | 100.0/− | −/− |
| Linezolid | 0.5–>8 | 1 | 2 | 98.1/1.3 | 98.7/1.3 |
| Quinupristin-dalfopristin | ≤0.5–>2 | ≤0.5 | 1 | 96.6/1.3 | 96.6/1.3 |
| Levofloxacin | 2–>4 | >4 | >4 | 0.2/99.8 | −/− |
| Tetracycline | ≤2–>8 | >8 | >8 | 36.8/62.3 | −/− |
| vanB E. faecium (16) | |||||
| Oritavancin | ≤0.008 | ≤0.008 | ≤0.008 | −/− | −/− |
| Ampicillin | >8 | >8 | >8 | 0.0/100.0 | 0.0/100.0 |
| Vancomycin | 8–>16 | >16 | >16 | 0.0/75.0 | 0.0/100.0 |
| Teicoplanin | ≤2 | ≤2 | ≤2 | 100.0/0.0 | 100.0/0.0 |
| Daptomycin | 0.5–4 | 2 | 2 | 100.0/− | −/− |
| Linezolid | 0.5–4 | 1 | 2 | 93.8/0.0 | 100.0/0.0 |
| Quinupristin-dalfopristin | ≤0.5–>2 | ≤0.5 | >2 | 87.5/12.5 | 87.5/12.5 |
| Levofloxacin | >4 | >4 | >4 | 0.0/100.0 | −/− |
| Tetracycline | ≤2–>8 | >8 | >8 | 37.5/62.5 | −/− |
| vanC enterococci (39)b | |||||
| Oritavancin | ≤0.008–0.015 | ≤0.008 | 0.015 | −/− | −/− |
| Ampicillin | ≤1–>16 | ≤1 | 2 | 97.4/2.6 | 97.4/2.6 |
| Vancomycin | 0.25–8 | 4 | 8 | 82.1/0.0 | 82.1/17.9 |
| Teicoplanin | ≤2 | ≤2 | ≤2 | 100.0/0.0 | 100.0/0.0 |
| Daptomycin | ≤0.06–4 | 1 | 2 | 100.0/− | −/− |
| Linezolid | 0.5–2 | 1 | 2 | 100.0/0.0 | 100.0/0.0 |
| Quinupristin-dalfopristin | ≤0.5–>2 | 2 | >2 | 7.7/48.7 | 7.7/30.8 |
| Levofloxacin | ≤0.5–>4 | 2 | 4 | 84.6/5.1 | −/− |
| Tetracycline | ≤2–>8 | ≤2 | >8 | 74.4/25.6 | −/− |
Oritavancin inhibited all tested enterococci at ≤0.5 μg/ml, with potent MIC50s and MIC90s against vancomycin-susceptible E. faecalis (MIC50 and MIC90, 0.015 and 0.03 μg/ml) and E. faecium (MIC50 and MIC90, ≤0.008 and ≤0.008 μg/ml) (Tables 1 and 2). MIC50s of oritavancin against vanB-carrying E. faecalis and E. faecium were equivalent to those obtained with the respective vancomycin-susceptible strains. Vancomycin-resistant (vanA) E. faecalis exhibited oritavancin MICs (MIC50 and MIC90, 0.25 and 0.5 μg/ml) 16-fold higher than those for vancomycin-susceptible isolates (MIC50 and MIC90, 0.015 and 0.03 μg/ml). Similarly, vanA-carrying E. faecium (MIC50 and MIC90, 0.03 and 0.06 μg/ml) exhibited higher (≥4-fold) oritavancin MICs than vancomycin-susceptible strains and vanB-harboring strains. Enterococcal isolates harboring intrinsic vancomycin resistance determinants (i.e., E. casseliflavus and E. gallinarum) showed variable vancomycin MICs (0.25 to 8 μg/ml; MIC50 and MIC90, 4 and 8 μg/ml); nevertheless, these strains were very susceptible to oritavancin (MIC50 and MIC90, ≤0.008 and 0.015 μg/ml) (Tables 1 and 2).
Ampicillin (MIC90, 2 μg/ml; VanA- and VanB-producing strains were 96.3% and 100% susceptible, respectively), daptomycin (MIC90, 1 to 2 μg/ml; 100% susceptible), and linezolid (MIC90, 1 μg/ml; 100% susceptible) were active against vancomycin-resistant E. faecalis isolates (Table 2). Oritavancin demonstrated in vitro MIC90s 2- to 4-fold and 64- to 128-fold lower than these comparator agents against vanA- and vanB-carrying E. faecalis strains, respectively. Among comparators, activity against vancomycin-resistant E. faecium was noted for daptomycin (MIC50 and MIC90, 2 and 2 μg/ml; 100% susceptible) and linezolid (MIC50 and MIC90, 1 and 2 μg/ml; 98.1 to 100% susceptible). Quinupristin-dalfopristin (MIC50 and MIC90, ≤0.5 and 1 μg/ml; 96.6% susceptible) demonstrated activity against vanA-carrying E. faecium (Table 2), while marginal coverage was noted against vancomycin-susceptible and vancomycin-resistant (vanB) strains (MIC50 and MIC90, ≤0.5 and >2 μg/ml; 72.1 to 87.5% susceptible). E. casseliflavus and E. gallinarum isolates were very susceptible (97.4 to 100%) to ampicillin (MIC50 and MIC90, ≤1 and 2 μg/ml), teicoplanin (MIC50 and MIC90, ≤2 and ≤2 μg/ml), daptomycin (MIC50 and MIC90, 1 and 2 μg/ml), and linezolid (MIC50 and MIC90, 1 and 2 μg/ml) (Table 2).
This report provides an update on the distribution of van genes among vancomycin-resistant E. faecalis and E. faecium strains causing bacteremia in U.S. and European hospitals. A study conducted in the United States from 1995 through 2002 reported vancomycin resistance rates among E. faecalis (2%) and E. faecium (60%) strains responsible for BSI similar to those observed in this study (2.8 and 55.9%, respectively) (20). However, the present study highlights the emergence of E. faecium (38.5% of all enterococci) as an important pathogen causing BSI, which is of great concern given the higher antimicrobial resistance and mortality rate associated with this species (10). Interestingly, two E. faecium strains from U.S. hospitals demonstrated the combination of a VanB phenotype and vanA genotype. Strains displaying these characteristics have been reported in the East Asia region (Japan, China, South Korea, and Taiwan) (8); however, this appears to be the first report of such strains in the United States.
The clinical options for treating serious infections caused by VRE are very restricted and often present limitations (13). Oritavancin has demonstrated in vitro concentration-dependent bactericidal activity against VRE at the predicted free peak concentration derived from administering a human dose of 800 mg (∼16 μg/ml) (15). In this report, the comparison of the in vitro activity of oritavancin and other agents revealed pronounced oritavancin activity against this collection of clinical isolates. Moreover, oritavancin demonstrated 4- to 128-fold-greater potency than the active comparator antimicrobial agents, particularly against VRE. These in vitro activity data suggest oritavancin as a promising agent for treating serious infections caused by vancomycin-susceptible and -resistant enterococci, as monotherapy or as part of combination regimens with other agents, contingent on further studies.
ACKNOWLEDGMENTS
We thank the following staff members at JMI Laboratories (North Liberty, IA) for technical support and manuscript assistance: A. Small, G. J. Moet, L. M. Deshpande, M. Castanheira, M. Janecheck, and P. R. Rhomberg. This study was sponsored by an educational/research grant from The Medicines Company (Parsippany, NJ) via the SENTRY Antimicrobial Surveillance Program platform.
Footnotes
Published ahead of print 19 December 2011
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