Antimicrobial activity of oritavancin and comparator agents when tested against Gram-positive bacterial isolates causing infections in cancer patients (2014–16)

Antimicrobial activity of oritavancin and comparator agents when tested against Gram-positive... Abstract Objectives The in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals. Methods A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%). Results Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015–0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008–0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region. Conclusions Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients. Introduction Infections remain a significant cause of morbidity and mortality among cancer patients.1 Although the epidemiology of isolates obtained from cancer patients has fluctuated over the past decades, Gram-positive cocci (GPC) remain the predominant pathogens in neutropenic and non-neutropenic cancer patients, although some institutions are reporting a resurgence of Gram-negative infections.2–4 Infections in cancer patients are predominantly caused by MRSA, MSSA, methicillin-resistant CoNS, VRE and viridans group streptococci (VGS),1,3,5 likely due to the widespread use of vascular catheters, ports and other foreign devices, intensive chemotherapy resulting in extensive oral and intestinal mucositis, and antimicrobial prophylaxis directed primarily at Enterobacteriaceae.4,6 Although fluoroquinolone prophylaxis has substantially reduced Gram-negative infections among neutropenic cancer patients,2 these agents have poor activity against most GPC and the emergence of fluoroquinolone-resistant isolates has led to many cancer centres discontinuing this practice.2,4 Oritavancin belongs to the lipoglycopeptide class of antimicrobial agents and acts by interrupting bacterial cell wall synthesis, in addition to disrupting cell membrane integrity, resulting in bacterial death.7 Oritavancin was approved in the USA (2014) and in Europe (2015) for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs).7 This drug demonstrates potent in vitro activity against Staphylococcus aureus (including MRSA), streptococci and enterococci. In addition, oritavancin remains potent against VRE.8,9 The present report describes oritavancin in vitro activity and potency against a GPC collection (2014–16) responsible for infections in a cancer patient population (haematology–oncology) in US and European medical centres. Methods Bacterial isolates A total of 1357 GPC were collected from patients hospitalized in the oncology units of 26 sites in Europe (Belgium, France, Germany, Ireland, Italy, Spain, Sweden and the UK), Ukraine Israel, Russia, Turkey and 25 institutions in the USA. Isolates were consecutively collected (one per patient episode) between January 2014 and December 2016 as part of the SENTRY Antimicrobial Surveillance Program. Only isolates deemed clinically significant by local criteria from patients with cancer were included. These pathogens were submitted to the coordinating monitoring laboratory (JMI Laboratories, North Liberty, IA, USA), where bacterial identifications for staphylococci and enterococci were confirmed by standard algorithms and/or MALDI-TOF MS (Bruker Daltonics, Bremen, Germany). All streptococci were subjected to MALDI-TOF MS. Antimicrobial susceptibility testing Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A10 document.10 Quality assurance was performed by concurrently testing CLSI-recommended strains.11 CLSI- and EUCAST-approved interpretive breakpoint criteria were applied (see footnote of Table 2).11,12 Results Isolates were predominantly from bloodstream infections (54.6%), skin and skin structure infections (20.9%), pneumonia (14.8%), intra-abdominal infections (4.6%) and urinary tract infections (3.0%). The most frequently isolated GPC were S. aureus (43.6%), followed by CoNS (14.4%), Enterococcus spp. (22.0%), VGS (9.3%) and β-haemolytic streptococci (BHS) (3.6%). The key resistant phenotypes differed considerably between US and European sites: MRSA, 39.9%/21.2% (USA/Europe); VRE (Enterococcus faecium), 69.1%/22.0%; and penicillin-resistant VGS, 14.3%/3.6% (Table 1). Table 1. Antimicrobial activity of oritavancin tested against the main organisms and organism groups of isolates causing infections in cancer patients in Europe and the USA Organism/organism group (no. of isolates)  No. of isolates at MIC in mg/L (cumulative %)   MIC50  MIC90  ≤0.0005  0.001  0.002  0.004  0.008  0.015  0.03  0.06  0.12  0.25  0.5  Europe   S. aureus (288)          14  131  103  32  8      0.015  0.06  4.9  50.3  86.1  97.2  100.0    MSSA (227)          12  108  76  25  6      0.015  0.06  5.3  52.9  86.3  97.4  100.0    MRSA (61)          2  23  27  7  2      0.03  0.06  3.3  41.0  85.2  96.7  100.0   CoNS (111)a        1  9  19  45  33  4      0.03  0.06  0.9  9.0  26.1  66.7  96.4  100.0   E. faecalis (57)b        3  18  20  9  5  2      0.015  0.06  5.3  36.8  71.9  87.7  96.5  100.0   E. faecium (82)    1  12  35  12  14  5  1  1  1    0.004  0.015  1.2  15.9  58.5  73.2  90.2  96.3  97.6  98.8  100.0    vancomycin susceptible (64)    1  10  33  10  10            0.004  0.015  1.6  17.2  68.8  84.4  100.0    vancomycin non-susceptible (18)c      2  2  2  4  5  1  1  1    0.015  0.12  11.1  22.2  33.3  55.6  83.3  88.9  94.4  100.0   BHS (15)          2  0  6  3  2  2    0.03  0.25  13.3  13.3  53.3  73.3  86.7  100.0    Streptococcus agalactiae (7)              4  2  0  1    0.03  –  57.1  85.7  85.7  100.0    Streptococcus pyogenes (3)          1  0  1  1        0.03  –  33.3  33.3  66.7  100.0    Streptococcus dysgalactiae (5)          1  0  1  0  2  1    0.12  –  20.0  20.0  40.0  40.0  80.0  100.0   VGS (56)d  1  1  5  9  9  7  8  9  1  6    0.015  0.25  1.8  3.6  12.5  28.6  44.6  57.1  71.4  87.5  89.3  100.0    Streptococcus anginosus group (10)      2  2  3  0  3          0.008  0.03  20.0  40.0  70.0  70.0  100.0  USA   S. aureus (303)          25  161  82  30  4  1    0.015  0.06  8.3  61.4  88.4  98.3  99.7  100.0    MSSA (182)          15  106  43  16  2      0.015  0.03  8.2  66.5  90.1  98.9  100.0    MRSA (121)          10  55  39  14  2  1    0.015  0.06  8.3  53.7  86.0  97.5  99.2  100.0   CoNS (84)e        1  8  9  34  21  10  1    0.03  0.12  1.2  10.7  21.4  61.9  86.9  98.8  100.0   E. faecalis (82)f        6  22  38  11  2  1  2    0.015  0.03  7.3  34.1  80.5  93.9  96.3  97.6  100.0   E. faecium (68)      1  13  7  15  12  13  7      0.015  0.12  1.5  20.6  30.9  52.9  70.6  89.7  100.0    vancomycin susceptible (21)      1  12  5  3            0.004  0.015  4.8  61.9  85.7  100.0    vancomycin non-susceptible (47)g        1  2  12  12  13  7      0.03  0.12  2.1  6.4  31.9  57.4  85.1  100.0   BHS (34)          4  9  6  5  5  4  1  0.03  0.25  11.8  38.2  55.9  70.6  85.3  97.1  100.0    S. agalactiae (18)          3  6  5  2  1  1    0.015  0.12  16.7  50.0  77.8  88.9  94.4  100.0    S. pyogenes (12)          1  3  1  3  4      0.06  0.12  8.3  33.3  41.7  66.7  100.0    S. dysgalactiae (4)                    3  1  0.25  –  75.0  100.0   VGS (70)h  4  2  6  10  15  9  10  8  2  3  1  0.008  0.06  5.7  8.6  17.1  31.4  52.9  65.7  80.0  91.4  94.3  98.6  100.0    S. anginosus group (8)      2  0  4  1  1          0.008  –  25.0  25.0  75.0  87.5  100.0  Organism/organism group (no. of isolates)  No. of isolates at MIC in mg/L (cumulative %)   MIC50  MIC90  ≤0.0005  0.001  0.002  0.004  0.008  0.015  0.03  0.06  0.12  0.25  0.5  Europe   S. aureus (288)          14  131  103  32  8      0.015  0.06  4.9  50.3  86.1  97.2  100.0    MSSA (227)          12  108  76  25  6      0.015  0.06  5.3  52.9  86.3  97.4  100.0    MRSA (61)          2  23  27  7  2      0.03  0.06  3.3  41.0  85.2  96.7  100.0   CoNS (111)a        1  9  19  45  33  4      0.03  0.06  0.9  9.0  26.1  66.7  96.4  100.0   E. faecalis (57)b        3  18  20  9  5  2      0.015  0.06  5.3  36.8  71.9  87.7  96.5  100.0   E. faecium (82)    1  12  35  12  14  5  1  1  1    0.004  0.015  1.2  15.9  58.5  73.2  