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Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009
International Journal of Antimicrobial Agents 37 (2011) 219–224
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Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009 Stephen P. Hawser a,∗ , Samuel K. Bouchillon b , Daryl J. Hoban b , Michael Dowzicky c , Tim Babinchak c a b c
IHMA Europe Sàrl, 4 Route de la Corniche, 1066 Epalinges, Switzerland International Health Management Associates, Schaumburg, IL, USA Pfizer, Inc., Collegeville, PA, USA
a r t i c l e
i n f o
Article history: Received 30 September 2010 Accepted 28 October 2010 Keywords: Staphylococcus aureus MRSA MIC creep Vancomycin
a b s t r a c t During 2004–2009, 20 004 isolates of Staphylococcus aureus were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Of these isolates, 8249 (41.2%) were meticillin-resistant S. aureus (MRSA) and 11 755 (58.8%) were meticillin-susceptible S. aureus (MSSA). A total of 4.0%, 5.3% and 3.0% of all S. aureus, MRSA and MSSA isolates, respectively, exhibited vancomycin minimum inhibitory concentrations (MICs) ≥2 g/mL. Whilst no vancomycin-resistant S. aureus were encountered in this study and the majority of these isolates remained susceptible to vancomycin at the Clinical and Laboratory Standards (CLSI) breakpoint of 2 g/mL, the total number of isolates with MICs creeping up to 2 g/mL and above increased in all S. aureus from 4.0% in 2004 to 7.7% in 2009 (P < 0.001). Moreover, in MRSA this phenotype increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). The increase was also notable for MSSA, which rose from 2.6% in 2004 to 5.6% in 2009 (P < 0.001). Of the 12 antibiotics tested, linezolid, minocycline, tigecycline and vancomycin were the most active agents by susceptibility against all S. aureus, all MRSA and all MSSA isolates. Against MRSA isolates with vancomycin MICs ≥ 2 g/mL, susceptibility to vancomycin decreased from 100% in 2004 to 95.77% in 2009 (P > 0.05). Similarly, in MSSA isolates susceptibility to vancomycin decreased from 100% in 2004 to 91.07% in 2009 (P > 0.05). These data suggest that although the number of isolates of S. aureus with reduced susceptibility to vancomycin has increased significantly from 2004 to 2009, this upward creep of MICs has not yet impacted significantly on the overall susceptibility of vancomycin against either MRSA or MSSA. © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Staphylococcus aureus is widely recognised as the causative pathogen of various infections, ranging from infections of the skin and soft tissues such as muscle, fat and chronic bone infections, to septicaemia and endocarditis for which various therapies including tigecycline are available [1–5]. Significant events in the evolution of S. aureus have included the development of hospital-associated meticillin resistance, the recent emergence of community strains of S. aureus that are meticillin-resistant and the emergence of isolates that express intermediate resistance or full resistance to vancomycin [6]. Fully vancomycin-resistant S. aureus (VRSA) strains due to the acquisition of the vanA gene from vancomycin-resistant enterococci were first reported from the USA in 2002 [7,8]. However, VRSA isolates are extremely rare, with only nine isolates detected to date. Reports of clinical S. aureus isolates demonstrating reduced
∗ Corresponding author. Tel.: +41 21 651 9030; fax: +41 21 651 9030. E-mail address: [email protected] (S.P. Hawser).
teicoplanin susceptibility and the in vivo emergence of resistance during teicoplanin therapy came from Europe in the early 1990s. These isolates, whilst also vancomycin-intermediate S. aureus (VISA) strains, remained susceptible to vancomycin therapy [6]. Heterogeneous VISA (hVISA) isolates are far more common than VRSA isolates [6]. In addition to increasing numbers of reports of hVISA and VISA, there has been significant interest regarding the changing patterns of vancomycin minimum inhibitory concentrations (MICs) within the S. aureus population. This has been driven partly by studies demonstrating poorer outcomes of vancomycin treatment for meticillin-resistant S. aureus (MRSA) infections with higher vancomycin MICs, even when these MICs are within the susceptible range [9,10]. This changing pattern has been referred to as ‘MIC creep’ [11]. Surveillance studies assist in understanding the extent and spread of various types of resistance and also assist in understanding whether MIC patterns for a given antibiotic/pathogen combination are evolving. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is one such programme that operates globally and is active in all of the major regions including Africa, Asia/Pacific,
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Table 1 Frequency of Staphylococcus aureus isolates with vancomycin (VAN) minimum inhibitory concentrations (MICs) ≥ 2 g/mL. Year
Isolates
Phenotype
2004–2009
All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)]
20 004 797 (4.0) 2525 101 (4.0) 2930 62 (2.1) 3612 94 (2.6) 4944 160 (3.2) 4348 253 (5.8) 1645 127 (7.7)
S. aureus
2004 2005 2006 2007 2008 2009
MRSA 8249 439 (5.3) 1158 65 (5.6) 1411 39 (2.8) 1531 50 (3.3) 2028 78 (3.8) 1481 136 (9.2) 640 71 (11.1)
MSSA 11 755 358 (3.0) 1367 36 (2.6) 1519 23 (1.5) 2081 44 (2.1) 2916 82 (2.8) 2867 117 (4.1) 1005 56 (5.6)
MRSA, meticillin-resistant Staphylococcus aureus; MSSA, meticillin-susceptible S. aureus.
Europe, Latin America, Middle East and North America. The current study involved a diverse collection of clinical isolates of S. aureus from multiple countries worldwide and aimed to understand the extent of the global changing patterns of vancomycin MICs in a 6-year period from 2004 to 2009.
2. Materials and methods 2.1. Clinical isolates Isolates from various clinical infections were collected and tested between January 2004 and October 2009 from 998 cumulative total investigative sites (55% participated more than 1 year) in 56 countries globally. Investigative sites were from Africa (22 sites; 2 countries), Asia (57 sites; 8 countries), Europe (312 sites; 26 countries), Latin America (135 sites; 12 countries), the Middle East (31 sites; 4 countries), North America (417 sites; 2 countries) and South Pacific (24 sites; 2 countries). Isolates were identified to species level and were tested at each site by the participating laboratory. Only one isolate per patient was accepted. Organism collection, transport, confirmation of organism identification, and development and management of a centralised database were coordinated by Laboratories International for Microbiology Studies (LIMS), a division of International Health Management Associates, Inc. (Schaumburg, IL).
