International Journal of Antimicrobial Agents 43 (2014) 465–469
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Short Communication
Daptomycin activity tested against 164 457 bacterial isolates from hospitalised patients: Summary of 8 years of a Worldwide Surveillance Programme (2005–2012) Helio S. Sader ∗ , David J. Farrell, Robert K. Flamm, Ronald N. Jones JMI Laboratories, 345 Beaver Kreek Center, Suite A, North Liberty, IA 52317, USA
a r t i c l e
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Article history: Received 10 October 2013 Accepted 23 January 2014 Keywords: Gram-positive infections Bacteraemia Hospital-acquired infections Antimicrobial resistance
a b s t r a c t We report the results of 8 years (2005–2012) of the Daptomycin Surveillance Programme Worldwide. Consecutive non-duplicate bacterial isolates (prevalence design) were collected from patients with documented infections in 410 medical centres and were susceptibility tested by reference broth microdilution methods. A total of 164 457 Gram-positive isolates were evaluated, including 97 542 Staphylococcus aureus, 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci and 15 883 -haemolytic streptococci. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions. Overall, the highest occurrence of non-susceptible isolates was observed among CoNS (0.19%), followed by Enterococcus faecium (0.18%), S. aureus (0.05%), Enterococcus faecalis (0.02%) and -haemolytic streptococci (0.00%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study interval. Against S. aureus, the daptomycin MIC50/90 was 0.25/0.5 mg/L in all geographic regions (99.95% susceptible overall). Only 53 daptomycin-non-susceptible S. aureus isolates were observed and the vast majority (49; 92.5%) had a daptomycin MIC value only 1 log2 dilution above the published susceptible breakpoint. Daptomycin was also active against CoNS (MIC50/90 , 0.25/0.5 mg/L; 99.81% susceptible), E. faecalis (MIC50/90 , 1/2 mg/L; 99.98% susceptible), E. faecium (MIC50/90 , 2/4 mg/L; 99.82% susceptible) including vancomycin-non-susceptible isolates (4521 isolates; MIC50/90 , 2/2 mg/L; 99.76% susceptible), and -haemolytic streptococci (MIC50/90 , ≤0.06/0.25 mg/L; 100.0% susceptible). In conclusion, daptomycin has remained very active against indicated species worldwide, and no significant year-to-year or regional variation in daptomycin activity has been detected. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Daptomycin is a lipopeptide with rapid in vitro bactericidal activity against a wide range of Gram-positive pathogens, including multidrug-resistant isolates of staphylococci and enterococci. Daptomycin was initially approved by the US Food and Drug Administration (FDA) in 2003 and by the European Medicines Agency (EMA) in 2005 for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible Grampositive bacteria using a dose of 4 mg/kg every 24 h (q24 h) [1]. In 2006 (USA) and 2007 (Europe), daptomycin received additional approvals for the treatment of right-sided infective endocarditis (RIE) due to Staphylococcus aureus and for S. aureus bacteraemia
∗ Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address: [email protected] (H.S. Sader).
when associated with RIE or ABSSSI at a dose of 6 mg/kg q24 h [2]. Furthermore, higher doses (usually 8–10 mg/kg q24 h) have been increasingly used, especially for the treatment of infections caused by S. aureus with elevated vancomycin minimum inhibitory concentrations (MICs) (>1 mg/L) as well as infective endocarditis caused by S. aureus or Enterococcus spp. including vancomycinresistant enterococcal isolates [3,4]. A large number of reports have shown that daptomycin remains very active against staphylococci, enterococci and streptococci; however, daptomycin-non-susceptible isolates have been rarely detected worldwide, with the mechanism being attributed to various gene mutations (mprF, yycFG, RNA polymerase subunits), changes in membrane fluidity and cell wall thickness, and alterations in membrane charge [5,6]. To understand the evolution of daptomycin non-susceptibility in staphylococci (MIC ≥ 2 mg/L), enterococci (MIC ≥ 8 mg/L) and streptococci (MIC ≥ 2 mg/L) since the initial daptomycin approval for clinical use, the results of
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.018 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1043 (99.9) 345 (>99.9) 698 (99.9) 854 (99.8) 12 777 (70.7) 9748 (89.8) 9511 (89.7) 237 (92.9) 2672 (33.8) 1166 (28.9) 1506 (39.3) – 26 696 (98.9) 11 922 (99.4) 14 774 (98.2) 7989 (95.8) 7254 (27.5) 6438 (37.8) 6215 (37.5) 223 (47.2) 462 (6.2) 246 (6.3) 216 (6.0) 311 (100.0) 66 819 (71.5) 40 875 (77.8) 25 944 (63.3) 10 451 (58.5) 665 (3.0) 494 (3.4) 475 (3.4) 19 (4.2) 94 (1.4) 57 (1.6) 37 (1.2) 4006 (98.0)
MIC90 1 0.5 0.25 0.12
2819 (3.0) 2042 (3.9) 777 (1.9) 1801 (9.7) 152 (0.8) 100 (0.8) 100 (0.8) 0 (0.6) 32 (0.4) 18 (0.4) 14 (0.4) 3369 (72.8) 112 (0.1) 87 (0.2) 25 (0.1) 277 (1.3) 85 (0.3) 51 (0.3) 48 (0.3) 3 (0.6) 9 (0.1) 5 (0.1) 4 (0.1) 8197 (51.6)