90.2  96.3  97.6  98.8  100.0    vancomycin susceptible (64)    1  10  33  10  10            0.004  0.015  1.6  17.2  68.8  84.4  100.0    vancomycin non-susceptible (18)c      2  2  2  4  5  1  1  1    0.015  0.12  11.1  22.2  33.3  55.6  83.3  88.9  94.4  100.0   BHS (15)          2  0  6  3  2  2    0.03  0.25  13.3  13.3  53.3  73.3  86.7  100.0    Streptococcus agalactiae (7)              4  2  0  1    0.03  –  57.1  85.7  85.7  100.0    Streptococcus pyogenes (3)          1  0  1  1        0.03  –  33.3  33.3  66.7  100.0    Streptococcus dysgalactiae (5)          1  0  1  0  2  1    0.12  –  20.0  20.0  40.0  40.0  80.0  100.0   VGS (56)d  1  1  5  9  9  7  8  9  1  6    0.015  0.25  1.8  3.6  12.5  28.6  44.6  57.1  71.4  87.5  89.3  100.0    Streptococcus anginosus group (10)      2  2  3  0  3          0.008  0.03  20.0  40.0  70.0  70.0  100.0  USA   S. aureus (303)          25  161  82  30  4  1    0.015  0.06  8.3  61.4  88.4  98.3  99.7  100.0    MSSA (182)          15  106  43  16  2      0.015  0.03  8.2  66.5  90.1  98.9  100.0    MRSA (121)          10  55  39  14  2  1    0.015  0.06  8.3  53.7  86.0  97.5  99.2  100.0   CoNS (84)e        1  8  9  34  21  10  1    0.03  0.12  1.2  10.7  21.4  61.9  86.9  98.8  100.0   E. faecalis (82)f        6  22  38  11  2  1  2    0.015  0.03  7.3  34.1  80.5  93.9  96.3  97.6  100.0   E. faecium (68)      1  13  7  15  12  13  7      0.015  0.12  1.5  20.6  30.9  52.9  70.6  89.7  100.0    vancomycin susceptible (21)      1  12  5  3            0.004  0.015  4.8  61.9  85.7  100.0    vancomycin non-susceptible (47)g        1  2  12  12  13  7      0.03  0.12  2.1  6.4  31.9  57.4  85.1  100.0   BHS (34)          4  9  6  5  5  4  1  0.03  0.25  11.8  38.2  55.9  70.6  85.3  97.1  100.0    S. agalactiae (18)          3  6  5  2  1  1    0.015  0.12  16.7  50.0  77.8  88.9  94.4  100.0    S. pyogenes (12)          1  3  1  3  4      0.06  0.12  8.3  33.3  41.7  66.7  100.0    S. dysgalactiae (4)                    3  1  0.25  –  75.0  100.0   VGS (70)h  4  2  6  10  15  9  10  8  2  3  1  0.008  0.06  5.7  8.6  17.1  31.4  52.9  65.7  80.0  91.4  94.3  98.6  100.0    S. anginosus group (8)      2  0  4  1  1          0.008  –  25.0  25.0  75.0  87.5  100.0  a Organisms include: Staphylococcus capitis (3), Staphylococcus caprae (1), Staphylococcus epidermidis (64), Staphylococcus haemolyticus (30) and Staphylococcus hominis (13). b All vancomycin susceptible. c Includes 15 isolates displaying a VanA phenotype (vancomycin and teicoplanin MIC at >4 and >8 mg/L, respectively) and 3 isolates with a VanB phenotype (vancomycin and teicoplanin MIC at >4 and ≤8 mg/L, respectively). d Organisms include: S. anginosus (9), Streptococcus constellatus (1), Streptococcus equinus (1), Streptococcus gallolyticus (1), Streptococcus gordonii (1), Streptococcus massiliensis (1), Streptococcus mitis group (12), Streptococcus mitis/oralis (9), Streptococcus oralis (9), Streptococcus parasanguinis (4), Streptococcus salivarius (5), Streptococcus salivarius/vestibularis (1) and Streptococcus sanguinis (2). e Organisms include: Staphylococcus caprae (2), S. epidermidis (65), S. haemolyticus (6), S. hominis (7), Staphylococcus lugdunensis (1), Staphylococcus simulans (2) and Staphylococcus warneri (1). f Three isolates with a VanA phenotype displaying oritavancin MIC values of 0.12–0.25 mg/L. g Includes 45 isolates with a VanA phenotype and 2 isolates with a VanB phenotype. h Organisms include: S. anginosus (4), S. anginosus group (1), Streptococcus australis (1), S. constellatus (3), Streptococcus cristatus (1), S. equinus (1), S. mitis (2), S. mitis group (15), S. mitis/oralis (21), S. oralis (9), S. parasanguinis (6), S. salivarius (2), S. sanguinis (2), Streptococcus sobrinus (1) and Streptococcus vestibularis (1). Table 1 shows the oritavancin MIC50/MIC90 results and the MIC distributions for US and European isolates. The MIC90 values ranged from 0.015 to 0.25 mg/L for the different species and were comparable for European and US isolates. The MIC values were ≤0.25 mg/L for all but 2 (both streptococci) of the 1357 isolates. Oritavancin showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015–0.03 and 0.06 mg/L for S. aureus, regardless of the methicillin susceptibility phenotype or geographical region (99.8% of European and US isolates were inhibited at ≤0.12 mg/L) (Tables 1 and 2). Oritavancin (MIC50/MIC90 0.03/0.06 mg/L; 99.5% susceptible) and comparator agents such as daptomycin (MIC50/MIC90 0.25/0.5 mg/L; 100.0% susceptible), vancomycin (MIC50/MIC90, 0.5/1 mg/L; 100.0% susceptible), teicoplanin (MIC50/MIC90 ≤2/≤2 mg/L; 100.0% susceptible), trimethoprim/sulfamethoxazole (MIC50/MIC90 ≤0.5/≤0.5 mg/L; 97.8% susceptible) and linezolid (MIC50/MIC90 1/1 mg/L; 100.0% susceptible) demonstrated coverage against MRSA from both Europe and the USA (Table 2). Comparative analyses showed that oritavancin MIC results (MIC50/MIC90 0.03/0.06 mg/L) were at least 8-fold lower than the tested comparators for European and US isolates (Table 2). One MRSA isolate from the USA for which the vancomycin MIC value was 2 mg/L was oritavancin non-susceptible (MIC 0.25 mg/L; Table 1). Table 2. Comparative antimicrobial activity of oritavancin and comparator agents tested against the main organisms and organism groups of isolates causing infections in cancer patients in Europe and the USA Organism/resistance group (no. tested/antimicrobial agent)  MIC50 (mg/L)  MIC90 (mg/L)  MIC range (mg/L)  CLSIa, %S/%R or %NS  S. aureus   MSSA (409)    oritavancin  0.015  0.06  ≤0.008–0.12  100.0/0.0    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  0.25  >8  ≤0.12 to >8  79.7/15.9    clindamycin  ≤0.25  ≤0.25  ≤0.25 to >2  99.0/1.0    tetracycline  ≤0.5  ≤0.5  0.25–2  96.6/2.9    linezolid  1  1  ≤0.12 to >8  100.0/0.0    levofloxacin  ≤0.12  0.5  ≤0.12 to >4  93.4/6.6    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  99.5/0.5   MRSA (182)    oritavancin  0.03  0.06  ≤0.008–0.25  99.5/0.5    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2–4  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  25.3/72.5    clindamycin  ≤0.25  >2  ≤0.25 to >2  69.8/29.7    tetracycline  ≤0.5  ≤0.5  ≤0.5 to >8  96.7/3.3    linezolid  1  1  0.25–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  21.4/77.5    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  97.8/2.2   CoNS (195)b    oritavancin  0.03  0.06  0.004–0.25  –/–    vancomycin  1  2  0.25–2  100.0/0.0    teicoplanin  ≤2  4  ≤2–8  100.0/0.0    daptomycin  0.5  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  29.7/67.7    clindamycin  ≤0.25  >2  ≤0.25 to >2  70.8/28.7    tetracycline  ≤0.5  4  ≤0.5 to >8  90.3/8.2    linezolid  0.5  1  ≤0.12–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  33.3/61.5    trimethoprim/sulfamethoxazole  4  >4  ≤0.5 to >4  47.7/52.3  E. faecalis (139)   oritavancin  0.015  0.03  0.004–0.25  98.6/1.4a   ampicillin  1  1  ≤0.5–2  100.0/0.0   vancomycin  1  2  ≤0.5 to >16  97.8/2.2   teicoplanin  ≤2  ≤2  ≤2 to >16  97.8/2.2   daptomycin  1  1  0.5–4  100.0/0.0   linezolid  1  1  ≤0.25–2  100.0/0.0   levofloxacin  1  >4  ≤0.5 to >4  72.7/26.6   erythromycin  >16  >16  ≤0.12 to >16  8.4/52.6   tetracycline  >8  >8  ≤1 to >8  23.0/76.3  E. faecium (150)   oritavancin  0.008  0.06  0.001–0.25  –/–   ampicillin  >8  >8  ≤0.5 to >8  11.3/88.7   vancomycin  1  >16  ≤0.5 to >16  56.7/43.3   teicoplanin  ≤2  >16  ≤2 to >16  60.0/37.3   daptomycin  2  2  ≤0.25 to >8  99.3/0.7   linezolid  1  1  0.25–8  99.3/0.7   levofloxacin  >4  >4  ≤0.5 to >4  10.0/86.7   erythromycin  >16  >16  ≤0.12 to >16  5.7/79.0   tetracycline  >8  >8  ≤1 to >8  33.3/64.7  BHS (49)c   oritavancin  0.03  0.25  0.008–0.5  98.0/2.0   penicillin  ≤0.06  ≤0.06  ≤0.06  100.0/0.0   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.25  0.5  0.25–0.5  100.0/0.0   daptomycin  0.12  0.25  ≤0.06–0.5  100.0/0.0   erythromycin  ≤0.12  >4  ≤0.12 to >4  65.3/32.7   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.7/14.3   levofloxacin  0.5  1  0.25 to >4  98.0/2.0   tetracycline  >8  >8  ≤0.5 to >8  30.6/69.4   linezolid  1  1  0.5–2  100.0/0.0  VGS (126)d   oritavancin  0.015  0.12  ≤0.005–0.5  99.2/0.8   penicillin  0.12  2  ≤0.06 to >4  65.1/9.5   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.5  0.5  0.25–1  100.0/0.0   daptomycin  0.5  1  ≤0.06 to >2  99.1/0.9   erythromycin  1  >4  ≤0.12 to >4  46.0/51.6   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.3/15.1   levofloxacin  1  >4  ≤0.12 to >4  86.5/11.1   tetracycline  ≤0.5  >8  ≤0.5 to >8  62.7/33.3   linezolid  0.5  1  0.25–2  100.0/0.0  Organism/resistance group (no. tested/antimicrobial agent)  MIC50 (mg/L)  MIC90 (mg/L)  MIC range (mg/L)  CLSIa, %S/%R or %NS  S. aureus   MSSA (409)    oritavancin  0.015  0.06  ≤0.008–0.12  100.0/0.0    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  0.25  >8  ≤0.12 to >8  79.7/15.9    clindamycin  ≤0.25  ≤0.25  ≤0.25 to >2  99.0/1.0    tetracycline  ≤0.5  ≤0.5  0.25–2  96.6/2.9    linezolid  1  1  ≤0.12 to >8  100.0/0.0    levofloxacin  ≤0.12  0.5  ≤0.12 to >4  93.4/6.6    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  99.5/0.5   MRSA (182)    oritavancin  0.03  0.06  ≤0.008–0.25  99.5/0.5    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2–4  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  25.3/72.5    clindamycin  ≤0.25  >2  ≤0.25 to >2  69.8/29.7    tetracycline  ≤0.5  ≤0.5  ≤0.5 to >8  96.7/3.3    linezolid  1  1  0.25–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  21.4/77.5    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  97.8/2.2   CoNS (195)b    oritavancin  0.03  0.06  0.004–0.25  –/–    vancomycin  1  2  0.25–2  100.0/0.0    teicoplanin  ≤2  4  ≤2–8  100.0/0.0    daptomycin  0.5  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  29.7/67.7    clindamycin  ≤0.25  >2  ≤0.25 to >2  70.8/28.7    tetracycline  ≤0.5  4  ≤0.5 to >8  90.3/8.2    linezolid  0.5  1  ≤0.12–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  33.3/61.5    trimethoprim/sulfamethoxazole  4  >4  ≤0.5 to >4  47.7/52.3  E. faecalis (139)   oritavancin  0.015  0.03  0.004–0.25  98.6/1.4a   ampicillin  1  1  ≤0.5–2  100.0/0.0   vancomycin  1  2  ≤0.5 to >16  97.8/2.2   teicoplanin  ≤2  ≤2  ≤2 to >16  97.8/2.2   daptomycin  1  1  0.5–4  100.0/0.0   linezolid  1  1  ≤0.25–2  100.0/0.0   levofloxacin  1  >4  ≤0.5 to >4  72.7/26.6   erythromycin  >16  >16  ≤0.12 to >16  8.4/52.6   tetracycline  >8  >8  ≤1 to >8  23.0/76.3  E. faecium (150)   oritavancin  0.008  0.06  0.001–0.25  –/–   ampicillin  >8  >8  ≤0.5 to >8  11.3/88.7   vancomycin  1  >16  ≤0.5 to >16  56.7/43.3   teicoplanin  ≤2  >16  ≤2 to >16  60.0/37.3   daptomycin  2  2  ≤0.25 to >8  99.3/0.7   linezolid  1  1  0.25–8  99.3/0.7   levofloxacin  >4  >4  ≤0.5 to >4  10.0/86.7   erythromycin  >16  >16  ≤0.12 to >16  5.7/79.0   tetracycline  >8  >8  ≤1 to >8  33.3/64.7  BHS (49)c   oritavancin  0.03  0.25  0.008–0.5  98.0/2.0   penicillin  ≤0.06  ≤0.06  ≤0.06  100.0/0.0   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.25  0.5  0.25–0.5  100.0/0.0   daptomycin  0.12  0.25  ≤0.06–0.5  100.0/0.0   erythromycin  ≤0.12  >4  ≤0.12 to >4  65.3/32.7   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.7/14.3   levofloxacin  0.5  1  0.25 to >4  98.0/2.0   tetracycline  >8  >8  ≤0.5 to >8  30.6/69.4   linezolid  1  1  0.5–2  100.0/0.0  VGS (126)d   oritavancin  0.015  0.12  ≤0.005–0.5  99.2/0.8   penicillin  0.12  2  ≤0.06 to >4  65.1/9.5   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.5  0.5  0.25–1  100.0/0.0   daptomycin  0.5  1  ≤0.06 to >2  99.1/0.9   erythromycin  1  >4  ≤0.12 to >4  46.0/51.6   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.3/15.1   levofloxacin  1  >4  ≤0.12 to >4  86.5/11.1   tetracycline  ≤0.5  >8  ≤0.5 to >8  62.7/33.3   linezolid  0.5  1  0.25–2  100.0/0.0  % S, percentage susceptible; %R, percentage resistant; %NS, percentage non-susceptible. a Criteria as published by the CLSI (2016). Oritavancin susceptible-only breakpoints of ≤0.12 mg/L for S. aureus and vancomycin-susceptible isolates of E. faecalis (also applied to all E. faecalis, including three VRE) and of ≤0.25 mg/L for BHS species and S. anginosus group, which was applied to BHS and VGS. EUCAST (2016) criteria used for teicoplanin against BHS and VGS. Oritavancin MIC values that were greater than the susceptible breakpoints were deemed to be non-susceptible (NS) for discussion purposes. b Organisms include: Staphylococcus capitis (3), S. caprae (3), S. epidermidis (129), S. haemolyticus (36), S. hominis (20), S. lugdunensis (1), S. simulans (2) and S. warneri (1). c Organisms include: S. agalactiae (25), S. dysgalactiae (9) and S. pyogenes (15). d Organisms include: S. anginosus (13), S. anginosus group (1), S. australis (1), S. constellatus (4), S. cristatus (1), S. equinus (2), S. gallolyticus (1), S. gordonii (1), S. massiliensis (1), S. mitis (2), S. mitis group (27), S. mitis/oralis (30), S. oralis (18), S. parasanguinis (10), S. salivarius (7), S. salivarius/vestibularis (1), S. sanguinis (4), S. sobrinus (1) and S. vestibularis (1). CoNS isolates from the USA demonstrated an MIC90 of oritavancin (0.12 mg/L) that was slightly higher than the MIC90 value for isolates from European countries (0.06 mg/L; Table 1). A total of 77.5% and 75.0% of CoNS from Europe and the USA, respectively, were methicillin resistant (data not shown). Overall, vancomycin, daptomycin, teicoplanin, tetracycline and linezolid demonstrated activity in vitro against CoNS while other comparators had limited coverage (29.7%–70.8% susceptible). These results were similar for European and US organism collections. Oritavancin showed comparable activity against Enterococcus faecalis from Europe (MIC50/MIC90 0.015/0.06 mg/L; 100.0% susceptible) and the USA (MIC50/MIC90 0.015/0.03 mg/L; 97.6% susceptible), inhibiting all vancomycin-susceptible isolates at the CLSI breakpoint for susceptibility (≤0.12 mg/L for vancomycin-susceptible E. faecalis) and all E. faecalis, including three VRE at ≤0.25 mg/L (Tables 1 and 2). E. faecalis isolates (2.2% VanA phenotype) from both regions were very susceptible (97.8%−100.0% susceptible) to ampicillin, daptomycin, vancomycin, teicoplanin and linezolid (Table 2). These comparators had MIC50 results (all MIC50 values ≤2 mg/L) that were at least 64-fold higher than those obtained for oritavancin (MIC50 0.015 mg/L). All E. faecium isolates (43.3% VRE; 69.1% in the USA and 22.0% in Europe) were inhibited by oritavancin at ≤0.25 mg/L. Higher MIC results were noted for oritavancin when tested against E. faecium from the USA (MIC50/MIC90 0.015/0.12 mg/L) versus Europe (MIC50/MIC90 0.004/0.015 mg/L) (Table 1). Daptomycin and linezolid showed coverage against E. faecium, including VRE isolates (Table 2). Oritavancin exhibited MIC50 results of 0.03 and 0.015 mg/L when tested against BHS and VGS isolates, respectively, regardless of geographical region (Tables 1 and 2). Two isolates (one BHS and one VGS) were non-susceptible (MIC 0.5 mg/L) to oritavancin. Other agents, such as penicillin, vancomycin, teicoplanin, daptomycin, linezolid and levofloxacin, demonstrated antimicrobial coverage (≥98.0% susceptible) against BHS (Table 2). When tested against VGS, oritavancin, teicoplanin, vancomycin, daptomycin and linezolid were all highly active (Table 2). Discussion Infection represents an important cause of increased morbidity and mortality in patients with cancer and early introduction of appropriate antimicrobial therapy is essential for patient survival.1–3,5 The spectrum of bacterial infections in both neutropenic and non-neutropenic cancer patients is known to undergo periodic changes that may be influenced by a number of factors, including antibacterial (fluoroquinolone) prophylaxis, the use of vascular access devices and intensive chemotherapy with attendant mucositis.1–3,5 Importantly, the negative effects of fluoroquinolone use in this patient population are not limited to the emergence of fluoroquinolone-resistant strains of Escherichia coli and other Gram-negative organisms but include the potential selection for many resistant GPC, most notably MRSA and