2.2. Antimicrobial susceptibility testing MICs were determined by the Clinical and Laboratory Standards Institute (CLSI) recommended broth microdilution testing method [12]. MIC interpretive criteria followed published guidelines established by the CLSI [13]. The CLSI vancomycin susceptibility breakpoint is 2 g/mL. Breakpoints for tigecycline were defined by the US Food and Drug Administration (FDA) as described in the tigecycline product information [4]. Meticillin resistance was screened by the central laboratory using the cefoxitin 30 g disk test. Quality controls were performed by each testing site on each day of testing using S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 according to CLSI guidelines [13].
2.3. Statistical analyses Statistical analysis was performed using the two-tailed Fisher’s exact test.
3. Results A total of 20 004 isolates of S. aureus were collected from 2004 to 2009 from 56 countries originating from all major regions including Africa, Asia/Pacific, Europe, the Middle East, Latin America and North America. The major infection sources were skin and skin structure (n = 6101; 30.5%), blood (n = 4684; 23.4%), respiratory tract (n = 4323; 21.6%) and body fluids other than blood (n = 2725; 13.6%). The remaining 10.9% of isolates were mostly from catheters/drains, central nervous system, ear/nose/throat, gastrointestinal, genitourinary, reproductive organs and skeletal sources. Of the 20 004 isolates, 8249 (41.2%) were MRSA and 11 755 (58.8%) were meticillin-susceptible S. aureus (MSSA) isolates. For the period 2004–2009, the proportion of isolates with vancomycin MICs ≥ 2 g/mL amongst S. aureus, MRSA and MSSA was 4.0%, 5.3% and 3.0%, respectively (Table 1). The frequency of these isolates increased from 4.0% in 2004 to 7.7% in 2009 (P < 0.001) for all S. aureus isolates taken together. Amongst MRSA, the frequency increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). A similar two-fold increase in MSSA isolates with MICs ≥ 2 g/mL was also noted, from 2.6% in 2004 to 5.6% in 2009 (P < 0.001) (Table 1). On a regional basis, MRSA rates for 2004–2009 ranged from 26.1% (Europe) to 52.5% (North America). For the MRSA isolates, the percentage of isolates with vancomycin MICs ≥ 2 g/mL ranged from 3.0% (North America) to 8.9% (Europe). The percentage of MSSA isolates with vancomycin MICs ≥ 2 g/mL was highest in Europe and Latin America (both 3.8%) and lowest in Africa (1.9%) (Table 2). In this study, 12 antibiotics were tested against all S. aureus isolates, MRSA and MSSA. The most active agents by susceptibility were consistently linezolid, minocycline, tigecycline and vancomycin (Table 3). Whilst linezolid, minocycline, tigecycline and vancomycin exhibited susceptibilities of >97% against MRSA and MSSA, as expected, the carbapenems, penicillins and levofloxacin exhibited low susceptibilities against MRSA isolates. Although MIC50 and MIC90 values (MICs for 50% and 90% of the organisms, respectively) for vancomycin were consistently 1 g/mL, a small proportion of the isolates exhibited intermediate resistance to vancomycin ranging from 0.06% (MSSA) to 0.08% (MRSA). As was the case for all MSSA isolates taken together (Table 3), MSSA isolates with vancomycin MICs ≥ 2 g/mL exhibited similar susceptibilities to the 12 antibiotics (Table 4). Tigecycline and linezolid susceptibilities were consistently ≥99.9% for all isolates as well as for MRSA and MSSA isolates with vancomycin MICs ≥ 2 g/mL. However, against isolates with vancomycin MICs ≥ 2 g/mL, vancomycin exhibited a susceptibility of 98.4% against MRSA isolates and 98% against MSSA isolates (Table 4).
S.P. Hawser et al. / International Journal of Antimicrobial Agents 37 (2011) 219–224 Table 2 Regional distribution and frequency of all meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible S. aureus (MSSA) isolates as well as isolates with vancomycin (VAN) minimum inhibitory concentrations (MICs) ≥ 2 g/mL. Phenotype
Region
No. (%) of isolates per region
No. (%) of isolates with VAN MIC ≥ 2 g/mL
MRSA (n = 8249)
Africa Asia/Pacific Europe Latin America Middle East North America
103 (27.8) 654 (41.7) 1721 (26.1) 1071 (45.4) 99 (28.6) 4601 (52.5)
7 (6.8) 55 (8.4) 153 (8.9) 80 (7.5) 7 (7.1) 137 (3.0)
MSSA (n = 11 755)
Africa Asia/Pacific Europe Latin America Middle East North America
267 (72.2) 913 (58.3) 4885 (73.9) 1288 (54.6) 247 (71.4) 4155 (47.5)
5 (1.9) 20 (2.2) 188 (3.8) 49 (3.8) 9 (3.6) 87 (2.1)
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susceptibilities were all 100%. However, from 2007 onwards vancomycin susceptibility gradually decreased from 98.72% to 95.77% in 2009 (P > 0.05). Furthermore, the percentage of isolates exhibiting intermediate resistance to vancomycin for the period 2004–2009 was 1.59%. Intermediate resistance to vancomycin in this study increased from 1.28% in 2007 to 4.23% in 2009 (P > 0.05). All S. aureus with MICs ≥ 2 g/mL were susceptible to tigecycline and linezolid throughout 2004–2009. However, susceptibility to minocycline decreased from 95.38% in 2004 to 73.24% in 2009 (P < 0.001). The patterns of annual activity of the agents were similar for MSSA. For the period 2004–2009, 98.04% of isolates were susceptible to vancomycin (Table 6). Furthermore, from 2004 to 2007 vancomycin susceptibilities were 100%. However, susceptibility decreased to 98.29% in 2008 and further decreased to 91.07% in 2009 (P > 0.05). As observed with MSSA, susceptibilities for tigecycline and linezolid remained at 100% throughout 2004–2009. Susceptibility to minocycline decreased from 100% in 2004 to 96.43% in 2009 (P > 0.05). 4. Discussion
By contrast, vancomycin exhibited susceptibilities of 99.92% and 99.94% against all MRSA and all MSSA, respectively (Table 3). For the period 2004–2009, 98.41% of the isolates were susceptible to vancomycin (Table 5). During 2004 to 2006, vancomycin
Vancomycin MIC creep has been demonstrated at a number of centres in the USA over recent years using Etest or broth MICs [11,14,15]. However, not all centres have detected this
Table 3 In vitro activities of 12 antibiotics against all isolates of Staphylococcus aureus, meticillin-resistant S. aureus (MRSA) and meticillin-susceptible S. aureus (MSSA). Antibiotic
Susceptibilitya %S
All (N = 20 004) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MRSA (n = 8249) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MSSA (n = 11 755) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin
MIC (g/mL) %I
%R
MIC50
MIC90
Min.