A summary of daptomycin MIC frequency distributions by organism group when tested against the entire collection (164 457 isolates) is given in Table 1. A total of 97 542 S. aureus isolates were tested and 43.3% were resistant to oxacillin (MRSA). The daptomycin MIC was ≤0.25 mg/L for the majority of S. aureus isolates (71.5%) and 98.9% of isolates were inhibited at a daptomycin MIC of ≤0.5 mg/L. Daptomycin MICs were generally similar among MRSA isolates (63.3% and 98.2% inhibited at ≤0.25 mg/L and ≤0.5 mg/L, respectively) compared with meticillin-susceptible S. aureus (77.8% and 99.4% inhibited at ≤0.25 mg/L and ≤0.5 mg/L, respectively). Only 53 daptomycin-non-susceptible S. aureus isolates (0.05%) were observed and the vast majority (49; 92.5%) were inhibited at a daptomycin concentration only 1 log2 dilution above the published susceptible breakpoint (highest MIC = 4 mg/L; 4
Staphylococcus aureus (97 542) MSSA (55 281) MRSA (42 261) CoNS (21 413) Enterococcus spp. (29 619) E. faecalis (18 740) Vancomycin-susceptible (18 221) Vancomycin-non-susceptible (519) E. faecium (9678) Vancomycin-susceptible (5157) Vancomycin-non-susceptible (4521) -Haemolytic streptococci (15 883)
3. Results
Organism (no. tested)
Daptomycin and various comparator agents were tested by Clinical and Laboratory Standards Institute (CLSI) (2012) broth microdilution methods in validated microdilution panels manufactured by Thermo Fisher, Inc. (Cleveland, OH). The test medium was Mueller–Hinton broth adjusted to contain physiological levels of calcium (50 mg/L) when testing daptomycin. In addition, 2.5–5% lysed horse blood supplement was used for testing -haemolytic streptococci. CLSI, European Committee on Antimicrobial Susceptibility Testing (EUCAST) and FDA interpretive criteria were used to categorise isolates as susceptible, intermediate or resistant [7–9]. A daptomycin susceptibility breakpoint of ≤1 mg/L was applied for staphylococci and -haemolytic streptococci, whilst ≤4 mg/L was applied to the enterococcal results, as recommended by the CLSI and the FDA [1,7]. EUCAST [8] has established daptomycin susceptible and resistant breakpoints for S. aureus (≤1 mg/L and ≥2 mg/L, respectively) but has not published daptomycin breakpoints for enterococcal isolates. The following quality control organisms were concurrently tested: S. aureus ATCC 29213; E. faecalis ATCC 29212; and Streptococcus pneumoniae ATCC 49619. All quality control results were within published limits [7].
Table 1 Summary of daptomycin activity tested against 164 457 bacterial isolates from hospitalised patients worldwide (2005–2012).
2.2. Susceptibility testing
MIC: minimum inhibitory concentration; MIC50/90 : MIC required to inhibit 50% and 90% of the isolates, respectively; MSSA: meticillin-susceptible S. aureus; MRSA: meticillin-resistant S. aureus; CoNS: coagulase-negative staphylococci.
0.25 0.25 0.25 0.25 1 1 1 1 2 2 2 ≤0.06 – – – – 5 (100.0) – – – 5 (100.0) 1 (100.0) 4 (100.0) –
MIC50 2
4
8
>8
A total of 164 457 consecutive unique patient isolates of clinical significance (one per patient episode) were collected between January 2005 and December 2012. Each participant centre followed a study protocol that indicated the number of consecutive isolates to be collected from specific sites of infection. The number of participant centres as well as the number of isolates per site of infection varied by geographic region as well as over time. The majority of isolates were collected from bacteraemia and skin and soft-tissue infections. Isolates were collected from North America (77 552 isolates), Europe/Mediterranean region (EMR) (46 081), Latin America (17 070) and the Asia-Pacific region (APAC) (23 754). Among 410 medical centres participating in this survey, 204 were from North America, 75 from EMR, 26 from Latin America and 105 from APAC. The organism collection included 97 542 S. aureus [43.3% meticillin-resistant S. aureus (MRSA)], 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci (18 740 Enterococcus faecalis, 9678 Enterococcus faecium and 1201 non-faecalis–non-faecium isolates) and 15 883 -haemolytic streptococci.
– – – – 18 (>99.9) 3 (100.0) 3 (100.0) – 12 (99.9) 5 (>99.9) 7 (99.9) –
MIC (mg/L) No. of isolates (cumulative %) inhibited at MIC in mg/L
2.1. Bacterial isolates
≤0.06
2. Materials and methods
4 (100.0) 1 (100.0) 3 (100.0) 2 (100.0) 1211 (99.9) 112 (>99.9) 109 (>99.9) 3 (100.0) 1012 (99.8) 686 (99.9) 326 (99.8) –
8 years (2005–2012) derived from the Daptomycin Surveillance Programme Worldwide were analysed.
0.5 0.5 0.5 0.5 2 2 2 1 4 4 2 0.25
H.S. Sader et al. / International Journal of Antimicrobial Agents 43 (2014) 465–469
49 (>99.9) 9 (>99.9) 40 (>99.9) 39 (>99.9) 7452 (95.8) 1794 (99.4) 1760 (99.4) 34 (99.4) 5380 (89.4) 2973 (86.6) 2407 (92.5) –
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H.S. Sader et al. / International Journal of Antimicrobial Agents 43 (2014) 465–469
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Table 2 Trends in non-susceptibility among organisms stratified by geographic region (2005–2012). Region/organism (no. of isolates)
No. (%) of daptomycin-non-susceptible isolates by year 2005
2006
2007
2008
2009
2010
2011
2012
All
North America Staphylococcus aureus (49 106) CoNS (8534) Enterococcus faecalis (7959) Enterococcus faecium (4155) -Haemolytic streptococci (7274)
2 (0.05) 1 (0.16) 0 (0.00) 0 (0.00) 0 (0.00)
6 (0.10) 0 (0.00) 0 (0.00) 1 (0.16) 0 (0.00)
7 (0.11) 6 (0.45) 0 (0.00) 0 (0.00) 0 (0.00)
10 (0.19) 6 (0.48) 0 (0.00) 4 (0.77) 0 (0.00)
1 (0.02) 0 (0.00) 1 (0.10) 2 (0.38) 0 (0.00)
6 (0.10) 0 (0.00) 2 (0.17) 6 (0.85) 0 (0.00)
2 (0.03) 1 (0.11) 0 (0.00) 1 (0.25) 0 (0.00)