VRE.3,4,13,14 Other reports document the selection of VGS with decreased susceptibility to fluoroquinolones in patients receiving levofloxacin prophylaxis.15 Studies have revealed higher mortality rates for infections caused by MRSA and VRE in cancer patients, most likely related to the severity of these infections, immunocompromised status due to chemotherapy and to delays in appropriate antimicrobial therapy.16,17 Although vancomycin remains the primary agent for treating documented infections due to MDR strains of GPC, it is far from optimal and increasing MICs among MRSA isolates have been shown to be an independent predictor of mortality in cancer patients with bloodstream infections due to MRSA.18 Thus, although promptly initiating antimicrobial agents that retain activity against the infecting organism is crucial for survival, therapeutic options for infections caused by MDR GPC may be very limited in some institutions or geographical areas.19 Recent studies by Rolston et al.20 documented the importance of GPC in cancer patients and suggested the use of bactericidal alternatives to vancomycin in this patient population. We evaluated a large collection of GPC isolated from patients with cancer from 51 European and US medical centres. The results of this investigation highlight the main problems of antimicrobial resistance affecting these patients and indicate that oritavancin represents a potential option for the treatment of serious GPC infections, including those caused by MRSA and VRE, in patients with cancer in European and US medical centres. Overall, 99.9% of S. aureus and vancomycin-susceptible E. faecalis and 98.9% of streptococci were susceptible to oritavancin at ≤0.12 and ≤0.25 mg/L, respectively. Oritavancin coverage against this GPC collection was comparable to that of other GPC agents, including daptomycin, linezolid, teicoplanin and vancomycin, while oritavancin, daptomycin and linezolid demonstrated activity against VRE, including VanA-type VRE. Results presented here provide invaluable information on the antimicrobial resistance profile of GPC isolates causing infections in patients with cancer and indicate that oritavancin exhibits potent activity against aerobic GPC, including MRSA and VRE, isolated from cancer patients hospitalized in European and US medical centres. These results build on the findings of Rolston et al.20 regarding the potential role of the lipoglycopeptides as alternatives to vancomycin in the treatment of infections due to GPC in patients with cancer. Whether single-dose oritavancin can optimize healthcare resource utilization, reduce treatment costs or improve convenience for ABSSSIs in patients with cancer compared with multi-dose, multi-day therapies remain to be demonstrated in clinical studies. Acknowledgements We express appreciation to the following persons for significant contributions to this manuscript (technical support and/or manuscript assistance): R. Arends, L. Duncan, L. Flanigan, M. Huband, M. Janechek, J. Oberholser, P. Rhomberg, J. Schuchert, J. Streit and L. Woosley. Funding This surveillance study was sponsored by a research grant from The Medicines Company (Parsippany, NJ, USA) via the SENTRY Antimicrobial Surveillance Program platform. JMI Laboratories also received compensation fees from The Medicines Company for services with regards to manuscript preparation. The Medicines Company was not involved in the collection, analysis or interpretation of data. Transparency declarations JMI Laboratories contracted to perform services for Achaogen, Actelion, Allecra Therapeutics, Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare. References 1 Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection  2014; 42: 5– 13. Google Scholar CrossRef Search ADS PubMed  2 Freifeld AG, Bow EJ, Sepkowitz KA et al.   Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis  2011; 52: e56– 93. Google Scholar CrossRef Search ADS PubMed  3 Mikulska M, Viscoli C, Orasch C et al.   Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect  2014; 68: 321– 31. Google Scholar CrossRef Search ADS PubMed  4 Rolston KV, Yadegarynia D, Kontoyiannis DP et al.   The spectrum of Gram-positive bloodstream infections in patients with hematologic malignancies, and the in vitro activity of various quinolones against Gram-positive bacteria isolated from cancer patients. Int J Infect Dis  2006; 10: 223– 30. Google Scholar CrossRef Search ADS PubMed  5 Rolston KV. Infections in cancer patients with solid tumors: a review. Infect Dis Ther  2017; 6: 69– 83. Google Scholar CrossRef Search ADS PubMed  6 Kara O, Zarakolu P, Ascioglu S et al.   Epidemiology and emerging resistance in bacterial bloodstream infections in patients with hematologic malignancies. Infect Dis (Lond)  2015; 47: 686– 93. Google Scholar CrossRef Search ADS PubMed  7 Brade KD, Rybak JM, Rybak MJ. Oritavancin: a new lipoglycopeptide antibiotic in the treatment of Gram-positive infections. Infect Dis Ther  2016; 5: 1– 15. Google Scholar CrossRef Search ADS PubMed  8 Mendes RE, Castanheira M, Farrell DJ et al.   Longitudinal (2001–14) analysis of enterococci and VRE causing invasive infections in European and US hospitals, including a contemporary (2010–13) analysis of oritavancin in vitro potency. J Antimicrob Chemother  2016; 71: 3453– 8. Google Scholar CrossRef Search ADS PubMed  9 Mendes RE, Farrell DJ, Sader HS et al.   Activity of oritavancin against Gram-positive clinical isolates responsible for documented skin and soft-tissue infections in European and US hospitals (2010–13). J Antimicrob Chemother  2015; 70: 498– 504. Google Scholar CrossRef Search ADS PubMed  10 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Tenth Edition: Approved Standard M07-A10 . CLSI, Wayne, PA, USA, 2015. 11 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement M100-S27 . CLSI, Wayne, PA, USA, 2017. 12 EUCAST. Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 7.1. 2017. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_7.1_Breakpoint_Tables.pdf. 13 Chiang HY, Perencevich EN, Nair R et al.   Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review and meta-analysis. Infect Control Hosp Epidemiol  2017; 38: 203– 15. Google Scholar CrossRef Search ADS PubMed  14 Kang CI, Song JH, Chung DR et al.   Bloodstream infections in adult patients with cancer: clinical features and pathogenic significance of Staphylococcus aureus bacteremia. Support Care Cancer  2012; 20: 2371– 8. Google Scholar CrossRef Search ADS PubMed  15 Razonable RR, Litzow MR, Khaliq Y et al.   Bacteremia due to viridans group streptococci with diminished susceptibility to levofloxacin among neutropenic patients receiving levofloxacin prophylaxis. Clin Infect Dis  2002; 34: 1469– 74. Google Scholar CrossRef Search ADS PubMed  16 Patel G, Huprikar S, Factor SH et al.   Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol  2008; 29: 1099– 106. Google Scholar CrossRef Search ADS PubMed  17 Tumbarello M, Sanguinetti M, Montuori E et al.   Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother  2007; 51: 1987– 94. Google Scholar CrossRef Search ADS PubMed  18 Mahajan SN, Shah JN, Hachem R et al.   Characteristics and outcomes of methicillin-resistant Staphylococcus aureus bloodstream infections in patients with cancer treated with vancomycin: 9-year experience at a comprehensive cancer center. Oncologist  2012; 17: 1329– 36. Google Scholar CrossRef Search ADS PubMed  19 Boucher HW, Talbot GH, Benjamin DKJr et al.   10 × '20 progress—development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis  2013; 56: 1685– 94. Google Scholar CrossRef Search ADS PubMed  20 Rolston KV, Jamal MA, Nesher L et al.   In vitro activity of ceftaroline and comparator agents against Gram-positive and Gram-negative clinical isolates from cancer patients. Int J Antimicrob Agents  2017; 49: 416– 21. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Antimicrobial activity of oritavancin and comparator agents when tested against Gram-positive bacterial isolates causing infections in cancer patients (2014–16)

Loading next page...