Max.
58.7 11.47 58.1 58.8 64.14 99.99 58.6 97.4 9.67 58.7 99.99 99.93
0 0 0.7 0 1.9 0 0.1 1.85 0 0 0 0.07
41.3 88.53 41.3 41.2 33.96 0.02 41.3 0.75 90.33 41.3 0.01 0
1 16 4 0.25 0.25 2 0.25 ≤0.25 >8 1 0.12 1
>8 >16 >64 16 32 4 16 0.5 >8 >16 0.25 1
≤0.03 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 >16 >32 >8 >16 >8 >8 >16 1 4
0 0 0 0 21.76 100 0 94.86 0 0 99.98 99.92
0 0 0 0 2.39 0 0 3.71 0 0 0 0.08
100 100 100 100 75.85 0 100 1.43 100 100 0.02 0
8 >16 32 1 8 2 4 ≤0.25 >8 16 0.12 1
>8 >16 >64 >16 >32 4 >16 4 >8 >16 0.25 1
0.25 0.5 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 0.25 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 >16 >32 4 >16 >8 >8 >16 1 4
99.9 19.52 98.81 99.98 93.88 99.97 99.69 99.17 16.45 99.91 100 99.94
0 0 1.16 0.03 1.56 0 0.25 0.54 0 0 0 0.06
0.1 80.48 0.03 0 4.56 0.03 0.06 0.28 83.55 0.09 0 0
1 4 2 ≤0.12 0.12 2 ≤0.12 ≤0.25 4 1 0.12 1
2 >16 4 0.25 0.5 4 0.25 0.5 >8 2 0.25 1
≤0.03 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 8 >32 >8 >16 >8 >8 >16 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC, minimum inhibitory concentration; MIC50/90 , MIC for 50% and 90% of the organisms, respectively; AMC, amoxicillin/clavulanic acid; TZP, piperacillin/tazobactam. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
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Table 4 In vitro activity of 12 antibiotics against meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible S. aureus (MSSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Antibiotic
MRSA (n = 439) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MSSA (n = 358) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin
Susceptibilitya
MIC (g/mL)
%S
%I
%R
MIC50
0 0 0 0 11.2 100 0 87.5 0 0 100 98.4
0 0 0 0 0.7 0 0 9.8 0 0 0 1.6
100 100 100 100 88.1 0 100 2.7 100 100 0 0
>8 >16 >64 16 16 2 16 ≤0.25 >8 >16 0.25 2
100 23.7 96.1 100 90 100 98.9 98.4 18.7 99.7 100 98
0 0 3.6 0 3.6 0 1.1 0.8 0 0 0 2
0 76.3 0.3 0 6.4 0 0 0.8 81.3 0.3 0 0
1 2 4 0.25 0.25 2 ≤0.12 ≤0.25 4 1 0.12 2
MIC90
Min.
Max.
>8 >16 >64 >16 >32 4 >16 8 >8 >16 0.5 2
0.5 2 0.12 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 0.5 0.5 0.03 2
>8 >16 >64 >16 >32 4 >16 >8 >8 >16 0.5 4
2 >16 8 0.5 2 4 1 1 >8 4 0.25 2
0.06 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 2
4 >16 >64 0.5 >32 4 8 >8 >8 16 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively; AMC, amoxicillin/clavulanic acid; TZP, piperacillin/tazobactam. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4]. Table 5 Annual in vitro activity of linezolid, minocycline, tigecycline and vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Year
Antibiotic
Susceptibilitya
MIC (g/mL)
%S
%I
%R
MIC50
MIC90
Min.
Max.
2004–2009 (N = 439)
Linezolid Minocycline Tigecycline Vancomycin
100 87.47 100 98.41
0 9.8 0 1.59
0 2.73 0 0
2 ≤0.25 0.25 2
4 8 0.5 2
≤0.5 ≤0.25 0.03 2
4 >8 0.5 4
2004 (n = 65)
Linezolid Minocycline Tigecycline Vancomycin
100 95.38 100 100
0 3.08 0 0
0 1.54 0 0
2 ≤0.25 0.25 2
4 4 0.5 2
≤0.5 ≤0.25 0.06 2
4 >8 0.5 2
2005 (n = 39)
Linezolid Minocycline Tigecycline Vancomycin
100 97.44 100 100
0 2.56 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 2 0.25 2
≤0.5 ≤0.25 0.06 2
4 8 0.5 2
2006 (n = 50)
Linezolid Minocycline Tigecycline Vancomycin
100 90 100 100
0 8 0 0
0 2 0 0
2 ≤0.25 0.25 2
4 4 0.5 2
1 ≤0.25 0.12 2
4 >8 0.5 2
2007 (n = 78)
Linezolid Minocycline Tigecycline Vancomycin
100 87.18 100 98.72
0 8.97 0 1.28
0 3.85 0 0
2 ≤0.25 0.25 2
4 8 0.5 2
≤0.5 ≤0.25 0.06 2
4 >8 0.5 4
2008 (n = 136)
Linezolid Minocycline Tigecycline Vancomycin
100 87.5 100 97.79
0 9.56 0 2.21
0 2.94 0 0
2 0.5 0.25 2
4 8 0.5 2
1 ≤0.25 0.03 2
4 >8 0.5 4
2009 (n = 71)
Linezolid Minocycline Tigecycline Vancomycin
100 73.24 100 95.77
0 22.54 0 4.23
0 4.23 0 0
2 0.5 0.25 2
4 8 0.5 2
1 ≤0.25 0.06 2
4 >8 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
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Table 6 Annual in vitro activity of linezolid, minocycline, tigecycline and vancomycin against meticillin-susceptible Staphylococcus aureus (MSSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Year (N)
Antibiotic
Susceptibilitya
MIC (g/mL)
%S
%I
%R
2004–2009 (N = 358)
Linezolid Minocycline Tigecycline Vancomycin
100 98.32 100 98.04
0 0.84 0 1.96
0 0.84 0 0
MIC50 2 ≤0.25 0.12 2
MIC90 4 1 0.25 2
≤0.5 ≤0.25 ≤0.008 2
Min.