3 (0.03) 3 (0.30) 0 (0.00) 2 (0.06) 0 (0.00)
37 (0.08) 17 (0.20) 3 (0.04) 16 (0.39) 0 (0.00)
Europe S. aureus (24 202) CoNS (7586) E. faecalis (5728) E. faecium (3247) -Haemolytic streptococci (5019)
0 (0.00) 1 (0.10) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 5 (0.41) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.09) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.11) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.03) 2 (0.19) 0 (0.00) 0 (0.00) 0 (0.00)
4 (0.13) 1 (0.16) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.07) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
7 (0.03) 11 (0.15) 0 (0.00) 0 (0.00) 0 (0.00)
Latin America S. aureus (9489) CoNS (2879) E. faecalis (2470) E. faecium (660) -Haemolytic streptococci (1376)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 2 (0.63) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.08) 2 (0.56) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 3 (0.67) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.23) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.01) 8 (0.28) 0 (0.00) 0 (0.00) 0 (0.00)
Asia-Pacific S. aureus (14 745) CoNS (2414) E. faecalis (2583) E. faecium (1616) -Haemolytic streptococci (2214)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.06) 1 (0.04) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.06) 2 (0.38) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.05) 1 (0.32) 0 (0.00) 1 (0.34) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.11) 1 (0.35) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.06) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.11) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
8 (0.05) 5 (0.21) 0 (0.00) 1 (0.06) 0 (0.00)
All regions combined S. aureus (97 542) CoNS (21 413) E. faecalis (18 740) E. faecium (9678) -Haemolytic streptococci (15 883)
2 (0.02) 2 (0.10) 0 (0.00) 0 (0.00) 0 (0.00)
7 (0.06) 8 (0.25) 0 (0.00) 1 (0.07) 0 (0.00)
9 (0.06) 9 (0.26) 0 (0.00) 0 (0.00) 0 (0.00)
12 (0.10) 10 (0.35) 0 (0.00) 5 (0.35) 0 (0.00)
1 (0.01) 3 (0.10) 1 (0.04) 2 (0.15) 0 (0.00)
9 (0.07) 4 (0.14) 2 (0.07) 6 (0.41) 0 (0.00)
7 (0.06) 2 (0.09) 0 (0.00) 1 (0.10) 0 (0.00)
6 (0.04) 3 (0.16) 0 (0.00) 2 (0.25) 0 (0.00)
53 (0.05) 41 (0.19) 3 (0.02) 17 (0.18) 0 (0.00)
CoNS: coagulase-negative staphylococci.
isolates). The daptomycin-non-susceptible isolates were isolated in the USA (37 isolates from 20 states, 1–4 per state), APAC (8 isolates from six countries), EMR (7 isolates from five countries) and Latin America (1 isolate from Mexico). The daptomycin MIC was 4 mg/L for only four S. aureus isolates. These four isolates displayed vancomycin MICs of 2 mg/L (three isolates) or 4 mg/L (one isolate) and were isolated from three US medical centres located in the states of New Jersey, New York and Washington. Daptomycin was also highly active against CoNS (21 413 isolates) with MIC50/90 values (MIC required to inhibit 50% and 90% of the isolates, respectively) at 0.25/0.5 mg/L and a 99.81% susceptibility rate (Table 1). Daptomycin was active against Enterococcus spp. isolates (29 619; MIC50/90 , 1/2 mg/L; 99.92% susceptible) according to CLSI breakpoint criteria (EUCAST has not defined daptomycin breakpoints for Enterococcus spp.). Among E. faecalis (18 740; MIC50/90 , 1/2 mg/L; 99.98% susceptible), 89.8% and 99.4% of isolates were inhibited at a daptomycin MIC of ≤1 mg/L and ≤2 mg/L, respectively, whereas E. faecium isolates (9678; MIC50/90 , 2/4 mg/L; 99.82% susceptible) exhibited daptomycin MICs slightly higher (two-fold), with 89.4% inhibited at ≤2 mg/L (Table 1). Furthermore, daptomycin MIC distributions for vancomycin-susceptible and -resistant isolates were very comparable; 100.0% and 99.8% of vancomycinnon-susceptible E. faecalis (519 isolates; MIC50/90 , 1/1 mg/L) and E. faecium (4521 isolates; MIC50/90 , 2/2 mg/L), respectively, were susceptible to daptomycin. Daptomycin was also very potent against -haemolytic streptococci (15 883 isolates) with a MIC50 of ≤0.06 mg/L, and 98.0% of isolates were inhibited at ≤0.25 mg/L (Table 1). MRSA rates were highest in North America (51.9%). followed by Latin America (41.7%) and APAC (41.7%), and were lowest in EMR (27.6%); daptomycin activity against S. aureus was very similar in all geographic regions. Daptomycin MIC50 and MIC90 values for CoNS,
Enterococcus spp., E. faecalis (including vancomycin-susceptible and -non-susceptible isolates) and E. faecium (including vancomycinsusceptible and -non-susceptible isolates) were identical in North America, EMR and Latin America, and slightly higher MIC90 values were noted in the APAC region (two-fold elevated; data not shown). Vancomycin non-susceptibility (MIC ≥ 8 mg/L) among E. faecalis/E. faecium was highest in North America (4.3/74.5%), followed by Latin America (3.5/43.0%), EMR (1.3/26.7%) and APAC (0.7/16.9%); and daptomycin activities against vancomycin-non-susceptible E. faecalis (MIC50/90 , 1/1–2 mg/L) and E. faecium (MIC50/90 , 2/2–4 mg/L) were similar to those noted for vancomycin-susceptible isolates in all geographic regions. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions (Table 2). Overall, the highest prevalence of non-susceptible isolates was observed among CoNS (0.19%), followed by E. faecium (0.18%), S. aureus (0.05%) and E. faecalis (0.02%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study period (2005–2012; Table 2). Table 3 lists the daptomycin MIC distributions for S. aureus from all regions combined and stratified by year. These results show no significant year-to-year variation in daptomycin activity during the study period. The activities of daptomycin and selected comparator agents were analysed for S. aureus isolates isolated from bloodstream infections (BSIs) worldwide (22 508 isolates) and daptomycin was highly active against this large collection of isolates (data not shown). Daptomycin MIC50 and MIC90 values were 0.25 mg/L and 0.5 mg/L, respectively (99.94% susceptible). Only 14 S. aureus isolates from BSI had a daptomycin MIC of ≥2 mg/L (12 isolates at 2 mg/L and 2 isolates at 4 mg/L). The daptomycin-non-susceptible bacteraemic S. aureus were isolated in the USA (12 isolates
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Table 3 Daptomycin minimum inhibitory concentration (MIC) distributions for 97 542 Staphylococcus aureus from medical centres worldwide stratified by year (2005–2012). Year
No. of isolates
No. of isolates (cumulative %) inhibited at MIC (mg/L)
MIC (mg/L)
≤0.06
0.12
0.25
0.5
1
2
4
MIC50
MIC90
8 (0.1) 26 (0.2) 25 (0.2) 9 (0.1) 9 (0.1) 14 (0.1) 6 (0.1) 15 (0.1)
249 (3.2) 471 (4.1) 595 (4.4) 277 (2.3) 166 (1.5) 518 (4.0) 193 (1.7) 350 (2.6)
5244 (68.5) 8906 (77.1) 10 423 (77.9) 7581 (64.4) 5807 (51.4) 9948 (79.0) 8449 (72.2) 10 461 (77.1)
2470 (99.2) 2633 (98.7) 2969 (98.8) 4146 (98.4) 5446 (98.3) 2696 (99.3) 3257 (99.4) 3079 (99.1)
63 (>99.9) 151 (99.9) 160 (99.9) 188 (99.9) 198 (>99.9) 87 (99.9) 70 (99.9) 126 (>99.9)
2 (100.0) 6 (>99.9) 9 (100.0) 9 (>99.9) 1 (100.0) 9 (100.0) 7 (100.0) 6 (100.0)
– 1 (100.0) – 3 (100.0) – – – –
0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Meticillin-susceptible S. aureus (MSSA) 2005 4843 5 (0.1) 2006 6644 18 (0.3) 2007 7672 18 (0.2) 2008 6792 9 (0.1) 2009 6778 7 (0.1) 2010 7780 13 (0.2) 2011 6945 5 (0.1) 2012 7827 12 (0.2)
196 (4.2) 339 (5.4) 414 (5.6) 195 (3.0) 122 (1.9) 395 (5.2) 138 (2.1) 243 (3.3)
3490 (76.2) 5195 (83.6) 6074 (84.8) 4694 (72.1) 3892 (59.3) 6117 (83.9) 5256 (77.7) 6157 (81.9)
1130 (99.5) 1034 (99.1) 1122 (99.4) 1845 (99.3) 2702 (99.2) 1226 (99.6) 1514 (99.5) 1349 (99.2)
21 (>99.9) 57 (>99.9) 42 (>99.9) 48 (>99.9) 55 (100.0) 29 (100.0) 28 (99.9) 65 (>99.9)
1 (100.0) –0 (>99.9) 2 (100.0) 1 (100.0) – – 4 (100.0) 1 (100.0)
– 1 (100.0) – – – – – –
0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Meticillin-resistant S. aureus (MRSA) 2005 3193 3 (0.1) 2006 5550 8 (0.1) 2007 6509 7 (0.1) 2008 5421 0 (0.0) 2009 4849 2 (99.9% susceptible) were also very active against these S. aureus isolates from BSIs but were four-fold less potent than daptomycin (MIC50/90 , 0.25/0.5 mg/L).
4. Discussion Daptomycin was initially approved for clinical use in 2003 in the USA and in 2005 in Europe and has demonstrated high rates of clinical success for a variety of Gram-positive infections, including indicated infections such as complicated skin and skinstructure infections, bacteraemia and infective endocarditis, as well as non-indicated infections such as osteomyelitis and neutropenic patients [2,10,11]. Despite the increasing use of daptomycin in clinical practice in the later years (especially in the USA), reports of daptomycin-non-susceptible isolates remain rare and stable [5,6,12]. The results of this investigation corroborate those reported by other investigators showing that the occurrence of daptomycinnon-susceptible isolates is very uncommon worldwide [13,14]. For all species/groups evaluated, daptomycin-non-susceptible isolates occurred sporadically. The highest daptomycin-non-susceptibility rates were 0.19% for CoNS and 0.18% for E. faecium. Among S. aureus, which is the main organism targeted for this compound, the overall non-susceptibility rate was 0.05%. Despite the fact that daptomycin has been widely used in the USA to treat serious S. aureus infections, the daptomycin-non-susceptibility rate was only 0.08% overall and did not display an increasing trend during the study interval (Table 2).
Large longitudinal surveillance networks, such as this daptomycin programme, can detect signs of emerging resistance as well as longitudinal trends. In an effort to understand the current level and progression of daptomycin non-susceptibility in staphylococcal species (MIC ≥ 2 mg/L), enterococci (MIC ≥ 8 mg/L) and -haemolytic streptococci (MIC ≥ 2 mg/L), we have presented an analysis of the Daptomycin Surveillance Programme Worldwide covering the initial 8 years (2005–2012) of clinical use. This network sampled more than 400 medical centres and provided results for 164 457 Gram-positive clinical isolates by reference testing against daptomycin and numerous comparators agents. The results presented here clearly indicate that daptomycin remains potent against these indicated species across five continents. Funding: This study was funded in part by an educational/research grant from Cubist Pharmaceuticals. Competing interests: JMI Laboratories, Inc. has received research and educational grants in 2010–2013 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, bioMérieux, Cempra, Cerexa, ContraFect, Cubist, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, Thermo Fisher and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest and Theravance. Ethical approval: Not required.