 
/lp/ou_press/antimicrobial-activity-of-oritavancin-and-comparator-agents-when-yK0V2boCCq
Publisher
Oxford University Press
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dkx485
Publisher site
See Article on Publisher Site

Abstract

Abstract Objectives The in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals. Methods A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%). Results Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015–0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008–0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region. Conclusions Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients. Introduction Infections remain a significant cause of morbidity and mortality among cancer patients.1 Although the epidemiology of isolates obtained from cancer patients has fluctuated over the past decades, Gram-positive cocci (GPC) remain the predominant pathogens in neutropenic and non-neutropenic cancer patients, although some institutions are reporting a resurgence of Gram-negative infections.2–4 Infections in cancer patients are predominantly caused by MRSA, MSSA, methicillin-resistant CoNS, VRE and viridans group streptococci (VGS),1,3,5 likely due to the widespread use of vascular catheters, ports and other foreign devices, intensive chemotherapy resulting in extensive oral and intestinal mucositis, and antimicrobial prophylaxis directed primarily at Enterobacteriaceae.4,6 Although fluoroquinolone prophylaxis has substantially reduced Gram-negative infections among neutropenic cancer patients,2 these agents have poor activity against most GPC and the emergence of fluoroquinolone-resistant isolates has led to many cancer centres discontinuing this practice.2,4 Oritavancin belongs to the lipoglycopeptide class of antimicrobial agents and acts by interrupting bacterial cell wall synthesis, in addition to disrupting cell membrane integrity, resulting in bacterial death.7 Oritavancin was approved in the USA (2014) and in Europe (2015) for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs).7 This drug demonstrates potent in vitro activity against Staphylococcus aureus (including MRSA), streptococci and enterococci. In addition, oritavancin remains potent against VRE.8,9 The present report describes oritavancin in vitro activity and potency against a GPC collection (2014–16) responsible for infections in a cancer patient population (haematology–oncology) in US and European medical centres. Methods Bacterial isolates A total of 1357 GPC were collected from patients hospitalized in the oncology units of 26 sites in Europe (Belgium, France, Germany, Ireland, Italy, Spain, Sweden and the UK), Ukraine Israel, Russia, Turkey and 25 institutions in the USA. Isolates were consecutively collected (one per patient episode) between January 2014 and December 2016 as part of the SENTRY Antimicrobial Surveillance Program. Only isolates deemed clinically significant by local criteria from patients with cancer were included. These pathogens were submitted to the coordinating monitoring laboratory (JMI Laboratories, North Liberty, IA, USA), where bacterial identifications for staphylococci and enterococci were confirmed by standard algorithms and/or MALDI-TOF MS (Bruker Daltonics, Bremen, Germany). All streptococci were subjected to MALDI-TOF MS. Antimicrobial susceptibility testing Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A10 document.10 Quality assurance was performed by concurrently testing CLSI-recommended strains.11 CLSI- and EUCAST-approved interpretive breakpoint criteria were applied (see footnote of Table 2).11,12 Results Isolates were predominantly from bloodstream infections (54.6%), skin and skin structure infections (20.9%), pneumonia (14.8%), intra-abdominal infections (4.6%) and urinary tract infections (3.0%). The most frequently isolated GPC were S. aureus (43.6%), followed by CoNS (14.4%), Enterococcus spp. (22.0%), VGS (9.3%) and β-haemolytic streptococci (BHS) (3.6%). The key resistant phenotypes differed considerably between US and European sites: MRSA, 39.9%/21.2% (USA/Europe); VRE (Enterococcus faecium), 69.1%/22.0%; and penicillin-resistant VGS, 14.3%/3.6% (Table 1). Table 1. Antimicrobial activity of oritavancin tested against the main organisms and organism groups of isolates causing infections in cancer patients in Europe and the USA Organism/organism group (no. of isolates)  No. of isolates at MIC in mg/L (cumulative %)   MIC50  MIC90  ≤0.0005  0.001  0.002  0.004  0.008  0.015  0.03  0.06  0.12  0.25  0.5  Europe   S. aureus (288)          14  131  103  32  8      0.015  0.06  4.9  50.3  86.1  97.2  100.0    MSSA (227)          12  108  76  25  6      0.015  0.06  5.3  52.9  86.3  97.4  100.0    MRSA (61)          2  23  27  7  2      0.03  0.06  3.3  41.0  85.2  96.7  100.0   CoNS (111)a        1  9  19  45  33  4      0.03  0.06  0.9  9.0  26.1  66.7  96.4  100.0   E. faecalis (57)b        3  18  20  9  5  2      0.015  0.06  5.3  36.8  71.9  87.7  96.5  100.0   E. faecium (82)    1  12  35  12  14  5  1  1  1    0.004  0.015  1.2  15.9  58.5  73.2  90.2  96.3  97.6  98.8  100.0    vancomycin susceptible (64)    1  10  33  10  10            0.004  0.015  1.6  17.2  68.8  84.4  100.0    vancomycin non-susceptible (18)c      2  2  2  4  5  1  1  1    0.015  0.12  11.1  22.2  33.3  55.6  83.3  88.9  94.4  100.0   BHS (15)          2  0  6  3  2  2    0.03  0.25  13.3  13.3  53.3  73.3  86.7  100.0    Streptococcus agalactiae (7)              4  2  0  1    0.03  –  57.1  85.7  85.7  100.0    Streptococcus pyogenes (3)          1  0  1  1        0.03  –  33.3  33.3  66.7  100.0    Streptococcus dysgalactiae (5)          1  0  1  0  2  1    0.12  –  20.0  20.0  40.0  40.0  80.0  100.0   VGS (56)d  1  1  5  9  9  7  8  9  1  6    0.015  0.25  1.8  3.6  12.5  28.6  44.6  57.1  71.4  87.5  89.3  100.0    Streptococcus anginosus group (10)      2  2  3  0  3          0.008  0.03  20.0  40.0  70.0  70.0  100.0  USA   S. aureus (303)          25  161  82  30  4  1    0.015  0.06  8.3  61.4  88.4  98.3  99.7  100.0    MSSA (182)          15  106  43  16  2      0.015  0.03  8.2  66.5  90.1  98.9  100.0    MRSA (121)          10  55  39  14  2  1    0.015  0.06  8.3  53.7  86.0  97.5  99.2  100.0   CoNS (84)e        1  8  9  34  21  10  1    0.03  0.12  1.2  10.7  21.4  61.9  86.9  98.8  100.0   E. faecalis (82)f        6  22  38  11  2  1  2    0.015  0.03  7.3  34.1  80.5  93.9  96.3  97.6  100.0   E. faecium (68)      1  13  7  15  12  13  7      0.015  0.12  1.5  20.6  30.9  52.9  70.6  89.7  100.0    vancomycin susceptible (21)      1  12  5  3            0.004  0.015  4.8  61.9  85.7  100.0    vancomycin non-susceptible (47)g        1  2  12  12  13  7      0.03  0.12  2.1  6.4  31.9  57.4  85.1  100.0   BHS (34)          4  9  6  5  5  4  1  0.03  0.25  11.8  38.2  55.9  70.6  85.3  97.1  100.0    S. agalactiae (18)          3  6  5  2  1  1    0.015  0.12  16.7  50.0  77.8  88.9  94.4  100.0    S. pyogenes (12)          1  3  1  3  4      0.06  0.12  8.3  33.3  41.7  66.7  100.0    S. dysgalactiae (4)                    3  1  0.25  –  75.0  100.0   VGS (70)h  4  2  6  10  15  9  10  8  2  3  1  0.008  0.06  5.7  8.6  17.1  31.4  52.9  65.7  80.0  91.4  94.3  98.6  100.0    S. anginosus group (8)      2  0  4  1  1          0.008  –  25.0  25.0  75.0  87.5  100.0  Organism/organism group (no. of isolates)  No. of isolates at MIC in mg/L (cumulative %)   MIC50  MIC90  ≤0.0005  0.001  0.002  0.004  0.008  0.015  0.03  0.06  0.12  0.25  0.5  Europe   S. aureus (288)          14  131  103  32  8      0.015  0.06  4.9  50.3  86.1  97.2  100.0    MSSA (227)          12  108  76  25  6      0.015  0.06  5.3  52.9  86.3  97.4  100.0    MRSA (61)          2  23  27  7  2      0.03  0.06  3.3  41.0  85.2  96.7  100.0   CoNS (111)a        1  9  19  45  33  4      0.03  0.06  0.9  9.0  26.1  66.7  96.4  100.0   E. faecalis (57)b        3  18  20  9  5  2      0.015  0.06  5.3  36.8  71.9  87.7  96.5  100.0   E. faecium (82)    1  12  35  12  14  5  1  1  1    0.004  0.015  1.2  15.9  58.5  73.2  90.2  96.3  97.6  98.8  100.0    vancomycin