Max.
2004 (n = 36)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 0.5 0.25 2
1 ≤0.25 0.06 2
4 0.5 0.25 2
2005 (n = 23)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 1 0.12 2
1 ≤0.25 ≤0.008 2
4 4 0.25 2
2006 (n = 44)
Linezolid Minocycline Tigecycline Vancomycin
100 97.73 100 100
0 2.27 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 0.5 0.25 2
1 ≤0.25 0.06 2
4 8 0.5 2
2007 (n = 82)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 1 0.5 2
1 ≤0.25 0.03 2
4 4 0.5 2
2008 (n = 117)
Linezolid Minocycline Tigecycline Vancomycin
100 97.44 100 98.29
0 1.71 0 1.71
0 0.85 0 0
2 ≤0.25 0.12 2
4 1 0.25 2
≤0.5 ≤0.25 0.03 2
4 >8 0.5 4
2009 (n = 56)
Linezolid Minocycline Tigecycline Vancomycin
100 96.43 100 91.07
0 0 0 8.93
0 3.57 0 0
2 ≤0.25 0.25 2
4 1 0.5 2
1 ≤0.25 0.12 2
4 >8 0.5 4
4 >8 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
phenomenon, with one centre in the USA having reported no change in vancomycin MICs between 1999 and 2006 [16]. In Europe, very gradual increases in glycopeptide MICs have been documented from France [17]. On the other hand, a Spanish study for isolates collected from 2002 to 2006 did not reveal any notable changes in the vancomycin MIC pattern [18]. An analysis of SENTRY surveillance data for the years 1998 to 2003, which included 35 458 S. aureus isolates, detected no change in vancomycin MICs over this time by standard CLSI methods [19]. It may appear from the abovementioned reports that changes in the patterns for vancomycin MICs may not be a phenomenon that all institutions experience. Most of those studies that have described MIC creep for vancomycin involved isolates prior to 2006. Data from the current study have shown that the proportion of isolates with elevated vancomycin MICs for the whole period 2004–2009 were 4.0%, 5.3% and 3.0% for S. aureus, MRSA and MSSA, respectively. The frequency of isolates with elevated MICs to vancomycin (≥2 g/mL) in S. aureus has increased significantly from 4% in 2004 to 7.7% in 2009. MRSA isolates showed a significant increase from 5.6% in 2004 to 11.1% in 2009. The phenomenon was not solely restricted to MRSA; isolates of MSSA with elevated vancomycin MICs rose from 2.6% in 2004 to 5.6% in 2009. Moreover, isolates with elevated vancomycin MICs were widely detected in all geographical regions, ranging from 3.0% in North America to 8.9% in Europe for MRSA isolates and from 1.9% in Africa to 3.8% in Europe and Latin America for MSSA. The data presented in this study demonstrate that the numbers of isolates with elevated vancomycin MICs ≥ 2 g/mL have increased significantly to notable levels of 7.7%, 11.1% and 5.6% in S. aureus, MRSA and MSSA, respectively (P < 0.001). These notable
increases are correlated with reduced susceptibilities to vancomycin and some other antibiotics. However, since the increased MICs demonstrated in this study remained largely within the CLSI susceptible breakpoint of 2 g/mL, only marginal increases in nonsusceptibility were noted without any significant decreases in vancomycin susceptibility over the course of the study. No VRSA were encountered throughout the 6-year study period. Tigecycline and linezolid susceptibilities remained high and were not affected by the increase in frequency of isolates with elevated vancomycin MICs. Three linezolid-resistant isolates were confirmed, one each in North America, Europe and Africa. The data suggest that the phenomenon of elevated vancomycin MICs now appears to be common to all geographical regions. Vancomycin MIC creep will likely further cause concerns as time progresses and, whilst the isolates in this study remained susceptible to tigecycline and linezolid, further surveillance to monitor this phenomenon is highly warranted. Importantly, whilst vancomycin MIC creep is occurring, the absence of high-level resistance to vancomycin is noteworthy. Consequently, MIC creep may be still overcome through appropriate and adequate drug dosing regimens, wherever possible. Funding: This study was sponsored by a grant from Pfizer, Inc. SKB and DJH are employees of International Health Management Associates, who were paid consultants to Pfizer in connection with the conduct of this study and the development of this manuscript. Competing interests: SPH is employed by IHMA Europe Sàrl, a wholly owned affiliate of International Health Management Associates, Inc. SKB and DJH are employed by International Health Management Associates, a clinical research organisation that has
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Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004–2009 Stephen P. Hawser a,∗ , Samuel K. Bouchillon b , Daryl J. Hoban b , Michael Dowzicky c , Tim Babinchak c a b c
IHMA Europe Sàrl, 4 Route de la Corniche, 1066 Epalinges, Switzerland International Health Management Associates, Schaumburg, IL, USA Pfizer, Inc., Collegeville, PA, USA
a r t i c l e
i n f o
Article history: Received 30 September 2010 Accepted 28 October 2010 Keywords: Staphylococcus aureus MRSA MIC creep Vancomycin