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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short Communication
Daptomycin activity tested against 164 457 bacterial isolates from hospitalised patients: Summary of 8 years of a Worldwide Surveillance Programme (2005–2012) Helio S. Sader ∗ , David J. Farrell, Robert K. Flamm, Ronald N. Jones JMI Laboratories, 345 Beaver Kreek Center, Suite A, North Liberty, IA 52317, USA
a r t i c l e
i n f o
Article history: Received 10 October 2013 Accepted 23 January 2014 Keywords: Gram-positive infections Bacteraemia Hospital-acquired infections Antimicrobial resistance
a b s t r a c t We report the results of 8 years (2005–2012) of the Daptomycin Surveillance Programme Worldwide. Consecutive non-duplicate bacterial isolates (prevalence design) were collected from patients with documented infections in 410 medical centres and were susceptibility tested by reference broth microdilution methods. A total of 164 457 Gram-positive isolates were evaluated, including 97 542 Staphylococcus aureus, 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci and 15 883 -haemolytic streptococci. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions. Overall, the highest occurrence of non-susceptible isolates was observed among CoNS (0.19%), followed by Enterococcus faecium (0.18%), S. aureus (0.05%), Enterococcus faecalis (0.02%) and -haemolytic streptococci (0.00%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study interval. Against S. aureus, the daptomycin MIC50/90 was 0.25/0.5 mg/L in all geographic regions (99.95% susceptible overall). Only 53 daptomycin-non-susceptible S. aureus isolates were observed and the vast majority (49; 92.5%) had a daptomycin MIC value only 1 log2 dilution above the published susceptible breakpoint. Daptomycin was also active against CoNS (MIC50/90 , 0.25/0.5 mg/L; 99.81% susceptible), E. faecalis (MIC50/90 , 1/2 mg/L; 99.98% susceptible), E. faecium (MIC50/90 , 2/4 mg/L; 99.82% susceptible) including vancomycin-non-susceptible isolates (4521 isolates; MIC50/90 , 2/2 mg/L; 99.76% susceptible), and -haemolytic streptococci (MIC50/90 , ≤0.06/0.25 mg/L; 100.0% susceptible). In conclusion, daptomycin has remained very active against indicated species worldwide, and no significant year-to-year or regional variation in daptomycin activity has been detected. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Daptomycin is a lipopeptide with rapid in vitro bactericidal activity against a wide range of Gram-positive pathogens, including multidrug-resistant isolates of staphylococci and enterococci. Daptomycin was initially approved by the US Food and Drug Administration (FDA) in 2003 and by the European Medicines Agency (EMA) in 2005 for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) caused by susceptible Grampositive bacteria using a dose of 4 mg/kg every 24 h (q24 h) [1]. In 2006 (USA) and 2007 (Europe), daptomycin received additional approvals for the treatment of right-sided infective endocarditis (RIE) due to Staphylococcus aureus and for S. aureus bacteraemia
∗ Corresponding author. Tel.: +1 319 665 3370; fax: +1 319 665 3371. E-mail address: [email protected] (H.S. Sader).
when associated with RIE or ABSSSI at a dose of 6 mg/kg q24 h [2]. Furthermore, higher doses (usually 8–10 mg/kg q24 h) have been increasingly used, especially for the treatment of infections caused by S. aureus with elevated vancomycin minimum inhibitory concentrations (MICs) (>1 mg/L) as well as infective endocarditis caused by S. aureus or Enterococcus spp. including vancomycinresistant enterococcal isolates [3,4]. A large number of reports have shown that daptomycin remains very active against staphylococci, enterococci and streptococci; however, daptomycin-non-susceptible isolates have been rarely detected worldwide, with the mechanism being attributed to various gene mutations (mprF, yycFG, RNA polymerase subunits), changes in membrane fluidity and cell wall thickness, and alterations in membrane charge [5,6]. To understand the evolution of daptomycin non-susceptibility in staphylococci (MIC ≥ 2 mg/L), enterococci (MIC ≥ 8 mg/L) and streptococci (MIC ≥ 2 mg/L) since the initial daptomycin approval for clinical use, the results of
http://dx.doi.org/10.1016/j.ijantimicag.2014.01.018 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1043 (99.9) 345 (>99.9) 698 (99.9) 854 (99.8) 12 777 (70.7) 9748 (89.8) 9511 (89.7) 237 (92.9) 2672 (33.8) 1166 (28.9) 1506 (39.3) – 26 696 (98.9) 11 922 (99.4) 14 774 (98.2) 7989 (95.8) 7254 (27.5) 6438 (37.8) 6215 (37.5) 223 (47.2) 462 (6.2) 246 (6.3) 216 (6.0) 311 (100.0) 66 819 (71.5) 40 875 (77.8) 25 944 (63.3) 10 451 (58.5) 665 (3.0) 494 (3.4) 475 (3.4) 19 (4.2) 94 (1.4) 57 (1.6) 37 (1.2) 4006 (98.0)
MIC90 1 0.5 0.25 0.12
2819 (3.0) 2042 (3.9) 777 (1.9) 1801 (9.7) 152 (0.8) 100 (0.8) 100 (0.8) 0 (0.6) 32 (0.4) 18 (0.4) 14 (0.4) 3369 (72.8) 112 (0.1) 87 (0.2) 25 (0.1) 277 (1.3) 85 (0.3) 51 (0.3) 48 (0.3) 3 (0.6) 9 (0.1) 5 (0.1) 4 (0.1) 8197 (51.6)
A summary of daptomycin MIC frequency distributions by organism group when tested against the entire collection (164 457 isolates) is given in Table 1. A total of 97 542 S. aureus isolates were tested and 43.3% were resistant to oxacillin (MRSA). The daptomycin MIC was ≤0.25 mg/L for the majority of S. aureus isolates (71.5%) and 98.9% of isolates were inhibited at a daptomycin MIC of ≤0.5 mg/L. Daptomycin MICs were generally similar among MRSA isolates (63.3% and 98.2% inhibited at ≤0.25 mg/L and ≤0.5 mg/L, respectively) compared with meticillin-susceptible S. aureus (77.8% and 99.4% inhibited at ≤0.25 mg/L and ≤0.5 mg/L, respectively). Only 53 daptomycin-non-susceptible S. aureus isolates (0.05%) were observed and the vast majority (49; 92.5%) were inhibited at a daptomycin concentration only 1 log2 dilution above the published susceptible breakpoint (highest MIC = 4 mg/L; 4
Staphylococcus aureus (97 542) MSSA (55 281) MRSA (42 261) CoNS (21 413) Enterococcus spp. (29 619) E. faecalis (18 740) Vancomycin-susceptible (18 221) Vancomycin-non-susceptible (519) E. faecium (9678) Vancomycin-susceptible (5157) Vancomycin-non-susceptible (4521) -Haemolytic streptococci (15 883)
3. Results
Organism (no. tested)
Daptomycin and various comparator agents were tested by Clinical and Laboratory Standards Institute (CLSI) (2012) broth microdilution methods in validated microdilution panels manufactured by Thermo Fisher, Inc. (Cleveland, OH). The test medium was Mueller–Hinton broth adjusted to contain physiological levels of calcium (50 mg/L) when testing daptomycin. In addition, 2.5–5% lysed horse blood supplement was used for testing -haemolytic streptococci. CLSI, European Committee on Antimicrobial Susceptibility Testing (EUCAST) and FDA interpretive criteria were used to categorise isolates as susceptible, intermediate or resistant [7–9]. A daptomycin susceptibility breakpoint of ≤1 mg/L was applied for staphylococci and -haemolytic streptococci, whilst ≤4 mg/L was applied to the enterococcal results, as recommended by the CLSI and the FDA [1,7]. EUCAST [8] has established daptomycin susceptible and resistant breakpoints for S. aureus (≤1 mg/L and ≥2 mg/L, respectively) but has not published daptomycin breakpoints for enterococcal isolates. The following quality control organisms were concurrently tested: S. aureus ATCC 29213; E. faecalis ATCC 29212; and Streptococcus pneumoniae ATCC 49619. All quality control results were within published limits [7].