susceptible (64)    1  10  33  10  10            0.004  0.015  1.6  17.2  68.8  84.4  100.0    vancomycin non-susceptible (18)c      2  2  2  4  5  1  1  1    0.015  0.12  11.1  22.2  33.3  55.6  83.3  88.9  94.4  100.0   BHS (15)          2  0  6  3  2  2    0.03  0.25  13.3  13.3  53.3  73.3  86.7  100.0    Streptococcus agalactiae (7)              4  2  0  1    0.03  –  57.1  85.7  85.7  100.0    Streptococcus pyogenes (3)          1  0  1  1        0.03  –  33.3  33.3  66.7  100.0    Streptococcus dysgalactiae (5)          1  0  1  0  2  1    0.12  –  20.0  20.0  40.0  40.0  80.0  100.0   VGS (56)d  1  1  5  9  9  7  8  9  1  6    0.015  0.25  1.8  3.6  12.5  28.6  44.6  57.1  71.4  87.5  89.3  100.0    Streptococcus anginosus group (10)      2  2  3  0  3          0.008  0.03  20.0  40.0  70.0  70.0  100.0  USA   S. aureus (303)          25  161  82  30  4  1    0.015  0.06  8.3  61.4  88.4  98.3  99.7  100.0    MSSA (182)          15  106  43  16  2      0.015  0.03  8.2  66.5  90.1  98.9  100.0    MRSA (121)          10  55  39  14  2  1    0.015  0.06  8.3  53.7  86.0  97.5  99.2  100.0   CoNS (84)e        1  8  9  34  21  10  1    0.03  0.12  1.2  10.7  21.4  61.9  86.9  98.8  100.0   E. faecalis (82)f        6  22  38  11  2  1  2    0.015  0.03  7.3  34.1  80.5  93.9  96.3  97.6  100.0   E. faecium (68)      1  13  7  15  12  13  7      0.015  0.12  1.5  20.6  30.9  52.9  70.6  89.7  100.0    vancomycin susceptible (21)      1  12  5  3            0.004  0.015  4.8  61.9  85.7  100.0    vancomycin non-susceptible (47)g        1  2  12  12  13  7      0.03  0.12  2.1  6.4  31.9  57.4  85.1  100.0   BHS (34)          4  9  6  5  5  4  1  0.03  0.25  11.8  38.2  55.9  70.6  85.3  97.1  100.0    S. agalactiae (18)          3  6  5  2  1  1    0.015  0.12  16.7  50.0  77.8  88.9  94.4  100.0    S. pyogenes (12)          1  3  1  3  4      0.06  0.12  8.3  33.3  41.7  66.7  100.0    S. dysgalactiae (4)                    3  1  0.25  –  75.0  100.0   VGS (70)h  4  2  6  10  15  9  10  8  2  3  1  0.008  0.06  5.7  8.6  17.1  31.4  52.9  65.7  80.0  91.4  94.3  98.6  100.0    S. anginosus group (8)      2  0  4  1  1          0.008  –  25.0  25.0  75.0  87.5  100.0  a Organisms include: Staphylococcus capitis (3), Staphylococcus caprae (1), Staphylococcus epidermidis (64), Staphylococcus haemolyticus (30) and Staphylococcus hominis (13). b All vancomycin susceptible. c Includes 15 isolates displaying a VanA phenotype (vancomycin and teicoplanin MIC at >4 and >8 mg/L, respectively) and 3 isolates with a VanB phenotype (vancomycin and teicoplanin MIC at >4 and ≤8 mg/L, respectively). d Organisms include: S. anginosus (9), Streptococcus constellatus (1), Streptococcus equinus (1), Streptococcus gallolyticus (1), Streptococcus gordonii (1), Streptococcus massiliensis (1), Streptococcus mitis group (12), Streptococcus mitis/oralis (9), Streptococcus oralis (9), Streptococcus parasanguinis (4), Streptococcus salivarius (5), Streptococcus salivarius/vestibularis (1) and Streptococcus sanguinis (2). e Organisms include: Staphylococcus caprae (2), S. epidermidis (65), S. haemolyticus (6), S. hominis (7), Staphylococcus lugdunensis (1), Staphylococcus simulans (2) and Staphylococcus warneri (1). f Three isolates with a VanA phenotype displaying oritavancin MIC values of 0.12–0.25 mg/L. g Includes 45 isolates with a VanA phenotype and 2 isolates with a VanB phenotype. h Organisms include: S. anginosus (4), S. anginosus group (1), Streptococcus australis (1), S. constellatus (3), Streptococcus cristatus (1), S. equinus (1), S. mitis (2), S. mitis group (15), S. mitis/oralis (21), S. oralis (9), S. parasanguinis (6), S. salivarius (2), S. sanguinis (2), Streptococcus sobrinus (1) and Streptococcus vestibularis (1). Table 1 shows the oritavancin MIC50/MIC90 results and the MIC distributions for US and European isolates. The MIC90 values ranged from 0.015 to 0.25 mg/L for the different species and were comparable for European and US isolates. The MIC values were ≤0.25 mg/L for all but 2 (both streptococci) of the 1357 isolates. Oritavancin showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015–0.03 and 0.06 mg/L for S. aureus, regardless of the methicillin susceptibility phenotype or geographical region (99.8% of European and US isolates were inhibited at ≤0.12 mg/L) (Tables 1 and 2). Oritavancin (MIC50/MIC90 0.03/0.06 mg/L; 99.5% susceptible) and comparator agents such as daptomycin (MIC50/MIC90 0.25/0.5 mg/L; 100.0% susceptible), vancomycin (MIC50/MIC90, 0.5/1 mg/L; 100.0% susceptible), teicoplanin (MIC50/MIC90 ≤2/≤2 mg/L; 100.0% susceptible), trimethoprim/sulfamethoxazole (MIC50/MIC90 ≤0.5/≤0.5 mg/L; 97.8% susceptible) and linezolid (MIC50/MIC90 1/1 mg/L; 100.0% susceptible) demonstrated coverage against MRSA from both Europe and the USA (Table 2). Comparative analyses showed that oritavancin MIC results (MIC50/MIC90 0.03/0.06 mg/L) were at least 8-fold lower than the tested comparators for European and US isolates (Table 2). One MRSA isolate from the USA for which the vancomycin MIC value was 2 mg/L was oritavancin non-susceptible (MIC 0.25 mg/L; Table 1). Table 2. Comparative antimicrobial activity of oritavancin and comparator agents tested against the main organisms and organism groups of isolates causing infections in cancer patients in Europe and the USA Organism/resistance group (no. tested/antimicrobial agent)  MIC50 (mg/L)  MIC90 (mg/L)  MIC range (mg/L)  CLSIa, %S/%R or %NS  S. aureus   MSSA (409)    oritavancin  0.015  0.06  ≤0.008–0.12  100.0/0.0    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  0.25  >8  ≤0.12 to >8  79.7/15.9    clindamycin  ≤0.25  ≤0.25  ≤0.25 to >2  99.0/1.0    tetracycline  ≤0.5  ≤0.5  0.25–2  96.6/2.9    linezolid  1  1  ≤0.12 to >8  100.0/0.0    levofloxacin  ≤0.12  0.5  ≤0.12 to >4  93.4/6.6    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  99.5/0.5   MRSA (182)    oritavancin  0.03  0.06  ≤0.008–0.25  99.5/0.5    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2–4  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  25.3/72.5    clindamycin  ≤0.25  >2  ≤0.25 to >2  69.8/29.7    tetracycline  ≤0.5  ≤0.5  ≤0.5 to >8  96.7/3.3    linezolid  1  1  0.25–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  21.4/77.5    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  97.8/2.2   CoNS (195)b    oritavancin  0.03  0.06  0.004–0.25  –/–    vancomycin  1  2  0.25–2  100.0/0.0    teicoplanin  ≤2  4  ≤2–8  100.0/0.0    daptomycin  0.5  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  29.7/67.7    clindamycin  ≤0.25  >2  ≤0.25 to >2  70.8/28.7    tetracycline  ≤0.5  4  ≤0.5 to >8  90.3/8.2    linezolid  0.5  1  ≤0.12–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  33.3/61.5    trimethoprim/sulfamethoxazole  4  >4  ≤0.5 to >4  47.7/52.3  E. faecalis (139)   oritavancin  0.015  0.03  0.004–0.25  98.6/1.4a   ampicillin  1  1  ≤0.5–2  100.0/0.0   vancomycin  1  2  ≤0.5 to >16  97.8/2.2   teicoplanin  ≤2  ≤2  ≤2 to >16  97.8/2.2   daptomycin  1  1  0.5–4  100.0/0.0   linezolid  1  1  ≤0.25–2  100.0/0.0   levofloxacin  1  >4  ≤0.5 to >4  72.7/26.6   erythromycin  >16  >16  ≤0.12 to >16  8.4/52.6   tetracycline  >8  >8  ≤1 to >8  23.0/76.3  E. faecium (150)   oritavancin  0.008  0.06  0.001–0.25  –/–   ampicillin  >8  >8  ≤0.5 to >8  11.3/88.7   vancomycin  1  >16  ≤0.5 to >16  56.7/43.3   teicoplanin  ≤2  >16  ≤2 to >16  60.0/37.3   daptomycin  2  2  ≤0.25 to >8  99.3/0.7   linezolid  1  1  0.25–8  99.3/0.7   levofloxacin  >4  >4  ≤0.5 to >4  10.0/86.7   erythromycin  >16  >16  ≤0.12 to >16  5.7/79.0   tetracycline  >8  >8  ≤1 to >8  33.3/64.7  BHS (49)c   oritavancin  0.03  0.25  0.008–0.5  98.0/2.0   penicillin  ≤0.06  ≤0.06  ≤0.06  100.0/0.0   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.25  0.5  0.25–0.5  100.0/0.0   daptomycin  0.12  0.25  ≤0.06–0.5  100.0/0.0   erythromycin  ≤0.12  >4  ≤0.12 to >4  65.3/32.7   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.7/14.3   levofloxacin  0.5  1  0.25 to >4  98.0/2.0   tetracycline  >8  >8  ≤0.5 to >8  30.6/69.4   linezolid  1  1  0.5–2  100.0/0.0  VGS (126)d   oritavancin  