a b s t r a c t During 2004–2009, 20 004 isolates of Staphylococcus aureus were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Of these isolates, 8249 (41.2%) were meticillin-resistant S. aureus (MRSA) and 11 755 (58.8%) were meticillin-susceptible S. aureus (MSSA). A total of 4.0%, 5.3% and 3.0% of all S. aureus, MRSA and MSSA isolates, respectively, exhibited vancomycin minimum inhibitory concentrations (MICs) ≥2 g/mL. Whilst no vancomycin-resistant S. aureus were encountered in this study and the majority of these isolates remained susceptible to vancomycin at the Clinical and Laboratory Standards (CLSI) breakpoint of 2 g/mL, the total number of isolates with MICs creeping up to 2 g/mL and above increased in all S. aureus from 4.0% in 2004 to 7.7% in 2009 (P < 0.001). Moreover, in MRSA this phenotype increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). The increase was also notable for MSSA, which rose from 2.6% in 2004 to 5.6% in 2009 (P < 0.001). Of the 12 antibiotics tested, linezolid, minocycline, tigecycline and vancomycin were the most active agents by susceptibility against all S. aureus, all MRSA and all MSSA isolates. Against MRSA isolates with vancomycin MICs ≥ 2 g/mL, susceptibility to vancomycin decreased from 100% in 2004 to 95.77% in 2009 (P > 0.05). Similarly, in MSSA isolates susceptibility to vancomycin decreased from 100% in 2004 to 91.07% in 2009 (P > 0.05). These data suggest that although the number of isolates of S. aureus with reduced susceptibility to vancomycin has increased significantly from 2004 to 2009, this upward creep of MICs has not yet impacted significantly on the overall susceptibility of vancomycin against either MRSA or MSSA. © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction Staphylococcus aureus is widely recognised as the causative pathogen of various infections, ranging from infections of the skin and soft tissues such as muscle, fat and chronic bone infections, to septicaemia and endocarditis for which various therapies including tigecycline are available [1–5]. Significant events in the evolution of S. aureus have included the development of hospital-associated meticillin resistance, the recent emergence of community strains of S. aureus that are meticillin-resistant and the emergence of isolates that express intermediate resistance or full resistance to vancomycin [6]. Fully vancomycin-resistant S. aureus (VRSA) strains due to the acquisition of the vanA gene from vancomycin-resistant enterococci were first reported from the USA in 2002 [7,8]. However, VRSA isolates are extremely rare, with only nine isolates detected to date. Reports of clinical S. aureus isolates demonstrating reduced
∗ Corresponding author. Tel.: +41 21 651 9030; fax: +41 21 651 9030. E-mail address: [email protected] (S.P. Hawser).
teicoplanin susceptibility and the in vivo emergence of resistance during teicoplanin therapy came from Europe in the early 1990s. These isolates, whilst also vancomycin-intermediate S. aureus (VISA) strains, remained susceptible to vancomycin therapy [6]. Heterogeneous VISA (hVISA) isolates are far more common than VRSA isolates [6]. In addition to increasing numbers of reports of hVISA and VISA, there has been significant interest regarding the changing patterns of vancomycin minimum inhibitory concentrations (MICs) within the S. aureus population. This has been driven partly by studies demonstrating poorer outcomes of vancomycin treatment for meticillin-resistant S. aureus (MRSA) infections with higher vancomycin MICs, even when these MICs are within the susceptible range [9,10]. This changing pattern has been referred to as ‘MIC creep’ [11]. Surveillance studies assist in understanding the extent and spread of various types of resistance and also assist in understanding whether MIC patterns for a given antibiotic/pathogen combination are evolving. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is one such programme that operates globally and is active in all of the major regions including Africa, Asia/Pacific,
0924-8579/$ – see front matter © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2010.10.029
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Table 1 Frequency of Staphylococcus aureus isolates with vancomycin (VAN) minimum inhibitory concentrations (MICs) ≥ 2 g/mL. Year
Isolates
Phenotype
2004–2009
All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)] All (n) VAN MIC ≥ 2 g/mL [n (%)]
20 004 797 (4.0) 2525 101 (4.0) 2930 62 (2.1) 3612 94 (2.6) 4944 160 (3.2) 4348 253 (5.8) 1645 127 (7.7)
S. aureus
2004 2005 2006 2007 2008 2009
MRSA 8249 439 (5.3) 1158 65 (5.6) 1411 39 (2.8) 1531 50 (3.3) 2028 78 (3.8) 1481 136 (9.2) 640 71 (11.1)
MSSA 11 755 358 (3.0) 1367 36 (2.6) 1519 23 (1.5) 2081 44 (2.1) 2916 82 (2.8) 2867 117 (4.1) 1005 56 (5.6)
MRSA, meticillin-resistant Staphylococcus aureus; MSSA, meticillin-susceptible S. aureus.
Europe, Latin America, Middle East and North America. The current study involved a diverse collection of clinical isolates of S. aureus from multiple countries worldwide and aimed to understand the extent of the global changing patterns of vancomycin MICs in a 6-year period from 2004 to 2009.
2. Materials and methods 2.1. Clinical isolates Isolates from various clinical infections were collected and tested between January 2004 and October 2009 from 998 cumulative total investigative sites (55% participated more than 1 year) in 56 countries globally. Investigative sites were from Africa (22 sites; 2 countries), Asia (57 sites; 8 countries), Europe (312 sites; 26 countries), Latin America (135 sites; 12 countries), the Middle East (31 sites; 4 countries), North America (417 sites; 2 countries) and South Pacific (24 sites; 2 countries). Isolates were identified to species level and were tested at each site by the participating laboratory. Only one isolate per patient was accepted. Organism collection, transport, confirmation of organism identification, and development and management of a centralised database were coordinated by Laboratories International for Microbiology Studies (LIMS), a division of International Health Management Associates, Inc. (Schaumburg, IL).