Table 1 Summary of daptomycin activity tested against 164 457 bacterial isolates from hospitalised patients worldwide (2005–2012).
2.2. Susceptibility testing
MIC: minimum inhibitory concentration; MIC50/90 : MIC required to inhibit 50% and 90% of the isolates, respectively; MSSA: meticillin-susceptible S. aureus; MRSA: meticillin-resistant S. aureus; CoNS: coagulase-negative staphylococci.
0.25 0.25 0.25 0.25 1 1 1 1 2 2 2 ≤0.06 – – – – 5 (100.0) – – – 5 (100.0) 1 (100.0) 4 (100.0) –
MIC50 2
4
8
>8
A total of 164 457 consecutive unique patient isolates of clinical significance (one per patient episode) were collected between January 2005 and December 2012. Each participant centre followed a study protocol that indicated the number of consecutive isolates to be collected from specific sites of infection. The number of participant centres as well as the number of isolates per site of infection varied by geographic region as well as over time. The majority of isolates were collected from bacteraemia and skin and soft-tissue infections. Isolates were collected from North America (77 552 isolates), Europe/Mediterranean region (EMR) (46 081), Latin America (17 070) and the Asia-Pacific region (APAC) (23 754). Among 410 medical centres participating in this survey, 204 were from North America, 75 from EMR, 26 from Latin America and 105 from APAC. The organism collection included 97 542 S. aureus [43.3% meticillin-resistant S. aureus (MRSA)], 21 413 coagulase-negative staphylococci (CoNS), 29 619 enterococci (18 740 Enterococcus faecalis, 9678 Enterococcus faecium and 1201 non-faecalis–non-faecium isolates) and 15 883 -haemolytic streptococci.
– – – – 18 (>99.9) 3 (100.0) 3 (100.0) – 12 (99.9) 5 (>99.9) 7 (99.9) –
MIC (mg/L) No. of isolates (cumulative %) inhibited at MIC in mg/L
2.1. Bacterial isolates
≤0.06
2. Materials and methods
4 (100.0) 1 (100.0) 3 (100.0) 2 (100.0) 1211 (99.9) 112 (>99.9) 109 (>99.9) 3 (100.0) 1012 (99.8) 686 (99.9) 326 (99.8) –
8 years (2005–2012) derived from the Daptomycin Surveillance Programme Worldwide were analysed.
0.5 0.5 0.5 0.5 2 2 2 1 4 4 2 0.25
H.S. Sader et al. / International Journal of Antimicrobial Agents 43 (2014) 465–469
49 (>99.9) 9 (>99.9) 40 (>99.9) 39 (>99.9) 7452 (95.8) 1794 (99.4) 1760 (99.4) 34 (99.4) 5380 (89.4) 2973 (86.6) 2407 (92.5) –
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Table 2 Trends in non-susceptibility among organisms stratified by geographic region (2005–2012). Region/organism (no. of isolates)
No. (%) of daptomycin-non-susceptible isolates by year 2005
2006
2007
2008
2009
2010
2011
2012
All
North America Staphylococcus aureus (49 106) CoNS (8534) Enterococcus faecalis (7959) Enterococcus faecium (4155) -Haemolytic streptococci (7274)
2 (0.05) 1 (0.16) 0 (0.00) 0 (0.00) 0 (0.00)
6 (0.10) 0 (0.00) 0 (0.00) 1 (0.16) 0 (0.00)
7 (0.11) 6 (0.45) 0 (0.00) 0 (0.00) 0 (0.00)
10 (0.19) 6 (0.48) 0 (0.00) 4 (0.77) 0 (0.00)
1 (0.02) 0 (0.00) 1 (0.10) 2 (0.38) 0 (0.00)
6 (0.10) 0 (0.00) 2 (0.17) 6 (0.85) 0 (0.00)
2 (0.03) 1 (0.11) 0 (0.00) 1 (0.25) 0 (0.00)
3 (0.03) 3 (0.30) 0 (0.00) 2 (0.06) 0 (0.00)
37 (0.08) 17 (0.20) 3 (0.04) 16 (0.39) 0 (0.00)
Europe S. aureus (24 202) CoNS (7586) E. faecalis (5728) E. faecium (3247) -Haemolytic streptococci (5019)
0 (0.00) 1 (0.10) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 5 (0.41) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.09) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.11) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.03) 2 (0.19) 0 (0.00) 0 (0.00) 0 (0.00)
4 (0.13) 1 (0.16) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.07) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
7 (0.03) 11 (0.15) 0 (0.00) 0 (0.00) 0 (0.00)
Latin America S. aureus (9489) CoNS (2879) E. faecalis (2470) E. faecium (660) -Haemolytic streptococci (1376)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 2 (0.63) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.08) 2 (0.56) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 3 (0.67) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 1 (0.23) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.01) 8 (0.28) 0 (0.00) 0 (0.00) 0 (0.00)
Asia-Pacific S. aureus (14 745) CoNS (2414) E. faecalis (2583) E. faecium (1616) -Haemolytic streptococci (2214)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.06) 1 (0.04) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.06) 2 (0.38) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.05) 1 (0.32) 0 (0.00) 1 (0.34) 0 (0.00)
0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
2 (0.11) 1 (0.35) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.06) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
1 (0.11) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00)