0.015  0.12  ≤0.005–0.5  99.2/0.8   penicillin  0.12  2  ≤0.06 to >4  65.1/9.5   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.5  0.5  0.25–1  100.0/0.0   daptomycin  0.5  1  ≤0.06 to >2  99.1/0.9   erythromycin  1  >4  ≤0.12 to >4  46.0/51.6   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.3/15.1   levofloxacin  1  >4  ≤0.12 to >4  86.5/11.1   tetracycline  ≤0.5  >8  ≤0.5 to >8  62.7/33.3   linezolid  0.5  1  0.25–2  100.0/0.0  Organism/resistance group (no. tested/antimicrobial agent)  MIC50 (mg/L)  MIC90 (mg/L)  MIC range (mg/L)  CLSIa, %S/%R or %NS  S. aureus   MSSA (409)    oritavancin  0.015  0.06  ≤0.008–0.12  100.0/0.0    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  0.25  >8  ≤0.12 to >8  79.7/15.9    clindamycin  ≤0.25  ≤0.25  ≤0.25 to >2  99.0/1.0    tetracycline  ≤0.5  ≤0.5  0.25–2  96.6/2.9    linezolid  1  1  ≤0.12 to >8  100.0/0.0    levofloxacin  ≤0.12  0.5  ≤0.12 to >4  93.4/6.6    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  99.5/0.5   MRSA (182)    oritavancin  0.03  0.06  ≤0.008–0.25  99.5/0.5    vancomycin  0.5  1  0.25–2  100.0/0.0    teicoplanin  ≤2  ≤2  ≤2–4  100.0/0.0    daptomycin  0.25  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  25.3/72.5    clindamycin  ≤0.25  >2  ≤0.25 to >2  69.8/29.7    tetracycline  ≤0.5  ≤0.5  ≤0.5 to >8  96.7/3.3    linezolid  1  1  0.25–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  21.4/77.5    trimethoprim/sulfamethoxazole  ≤0.5  ≤0.5  ≤0.5 to >4  97.8/2.2   CoNS (195)b    oritavancin  0.03  0.06  0.004–0.25  –/–    vancomycin  1  2  0.25–2  100.0/0.0    teicoplanin  ≤2  4  ≤2–8  100.0/0.0    daptomycin  0.5  0.5  ≤0.12–1  100.0/0.0    erythromycin  >8  >8  ≤0.12 to >8  29.7/67.7    clindamycin  ≤0.25  >2  ≤0.25 to >2  70.8/28.7    tetracycline  ≤0.5  4  ≤0.5 to >8  90.3/8.2    linezolid  0.5  1  ≤0.12–2  100.0/0.0    levofloxacin  >4  >4  ≤0.12 to >4  33.3/61.5    trimethoprim/sulfamethoxazole  4  >4  ≤0.5 to >4  47.7/52.3  E. faecalis (139)   oritavancin  0.015  0.03  0.004–0.25  98.6/1.4a   ampicillin  1  1  ≤0.5–2  100.0/0.0   vancomycin  1  2  ≤0.5 to >16  97.8/2.2   teicoplanin  ≤2  ≤2  ≤2 to >16  97.8/2.2   daptomycin  1  1  0.5–4  100.0/0.0   linezolid  1  1  ≤0.25–2  100.0/0.0   levofloxacin  1  >4  ≤0.5 to >4  72.7/26.6   erythromycin  >16  >16  ≤0.12 to >16  8.4/52.6   tetracycline  >8  >8  ≤1 to >8  23.0/76.3  E. faecium (150)   oritavancin  0.008  0.06  0.001–0.25  –/–   ampicillin  >8  >8  ≤0.5 to >8  11.3/88.7   vancomycin  1  >16  ≤0.5 to >16  56.7/43.3   teicoplanin  ≤2  >16  ≤2 to >16  60.0/37.3   daptomycin  2  2  ≤0.25 to >8  99.3/0.7   linezolid  1  1  0.25–8  99.3/0.7   levofloxacin  >4  >4  ≤0.5 to >4  10.0/86.7   erythromycin  >16  >16  ≤0.12 to >16  5.7/79.0   tetracycline  >8  >8  ≤1 to >8  33.3/64.7  BHS (49)c   oritavancin  0.03  0.25  0.008–0.5  98.0/2.0   penicillin  ≤0.06  ≤0.06  ≤0.06  100.0/0.0   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.25  0.5  0.25–0.5  100.0/0.0   daptomycin  0.12  0.25  ≤0.06–0.5  100.0/0.0   erythromycin  ≤0.12  >4  ≤0.12 to >4  65.3/32.7   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.7/14.3   levofloxacin  0.5  1  0.25 to >4  98.0/2.0   tetracycline  >8  >8  ≤0.5 to >8  30.6/69.4   linezolid  1  1  0.5–2  100.0/0.0  VGS (126)d   oritavancin  0.015  0.12  ≤0.005–0.5  99.2/0.8   penicillin  0.12  2  ≤0.06 to >4  65.1/9.5   teicoplanin  ≤2  ≤2  ≤2  100.0/0.0a   vancomycin  0.5  0.5  0.25–1  100.0/0.0   daptomycin  0.5  1  ≤0.06 to >2  99.1/0.9   erythromycin  1  >4  ≤0.12 to >4  46.0/51.6   clindamycin  ≤0.25  >2  ≤0.25 to >2  83.3/15.1   levofloxacin  1  >4  ≤0.12 to >4  86.5/11.1   tetracycline  ≤0.5  >8  ≤0.5 to >8  62.7/33.3   linezolid  0.5  1  0.25–2  100.0/0.0  % S, percentage susceptible; %R, percentage resistant; %NS, percentage non-susceptible. a Criteria as published by the CLSI (2016). Oritavancin susceptible-only breakpoints of ≤0.12 mg/L for S. aureus and vancomycin-susceptible isolates of E. faecalis (also applied to all E. faecalis, including three VRE) and of ≤0.25 mg/L for BHS species and S. anginosus group, which was applied to BHS and VGS. EUCAST (2016) criteria used for teicoplanin against BHS and VGS. Oritavancin MIC values that were greater than the susceptible breakpoints were deemed to be non-susceptible (NS) for discussion purposes. b Organisms include: Staphylococcus capitis (3), S. caprae (3), S. epidermidis (129), S. haemolyticus (36), S. hominis (20), S. lugdunensis (1), S. simulans (2) and S. warneri (1). c Organisms include: S. agalactiae (25), S. dysgalactiae (9) and S. pyogenes (15). d Organisms include: S. anginosus (13), S. anginosus group (1), S. australis (1), S. constellatus (4), S. cristatus (1), S. equinus (2), S. gallolyticus (1), S. gordonii (1), S. massiliensis (1), S. mitis (2), S. mitis group (27), S. mitis/oralis (30), S. oralis (18), S. parasanguinis (10), S. salivarius (7), S. salivarius/vestibularis (1), S. sanguinis (4), S. sobrinus (1) and S. vestibularis (1). CoNS isolates from the USA demonstrated an MIC90 of oritavancin (0.12 mg/L) that was slightly higher than the MIC90 value for isolates from European countries (0.06 mg/L; Table 1). A total of 77.5% and 75.0% of CoNS from Europe and the USA, respectively, were methicillin resistant (data not shown). Overall, vancomycin, daptomycin, teicoplanin, tetracycline and linezolid demonstrated activity in vitro against CoNS while other comparators had limited coverage (29.7%–70.8% susceptible). These results were similar for European and US organism collections. Oritavancin showed comparable activity against Enterococcus faecalis from Europe (MIC50/MIC90 0.015/0.06 mg/L; 100.0% susceptible) and the USA (MIC50/MIC90 0.015/0.03 mg/L; 97.6% susceptible), inhibiting all vancomycin-susceptible isolates at the CLSI breakpoint for susceptibility (≤0.12 mg/L for vancomycin-susceptible E. faecalis) and all E. faecalis, including three VRE at ≤0.25 mg/L (Tables 1 and 2). E. faecalis isolates (2.2% VanA phenotype) from both regions were very susceptible (97.8%−100.0% susceptible) to ampicillin, daptomycin, vancomycin, teicoplanin and linezolid (Table 2). These comparators had MIC50 results (all MIC50 values ≤2 mg/L) that were at least 64-fold higher than those obtained for oritavancin (MIC50 0.015 mg/L). All E. faecium isolates (43.3% VRE; 69.1% in the USA and 22.0% in Europe) were inhibited by oritavancin at ≤0.25 mg/L. Higher MIC results were noted for oritavancin when tested against E. faecium from the USA (MIC50/MIC90 0.015/0.12 mg/L) versus Europe (MIC50/MIC90 0.004/0.015 mg/L) (Table 1). Daptomycin and linezolid showed coverage against E. faecium, including VRE isolates (Table 2). Oritavancin exhibited MIC50 results of 0.03 and 0.015 mg/L when tested against BHS and VGS isolates, respectively, regardless of geographical region (Tables 1 and 2). Two isolates (one BHS and one VGS) were non-susceptible (MIC 0.5 mg/L) to oritavancin. Other agents, such as penicillin, vancomycin, teicoplanin, daptomycin, linezolid and levofloxacin, demonstrated antimicrobial coverage (≥98.0% susceptible) against BHS (Table 2). When tested against VGS, oritavancin, teicoplanin, vancomycin, daptomycin and linezolid were all highly active (Table 2). Discussion Infection represents an important cause of increased morbidity and mortality in patients with cancer and early introduction of appropriate antimicrobial therapy is essential for patient survival.1–3,5 The spectrum of bacterial infections in both neutropenic and non-neutropenic cancer patients is known to undergo periodic changes that may be influenced by a number of factors, including antibacterial (fluoroquinolone) prophylaxis, the use of vascular access devices and intensive chemotherapy with attendant mucositis.1–3,5 Importantly, the negative effects of fluoroquinolone use in this patient population are not limited to the emergence of fluoroquinolone-resistant strains of Escherichia coli and other Gram-negative organisms but include the potential selection for many resistant GPC, most notably MRSA and VRE.3,4,13,14 Other reports document the selection of VGS with decreased susceptibility