2.2. Antimicrobial susceptibility testing MICs were determined by the Clinical and Laboratory Standards Institute (CLSI) recommended broth microdilution testing method [12]. MIC interpretive criteria followed published guidelines established by the CLSI [13]. The CLSI vancomycin susceptibility breakpoint is 2 g/mL. Breakpoints for tigecycline were defined by the US Food and Drug Administration (FDA) as described in the tigecycline product information [4]. Meticillin resistance was screened by the central laboratory using the cefoxitin 30 g disk test. Quality controls were performed by each testing site on each day of testing using S. aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 according to CLSI guidelines [13].
2.3. Statistical analyses Statistical analysis was performed using the two-tailed Fisher’s exact test.
3. Results A total of 20 004 isolates of S. aureus were collected from 2004 to 2009 from 56 countries originating from all major regions including Africa, Asia/Pacific, Europe, the Middle East, Latin America and North America. The major infection sources were skin and skin structure (n = 6101; 30.5%), blood (n = 4684; 23.4%), respiratory tract (n = 4323; 21.6%) and body fluids other than blood (n = 2725; 13.6%). The remaining 10.9% of isolates were mostly from catheters/drains, central nervous system, ear/nose/throat, gastrointestinal, genitourinary, reproductive organs and skeletal sources. Of the 20 004 isolates, 8249 (41.2%) were MRSA and 11 755 (58.8%) were meticillin-susceptible S. aureus (MSSA) isolates. For the period 2004–2009, the proportion of isolates with vancomycin MICs ≥ 2 g/mL amongst S. aureus, MRSA and MSSA was 4.0%, 5.3% and 3.0%, respectively (Table 1). The frequency of these isolates increased from 4.0% in 2004 to 7.7% in 2009 (P < 0.001) for all S. aureus isolates taken together. Amongst MRSA, the frequency increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). A similar two-fold increase in MSSA isolates with MICs ≥ 2 g/mL was also noted, from 2.6% in 2004 to 5.6% in 2009 (P < 0.001) (Table 1). On a regional basis, MRSA rates for 2004–2009 ranged from 26.1% (Europe) to 52.5% (North America). For the MRSA isolates, the percentage of isolates with vancomycin MICs ≥ 2 g/mL ranged from 3.0% (North America) to 8.9% (Europe). The percentage of MSSA isolates with vancomycin MICs ≥ 2 g/mL was highest in Europe and Latin America (both 3.8%) and lowest in Africa (1.9%) (Table 2). In this study, 12 antibiotics were tested against all S. aureus isolates, MRSA and MSSA. The most active agents by susceptibility were consistently linezolid, minocycline, tigecycline and vancomycin (Table 3). Whilst linezolid, minocycline, tigecycline and vancomycin exhibited susceptibilities of >97% against MRSA and MSSA, as expected, the carbapenems, penicillins and levofloxacin exhibited low susceptibilities against MRSA isolates. Although MIC50 and MIC90 values (MICs for 50% and 90% of the organisms, respectively) for vancomycin were consistently 1 g/mL, a small proportion of the isolates exhibited intermediate resistance to vancomycin ranging from 0.06% (MSSA) to 0.08% (MRSA). As was the case for all MSSA isolates taken together (Table 3), MSSA isolates with vancomycin MICs ≥ 2 g/mL exhibited similar susceptibilities to the 12 antibiotics (Table 4). Tigecycline and linezolid susceptibilities were consistently ≥99.9% for all isolates as well as for MRSA and MSSA isolates with vancomycin MICs ≥ 2 g/mL. However, against isolates with vancomycin MICs ≥ 2 g/mL, vancomycin exhibited a susceptibility of 98.4% against MRSA isolates and 98% against MSSA isolates (Table 4).
S.P. Hawser et al. / International Journal of Antimicrobial Agents 37 (2011) 219–224 Table 2 Regional distribution and frequency of all meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible S. aureus (MSSA) isolates as well as isolates with vancomycin (VAN) minimum inhibitory concentrations (MICs) ≥ 2 g/mL. Phenotype
Region
No. (%) of isolates per region
No. (%) of isolates with VAN MIC ≥ 2 g/mL
MRSA (n = 8249)
Africa Asia/Pacific Europe Latin America Middle East North America
103 (27.8) 654 (41.7) 1721 (26.1) 1071 (45.4) 99 (28.6) 4601 (52.5)
7 (6.8) 55 (8.4) 153 (8.9) 80 (7.5) 7 (7.1) 137 (3.0)
MSSA (n = 11 755)
Africa Asia/Pacific Europe Latin America Middle East North America
267 (72.2) 913 (58.3) 4885 (73.9) 1288 (54.6) 247 (71.4) 4155 (47.5)
5 (1.9) 20 (2.2) 188 (3.8) 49 (3.8) 9 (3.6) 87 (2.1)
221
susceptibilities were all 100%. However, from 2007 onwards vancomycin susceptibility gradually decreased from 98.72% to 95.77% in 2009 (P > 0.05). Furthermore, the percentage of isolates exhibiting intermediate resistance to vancomycin for the period 2004–2009 was 1.59%. Intermediate resistance to vancomycin in this study increased from 1.28% in 2007 to 4.23% in 2009 (P > 0.05). All S. aureus with MICs ≥ 2 g/mL were susceptible to tigecycline and linezolid throughout 2004–2009. However, susceptibility to minocycline decreased from 95.38% in 2004 to 73.24% in 2009 (P < 0.001). The patterns of annual activity of the agents were similar for MSSA. For the period 2004–2009, 98.04% of isolates were susceptible to vancomycin (Table 6). Furthermore, from 2004 to 2007 vancomycin susceptibilities were 100%. However, susceptibility decreased to 98.29% in 2008 and further decreased to 91.07% in 2009 (P > 0.05). As observed with MSSA, susceptibilities for tigecycline and linezolid remained at 100% throughout 2004–2009. Susceptibility to minocycline decreased from 100% in 2004 to 96.43% in 2009 (P > 0.05). 4. Discussion
By contrast, vancomycin exhibited susceptibilities of 99.92% and 99.94% against all MRSA and all MSSA, respectively (Table 3). For the period 2004–2009, 98.41% of the isolates were susceptible to vancomycin (Table 5). During 2004 to 2006, vancomycin
Vancomycin MIC creep has been demonstrated at a number of centres in the USA over recent years using Etest or broth MICs [11,14,15]. However, not all centres have detected this
Table 3 In vitro activities of 12 antibiotics against all isolates of Staphylococcus aureus, meticillin-resistant S. aureus (MRSA) and meticillin-susceptible S. aureus (MSSA). Antibiotic
Susceptibilitya %S
All (N = 20 004) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MRSA (n = 8249) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MSSA (n = 11 755) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin
MIC (g/mL) %I
%R
MIC50
MIC90
Min.