8 (0.05) 5 (0.21) 0 (0.00) 1 (0.06) 0 (0.00)
All regions combined S. aureus (97 542) CoNS (21 413) E. faecalis (18 740) E. faecium (9678) -Haemolytic streptococci (15 883)
2 (0.02) 2 (0.10) 0 (0.00) 0 (0.00) 0 (0.00)
7 (0.06) 8 (0.25) 0 (0.00) 1 (0.07) 0 (0.00)
9 (0.06) 9 (0.26) 0 (0.00) 0 (0.00) 0 (0.00)
12 (0.10) 10 (0.35) 0 (0.00) 5 (0.35) 0 (0.00)
1 (0.01) 3 (0.10) 1 (0.04) 2 (0.15) 0 (0.00)
9 (0.07) 4 (0.14) 2 (0.07) 6 (0.41) 0 (0.00)
7 (0.06) 2 (0.09) 0 (0.00) 1 (0.10) 0 (0.00)
6 (0.04) 3 (0.16) 0 (0.00) 2 (0.25) 0 (0.00)
53 (0.05) 41 (0.19) 3 (0.02) 17 (0.18) 0 (0.00)
CoNS: coagulase-negative staphylococci.
isolates). The daptomycin-non-susceptible isolates were isolated in the USA (37 isolates from 20 states, 1–4 per state), APAC (8 isolates from six countries), EMR (7 isolates from five countries) and Latin America (1 isolate from Mexico). The daptomycin MIC was 4 mg/L for only four S. aureus isolates. These four isolates displayed vancomycin MICs of 2 mg/L (three isolates) or 4 mg/L (one isolate) and were isolated from three US medical centres located in the states of New Jersey, New York and Washington. Daptomycin was also highly active against CoNS (21 413 isolates) with MIC50/90 values (MIC required to inhibit 50% and 90% of the isolates, respectively) at 0.25/0.5 mg/L and a 99.81% susceptibility rate (Table 1). Daptomycin was active against Enterococcus spp. isolates (29 619; MIC50/90 , 1/2 mg/L; 99.92% susceptible) according to CLSI breakpoint criteria (EUCAST has not defined daptomycin breakpoints for Enterococcus spp.). Among E. faecalis (18 740; MIC50/90 , 1/2 mg/L; 99.98% susceptible), 89.8% and 99.4% of isolates were inhibited at a daptomycin MIC of ≤1 mg/L and ≤2 mg/L, respectively, whereas E. faecium isolates (9678; MIC50/90 , 2/4 mg/L; 99.82% susceptible) exhibited daptomycin MICs slightly higher (two-fold), with 89.4% inhibited at ≤2 mg/L (Table 1). Furthermore, daptomycin MIC distributions for vancomycin-susceptible and -resistant isolates were very comparable; 100.0% and 99.8% of vancomycinnon-susceptible E. faecalis (519 isolates; MIC50/90 , 1/1 mg/L) and E. faecium (4521 isolates; MIC50/90 , 2/2 mg/L), respectively, were susceptible to daptomycin. Daptomycin was also very potent against -haemolytic streptococci (15 883 isolates) with a MIC50 of ≤0.06 mg/L, and 98.0% of isolates were inhibited at ≤0.25 mg/L (Table 1). MRSA rates were highest in North America (51.9%). followed by Latin America (41.7%) and APAC (41.7%), and were lowest in EMR (27.6%); daptomycin activity against S. aureus was very similar in all geographic regions. Daptomycin MIC50 and MIC90 values for CoNS,
Enterococcus spp., E. faecalis (including vancomycin-susceptible and -non-susceptible isolates) and E. faecium (including vancomycinsusceptible and -non-susceptible isolates) were identical in North America, EMR and Latin America, and slightly higher MIC90 values were noted in the APAC region (two-fold elevated; data not shown). Vancomycin non-susceptibility (MIC ≥ 8 mg/L) among E. faecalis/E. faecium was highest in North America (4.3/74.5%), followed by Latin America (3.5/43.0%), EMR (1.3/26.7%) and APAC (0.7/16.9%); and daptomycin activities against vancomycin-non-susceptible E. faecalis (MIC50/90 , 1/1–2 mg/L) and E. faecium (MIC50/90 , 2/2–4 mg/L) were similar to those noted for vancomycin-susceptible isolates in all geographic regions. The prevalence of daptomycin-non-susceptible isolates was extremely low for all species in all geographic regions (Table 2). Overall, the highest prevalence of non-susceptible isolates was observed among CoNS (0.19%), followed by E. faecium (0.18%), S. aureus (0.05%) and E. faecalis (0.02%). Moreover, no trend towards increased daptomycin resistance (non-susceptibility) was observed for any species in any geographic region during the study period (2005–2012; Table 2). Table 3 lists the daptomycin MIC distributions for S. aureus from all regions combined and stratified by year. These results show no significant year-to-year variation in daptomycin activity during the study period. The activities of daptomycin and selected comparator agents were analysed for S. aureus isolates isolated from bloodstream infections (BSIs) worldwide (22 508 isolates) and daptomycin was highly active against this large collection of isolates (data not shown). Daptomycin MIC50 and MIC90 values were 0.25 mg/L and 0.5 mg/L, respectively (99.94% susceptible). Only 14 S. aureus isolates from BSI had a daptomycin MIC of ≥2 mg/L (12 isolates at 2 mg/L and 2 isolates at 4 mg/L). The daptomycin-non-susceptible bacteraemic S. aureus were isolated in the USA (12 isolates