to fluoroquinolones in patients receiving levofloxacin prophylaxis.15 Studies have revealed higher mortality rates for infections caused by MRSA and VRE in cancer patients, most likely related to the severity of these infections, immunocompromised status due to chemotherapy and to delays in appropriate antimicrobial therapy.16,17 Although vancomycin remains the primary agent for treating documented infections due to MDR strains of GPC, it is far from optimal and increasing MICs among MRSA isolates have been shown to be an independent predictor of mortality in cancer patients with bloodstream infections due to MRSA.18 Thus, although promptly initiating antimicrobial agents that retain activity against the infecting organism is crucial for survival, therapeutic options for infections caused by MDR GPC may be very limited in some institutions or geographical areas.19 Recent studies by Rolston et al.20 documented the importance of GPC in cancer patients and suggested the use of bactericidal alternatives to vancomycin in this patient population. We evaluated a large collection of GPC isolated from patients with cancer from 51 European and US medical centres. The results of this investigation highlight the main problems of antimicrobial resistance affecting these patients and indicate that oritavancin represents a potential option for the treatment of serious GPC infections, including those caused by MRSA and VRE, in patients with cancer in European and US medical centres. Overall, 99.9% of S. aureus and vancomycin-susceptible E. faecalis and 98.9% of streptococci were susceptible to oritavancin at ≤0.12 and ≤0.25 mg/L, respectively. Oritavancin coverage against this GPC collection was comparable to that of other GPC agents, including daptomycin, linezolid, teicoplanin and vancomycin, while oritavancin, daptomycin and linezolid demonstrated activity against VRE, including VanA-type VRE. Results presented here provide invaluable information on the antimicrobial resistance profile of GPC isolates causing infections in patients with cancer and indicate that oritavancin exhibits potent activity against aerobic GPC, including MRSA and VRE, isolated from cancer patients hospitalized in European and US medical centres. These results build on the findings of Rolston et al.20 regarding the potential role of the lipoglycopeptides as alternatives to vancomycin in the treatment of infections due to GPC in patients with cancer. Whether single-dose oritavancin can optimize healthcare resource utilization, reduce treatment costs or improve convenience for ABSSSIs in patients with cancer compared with multi-dose, multi-day therapies remain to be demonstrated in clinical studies. Acknowledgements We express appreciation to the following persons for significant contributions to this manuscript (technical support and/or manuscript assistance): R. Arends, L. Duncan, L. Flanigan, M. Huband, M. Janechek, J. Oberholser, P. Rhomberg, J. Schuchert, J. Streit and L. Woosley. Funding This surveillance study was sponsored by a research grant from The Medicines Company (Parsippany, NJ, USA) via the SENTRY Antimicrobial Surveillance Program platform. JMI Laboratories also received compensation fees from The Medicines Company for services with regards to manuscript preparation. The Medicines Company was not involved in the collection, analysis or interpretation of data. Transparency declarations JMI Laboratories contracted to perform services for Achaogen, Actelion, Allecra Therapeutics, Allergan, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Duke, Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, Theravance Biopharma, ThermoFisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare. References 1 Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection  2014; 42: 5– 13. Google Scholar CrossRef Search ADS PubMed  2 Freifeld AG, Bow EJ, Sepkowitz KA et al.   Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis  2011; 52: e56– 93. Google Scholar CrossRef Search ADS PubMed  3 Mikulska M, Viscoli C, Orasch C et al.   Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect  2014; 68: 321– 31. Google Scholar CrossRef Search ADS PubMed  4 Rolston KV, Yadegarynia D, Kontoyiannis DP et al.   The spectrum of Gram-positive bloodstream infections in patients with hematologic malignancies, and the in vitro activity of various quinolones against Gram-positive bacteria isolated from cancer patients. Int J Infect Dis  2006; 10: 223– 30. Google Scholar CrossRef Search ADS PubMed  5 Rolston KV. Infections in cancer patients with solid tumors: a review. Infect Dis Ther  2017; 6: 69– 83. Google Scholar CrossRef Search ADS PubMed  6 Kara O, Zarakolu P, Ascioglu S et al.   Epidemiology and emerging resistance in bacterial bloodstream infections in patients with hematologic malignancies. Infect Dis (Lond)  2015; 47: 686– 93. Google Scholar CrossRef Search ADS PubMed  7 Brade KD, Rybak JM, Rybak MJ. Oritavancin: a new lipoglycopeptide antibiotic in the treatment of Gram-positive infections. Infect Dis Ther  2016; 5: 1– 15. Google Scholar CrossRef Search ADS PubMed  8 Mendes RE, Castanheira M, Farrell DJ et al.   Longitudinal (2001–14) analysis of enterococci and VRE causing invasive infections in European and US hospitals, including a contemporary (2010–13) analysis of oritavancin in vitro potency. J Antimicrob Chemother  2016; 71: 3453– 8. Google Scholar CrossRef Search ADS PubMed  9 Mendes RE, Farrell DJ, Sader HS et al.   Activity of oritavancin against Gram-positive clinical isolates responsible for documented skin and soft-tissue infections in European and US hospitals (2010–13). J Antimicrob Chemother  2015; 70: 498– 504. Google Scholar CrossRef Search ADS PubMed  10 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Tenth Edition: Approved Standard M07-A10 . CLSI, Wayne, PA, USA, 2015. 11 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Seventh Informational Supplement M100-S27 . CLSI, Wayne, PA, USA, 2017. 12 EUCAST. Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 7.1. 2017. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_7.1_Breakpoint_Tables.pdf. 13 Chiang HY, Perencevich EN, Nair R et al.   Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review and meta-analysis. Infect Control Hosp Epidemiol  2017; 38: 203– 15. Google Scholar CrossRef Search ADS PubMed  14 Kang CI, Song JH, Chung DR et al.   Bloodstream infections in adult patients with cancer: clinical features and pathogenic significance of Staphylococcus aureus bacteremia. Support Care Cancer  2012; 20: 2371– 8. Google Scholar CrossRef Search ADS PubMed  15 Razonable RR, Litzow MR, Khaliq Y et al.   Bacteremia due to viridans group streptococci with diminished susceptibility to levofloxacin among neutropenic patients receiving levofloxacin prophylaxis. Clin Infect Dis  2002; 34: 1469– 74. Google Scholar CrossRef Search ADS PubMed  16 Patel G, Huprikar S, Factor SH et al.   Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol  2008; 29: 1099– 106. Google Scholar CrossRef Search ADS PubMed  17 Tumbarello M, Sanguinetti M, Montuori E et al.   Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother  2007; 51: 1987– 94. Google Scholar CrossRef Search ADS PubMed  18 Mahajan SN, Shah JN, Hachem R et al.   Characteristics and outcomes of methicillin-resistant Staphylococcus aureus bloodstream infections in patients with cancer treated with vancomycin: 9-year experience at a comprehensive cancer center. Oncologist  2012; 17: 1329– 36. Google Scholar CrossRef Search ADS PubMed  19 Boucher HW, Talbot GH, Benjamin DKJr et al.   10 × '20 progress—development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis  2013; 56: 1685– 94. Google Scholar CrossRef Search ADS PubMed  20 Rolston KV, Jamal MA, Nesher L et al.   In vitro activity of ceftaroline and comparator agents against Gram-positive and Gram-negative clinical isolates from cancer patients. Int J Antimicrob Agents  2017; 49: 416– 21. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from
Google Scholar,
PubMed
Create lists to
organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off