Max.
58.7 11.47 58.1 58.8 64.14 99.99 58.6 97.4 9.67 58.7 99.99 99.93
0 0 0.7 0 1.9 0 0.1 1.85 0 0 0 0.07
41.3 88.53 41.3 41.2 33.96 0.02 41.3 0.75 90.33 41.3 0.01 0
1 16 4 0.25 0.25 2 0.25 ≤0.25 >8 1 0.12 1
>8 >16 >64 16 32 4 16 0.5 >8 >16 0.25 1
≤0.03 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 >16 >32 >8 >16 >8 >8 >16 1 4
0 0 0 0 21.76 100 0 94.86 0 0 99.98 99.92
0 0 0 0 2.39 0 0 3.71 0 0 0 0.08
100 100 100 100 75.85 0 100 1.43 100 100 0.02 0
8 >16 32 1 8 2 4 ≤0.25 >8 16 0.12 1
>8 >16 >64 >16 >32 4 >16 4 >8 >16 0.25 1
0.25 0.5 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 0.25 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 >16 >32 4 >16 >8 >8 >16 1 4
99.9 19.52 98.81 99.98 93.88 99.97 99.69 99.17 16.45 99.91 100 99.94
0 0 1.16 0.03 1.56 0 0.25 0.54 0 0 0 0.06
0.1 80.48 0.03 0 4.56 0.03 0.06 0.28 83.55 0.09 0 0
1 4 2 ≤0.12 0.12 2 ≤0.12 ≤0.25 4 1 0.12 1
2 >16 4 0.25 0.5 4 0.25 0.5 >8 2 0.25 1
≤0.03 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 ≤0.12
>8 >16 >64 8 >32 >8 >16 >8 >8 >16 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC, minimum inhibitory concentration; MIC50/90 , MIC for 50% and 90% of the organisms, respectively; AMC, amoxicillin/clavulanic acid; TZP, piperacillin/tazobactam. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
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Table 4 In vitro activity of 12 antibiotics against meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-susceptible S. aureus (MSSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Antibiotic
MRSA (n = 439) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin MSSA (n = 358) AMC Ampicillin Ceftriaxone Imipenem Levofloxacin Linezolid Meropenem Minocycline Penicillin TZP Tigecycline Vancomycin
Susceptibilitya
MIC (g/mL)
%S
%I
%R
MIC50
0 0 0 0 11.2 100 0 87.5 0 0 100 98.4
0 0 0 0 0.7 0 0 9.8 0 0 0 1.6
100 100 100 100 88.1 0 100 2.7 100 100 0 0
>8 >16 >64 16 16 2 16 ≤0.25 >8 >16 0.25 2
100 23.7 96.1 100 90 100 98.9 98.4 18.7 99.7 100 98
0 0 3.6 0 3.6 0 1.1 0.8 0 0 0 2
0 76.3 0.3 0 6.4 0 0 0.8 81.3 0.3 0 0
1 2 4 0.25 0.25 2 ≤0.12 ≤0.25 4 1 0.12 2
MIC90
Min.
Max.
>8 >16 >64 >16 >32 4 >16 8 >8 >16 0.5 2
0.5 2 0.12 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 0.5 0.5 0.03 2
>8 >16 >64 >16 >32 4 >16 >8 >8 >16 0.5 4
2 >16 8 0.5 2 4 1 1 >8 4 0.25 2
0.06 ≤0.06 ≤0.03 ≤0.12 ≤0.06 ≤0.5 ≤0.12 ≤0.25 ≤0.06 ≤0.25 ≤0.008 2
4 >16 >64 0.5 >32 4 8 >8 >8 16 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively; AMC, amoxicillin/clavulanic acid; TZP, piperacillin/tazobactam. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4]. Table 5 Annual in vitro activity of linezolid, minocycline, tigecycline and vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Year
Antibiotic
Susceptibilitya
MIC (g/mL)
%S
%I
%R
MIC50
MIC90
Min.
Max.
2004–2009 (N = 439)
Linezolid Minocycline Tigecycline Vancomycin
100 87.47 100 98.41
0 9.8 0 1.59
0 2.73 0 0
2 ≤0.25 0.25 2
4 8 0.5 2
≤0.5 ≤0.25 0.03 2
4 >8 0.5 4
2004 (n = 65)
Linezolid Minocycline Tigecycline Vancomycin
100 95.38 100 100
0 3.08 0 0
0 1.54 0 0
2 ≤0.25 0.25 2
4 4 0.5 2
≤0.5 ≤0.25 0.06 2
4 >8 0.5 2
2005 (n = 39)
Linezolid Minocycline Tigecycline Vancomycin
100 97.44 100 100
0 2.56 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 2 0.25 2
≤0.5 ≤0.25 0.06 2
4 8 0.5 2
2006 (n = 50)
Linezolid Minocycline Tigecycline Vancomycin
100 90 100 100
0 8 0 0
0 2 0 0
2 ≤0.25 0.25 2
4 4 0.5 2
1 ≤0.25 0.12 2
4 >8 0.5 2
2007 (n = 78)
Linezolid Minocycline Tigecycline Vancomycin
100 87.18 100 98.72
0 8.97 0 1.28
0 3.85 0 0
2 ≤0.25 0.25 2
4 8 0.5 2
≤0.5 ≤0.25 0.06 2
4 >8 0.5 4
2008 (n = 136)
Linezolid Minocycline Tigecycline Vancomycin
100 87.5 100 97.79
0 9.56 0 2.21
0 2.94 0 0
2 0.5 0.25 2
4 8 0.5 2
1 ≤0.25 0.03 2
4 >8 0.5 4
2009 (n = 71)
Linezolid Minocycline Tigecycline Vancomycin
100 73.24 100 95.77
0 22.54 0 4.23
0 4.23 0 0
2 0.5 0.25 2
4 8 0.5 2
1 ≤0.25 0.06 2
4 >8 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
S.P. Hawser et al. / International Journal of Antimicrobial Agents 37 (2011) 219–224
223
Table 6 Annual in vitro activity of linezolid, minocycline, tigecycline and vancomycin against meticillin-susceptible Staphylococcus aureus (MSSA) with elevated vancomycin minimum inhibitory concentrations (MICs) (≥2 g/mL). Year (N)
Antibiotic
Susceptibilitya
MIC (g/mL)
%S
%I
%R
2004–2009 (N = 358)
Linezolid Minocycline Tigecycline Vancomycin
100 98.32 100 98.04
0 0.84 0 1.96
0 0.84 0 0
MIC50 2 ≤0.25 0.12 2
MIC90 4 1 0.25 2
≤0.5 ≤0.25 ≤0.008 2
Min.