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Table 3 Daptomycin minimum inhibitory concentration (MIC) distributions for 97 542 Staphylococcus aureus from medical centres worldwide stratified by year (2005–2012). Year
No. of isolates
No. of isolates (cumulative %) inhibited at MIC (mg/L)
MIC (mg/L)
≤0.06
0.12
0.25
0.5
1
2
4
MIC50
MIC90
8 (0.1) 26 (0.2) 25 (0.2) 9 (0.1) 9 (0.1) 14 (0.1) 6 (0.1) 15 (0.1)
249 (3.2) 471 (4.1) 595 (4.4) 277 (2.3) 166 (1.5) 518 (4.0) 193 (1.7) 350 (2.6)
5244 (68.5) 8906 (77.1) 10 423 (77.9) 7581 (64.4) 5807 (51.4) 9948 (79.0) 8449 (72.2) 10 461 (77.1)
2470 (99.2) 2633 (98.7) 2969 (98.8) 4146 (98.4) 5446 (98.3) 2696 (99.3) 3257 (99.4) 3079 (99.1)
63 (>99.9) 151 (99.9) 160 (99.9) 188 (99.9) 198 (>99.9) 87 (99.9) 70 (99.9) 126 (>99.9)
2 (100.0) 6 (>99.9) 9 (100.0) 9 (>99.9) 1 (100.0) 9 (100.0) 7 (100.0) 6 (100.0)
– 1 (100.0) – 3 (100.0) – – – –
0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Meticillin-susceptible S. aureus (MSSA) 2005 4843 5 (0.1) 2006 6644 18 (0.3) 2007 7672 18 (0.2) 2008 6792 9 (0.1) 2009 6778 7 (0.1) 2010 7780 13 (0.2) 2011 6945 5 (0.1) 2012 7827 12 (0.2)
196 (4.2) 339 (5.4) 414 (5.6) 195 (3.0) 122 (1.9) 395 (5.2) 138 (2.1) 243 (3.3)
3490 (76.2) 5195 (83.6) 6074 (84.8) 4694 (72.1) 3892 (59.3) 6117 (83.9) 5256 (77.7) 6157 (81.9)
1130 (99.5) 1034 (99.1) 1122 (99.4) 1845 (99.3) 2702 (99.2) 1226 (99.6) 1514 (99.5) 1349 (99.2)
21 (>99.9) 57 (>99.9) 42 (>99.9) 48 (>99.9) 55 (100.0) 29 (100.0) 28 (99.9) 65 (>99.9)
1 (100.0) –0 (>99.9) 2 (100.0) 1 (100.0) – – 4 (100.0) 1 (100.0)
– 1 (100.0) – – – – – –
0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Meticillin-resistant S. aureus (MRSA) 2005 3193 3 (0.1) 2006 5550 8 (0.1) 2007 6509 7 (0.1) 2008 5421 0 (0.0) 2009 4849 2 (99.9% susceptible) were also very active against these S. aureus isolates from BSIs but were four-fold less potent than daptomycin (MIC50/90 , 0.25/0.5 mg/L).
4. Discussion Daptomycin was initially approved for clinical use in 2003 in the USA and in 2005 in Europe and has demonstrated high rates of clinical success for a variety of Gram-positive infections, including indicated infections such as complicated skin and skinstructure infections, bacteraemia and infective endocarditis, as well as non-indicated infections such as osteomyelitis and neutropenic patients [2,10,11]. Despite the increasing use of daptomycin in clinical practice in the later years (especially in the USA), reports of daptomycin-non-susceptible isolates remain rare and stable [5,6,12]. The results of this investigation corroborate those reported by other investigators showing that the occurrence of daptomycinnon-susceptible isolates is very uncommon worldwide [13,14]. For all species/groups evaluated, daptomycin-non-susceptible isolates occurred sporadically. The highest daptomycin-non-susceptibility rates were 0.19% for CoNS and 0.18% for E. faecium. Among S. aureus, which is the main organism targeted for this compound, the overall non-susceptibility rate was 0.05%. Despite the fact that daptomycin has been widely used in the USA to treat serious S. aureus infections, the daptomycin-non-susceptibility rate was only 0.08% overall and did not display an increasing trend during the study interval (Table 2).
Large longitudinal surveillance networks, such as this daptomycin programme, can detect signs of emerging resistance as well as longitudinal trends. In an effort to understand the current level and progression of daptomycin non-susceptibility in staphylococcal species (MIC ≥ 2 mg/L), enterococci (MIC ≥ 8 mg/L) and -haemolytic streptococci (MIC ≥ 2 mg/L), we have presented an analysis of the Daptomycin Surveillance Programme Worldwide covering the initial 8 years (2005–2012) of clinical use. This network sampled more than 400 medical centres and provided results for 164 457 Gram-positive clinical isolates by reference testing against daptomycin and numerous comparators agents. The results presented here clearly indicate that daptomycin remains potent against these indicated species across five continents. Funding: This study was funded in part by an educational/research grant from Cubist Pharmaceuticals. Competing interests: JMI Laboratories, Inc. has received research and educational grants in 2010–2013 from Achaogen, Aires, American Proficiency Institute (API), Anacor, Astellas, AstraZeneca, bioMérieux, Cempra, Cerexa, ContraFect, Cubist, Dipexium, Enanta, Furiex, GlaxoSmithKline, Johnson & Johnson, LegoChem Biosciences Inc., Meiji Seika Kaisha, Nabriva, Novartis, Pfizer, PPD Therapeutics, Premier Research Group, Rempex, Rib-X Pharmaceuticals, Seachaid, Shionogi, The Medicines Co., Theravance, Thermo Fisher and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-Forest and Theravance. Ethical approval: Not required.
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