Max.
2004 (n = 36)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 0.5 0.25 2
1 ≤0.25 0.06 2
4 0.5 0.25 2
2005 (n = 23)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 1 0.12 2
1 ≤0.25 ≤0.008 2
4 4 0.25 2
2006 (n = 44)
Linezolid Minocycline Tigecycline Vancomycin
100 97.73 100 100
0 2.27 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 0.5 0.25 2
1 ≤0.25 0.06 2
4 8 0.5 2
2007 (n = 82)
Linezolid Minocycline Tigecycline Vancomycin
100 100 100 100
0 0 0 0
0 0 0 0
2 ≤0.25 0.12 2
4 1 0.5 2
1 ≤0.25 0.03 2
4 4 0.5 2
2008 (n = 117)
Linezolid Minocycline Tigecycline Vancomycin
100 97.44 100 98.29
0 1.71 0 1.71
0 0.85 0 0
2 ≤0.25 0.12 2
4 1 0.25 2
≤0.5 ≤0.25 0.03 2
4 >8 0.5 4
2009 (n = 56)
Linezolid Minocycline Tigecycline Vancomycin
100 96.43 100 91.07
0 0 0 8.93
0 3.57 0 0
2 ≤0.25 0.25 2
4 1 0.5 2
1 ≤0.25 0.12 2
4 >8 0.5 4
4 >8 0.5 4
%S, percent susceptible; %I, percent intermediate; %R, percent resistant; MIC50/90 , MIC for 50% and 90% of the organisms, respectively. a Susceptibility breakpoints as defined by the Clinical and Laboratory Standards Institute (CLSI) [13], except for tigecycline whose breakpoints were defined by the US Food and Drug Administration (FDA) product information [4].
phenomenon, with one centre in the USA having reported no change in vancomycin MICs between 1999 and 2006 [16]. In Europe, very gradual increases in glycopeptide MICs have been documented from France [17]. On the other hand, a Spanish study for isolates collected from 2002 to 2006 did not reveal any notable changes in the vancomycin MIC pattern [18]. An analysis of SENTRY surveillance data for the years 1998 to 2003, which included 35 458 S. aureus isolates, detected no change in vancomycin MICs over this time by standard CLSI methods [19]. It may appear from the abovementioned reports that changes in the patterns for vancomycin MICs may not be a phenomenon that all institutions experience. Most of those studies that have described MIC creep for vancomycin involved isolates prior to 2006. Data from the current study have shown that the proportion of isolates with elevated vancomycin MICs for the whole period 2004–2009 were 4.0%, 5.3% and 3.0% for S. aureus, MRSA and MSSA, respectively. The frequency of isolates with elevated MICs to vancomycin (≥2 g/mL) in S. aureus has increased significantly from 4% in 2004 to 7.7% in 2009. MRSA isolates showed a significant increase from 5.6% in 2004 to 11.1% in 2009. The phenomenon was not solely restricted to MRSA; isolates of MSSA with elevated vancomycin MICs rose from 2.6% in 2004 to 5.6% in 2009. Moreover, isolates with elevated vancomycin MICs were widely detected in all geographical regions, ranging from 3.0% in North America to 8.9% in Europe for MRSA isolates and from 1.9% in Africa to 3.8% in Europe and Latin America for MSSA. The data presented in this study demonstrate that the numbers of isolates with elevated vancomycin MICs ≥ 2 g/mL have increased significantly to notable levels of 7.7%, 11.1% and 5.6% in S. aureus, MRSA and MSSA, respectively (P < 0.001). These notable
increases are correlated with reduced susceptibilities to vancomycin and some other antibiotics. However, since the increased MICs demonstrated in this study remained largely within the CLSI susceptible breakpoint of 2 g/mL, only marginal increases in nonsusceptibility were noted without any significant decreases in vancomycin susceptibility over the course of the study. No VRSA were encountered throughout the 6-year study period. Tigecycline and linezolid susceptibilities remained high and were not affected by the increase in frequency of isolates with elevated vancomycin MICs. Three linezolid-resistant isolates were confirmed, one each in North America, Europe and Africa. The data suggest that the phenomenon of elevated vancomycin MICs now appears to be common to all geographical regions. Vancomycin MIC creep will likely further cause concerns as time progresses and, whilst the isolates in this study remained susceptible to tigecycline and linezolid, further surveillance to monitor this phenomenon is highly warranted. Importantly, whilst vancomycin MIC creep is occurring, the absence of high-level resistance to vancomycin is noteworthy. Consequently, MIC creep may be still overcome through appropriate and adequate drug dosing regimens, wherever possible. Funding: This study was sponsored by a grant from Pfizer, Inc. SKB and DJH are employees of International Health Management Associates, who were paid consultants to Pfizer in connection with the conduct of this study and the development of this manuscript. Competing interests: SPH is employed by IHMA Europe Sàrl, a wholly owned affiliate of International Health Management Associates, Inc. SKB and DJH are employed by International Health Management Associates, a clinical research organisation that has
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