Emerging elevated mupirocin resistance rates among staphylococcal isolates in the SENTRY Antimicrobial Surveillance Program (2000): correlations of results from disk diffusion, Etest and reference dilution methods

Diagnostic Microbiology and Infectious Disease 42 (2002) 283–290

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Surveillance

Emerging elevated mupirocin resistance rates among staphylococcal isolates in the SENTRY Antimicrobial Surveillance Program (2000): correlations of results from disk diffusion, Etest and reference dilution methods L.M. Deshpandea, A.M. Fixa, M.A. Pfallerb, The SENTRY Antimicrobial Surveillance Program Participants Group, R. N. Jonesa,c,* a

The JONES Group/JMI Laboratories, North Liberty, IA, USA University of Iowa College of Medicine, Iowa City, IA, USA c Tufts University School of Medicine, Boston, MA, USA

b

Received 25 September 2001; accepted 24 October 2001

Abstract Staphylococci cause one-third of all serious invasive infections in the SENTRY Antimicrobial Surveillance Program including bacteremias and lower respiratory tract infections. Staphylococci are also commensals of the skin and nasal passages; therefore, topical agents active against these organisms are valuable in preventing infections or transfer of the organisms between patients and/or health care workers. Mupirocin is a potent topical anti-staphylococcal compound, but its effectiveness has been compromised by emerging resistance. In early 2000, the SENTRY Program detected 302 mupirocin-resistant isolates (131 Staphylococcus aureus, and 171 coagulase-negative staphylococci [CoNS]) from the United States (19/25 medical centers), Canada (4/5), Latin America (3/9) and Europe (7/18). One hundred sixty-eight mupirocin-resistant and 59 susceptible isolates were tested further by reference MIC, Etest (AB BIODISK, Solna, Sweden) and disk diffusion (5-␮g) methods. Mupirocin resistance rates for blood stream infections varied by geographic area: for S. aureus from 1.9 to 5.6%, and for CoNS from 12.8 to 39.9%. Using elevated mupirocin MIC results, two resistant populations were noted: low-level resistance at 8 –128 ␮g/mL and high-level resistance at ⱖ1024 ␮g/mL. Acceptable correlation was observed between Etest and disk diffusion results (r ⫽ 0.84) without serious intermethod interpretive errors. High-level resistant isolates had heavy growth with no visible zone around the disk; low-level resistant isolates produced hazy zones of inhibition, and susceptible strains had clear zones of inhibition at ⱖ17 mm. As mupirocin resistance can be plasmid-mediated, the prudent and appropriate use of this topical agent is important to minimize the ongoing development of resistance. Local surveillance for emerging mupirocin resistance appears warranted particularly in the United States and Canada, pragmatically using a disk diffusion test screening. Where more precise data are needed, the Etest is a very accurate method for distinguishing mupirocin low-level from high-level resistance patterns. © 2002 Elsevier Science Inc. All rights reserved.

1. Introduction Staphylococci (Staphylococcus aureus and coagulasenegative staphylococci [CoNS]) are the cause of one-third of all serious invasive infections within the SENTRY Antimicrobial Surveillance Program; 35% of the bacteremias and 27% of all lower respiratory tract infections (LRTI). Staphylococci are also commensals of the skin and nasal passages; therefore, topical agents against these organisms * Corresponding author. Tel.: ⫹1-319-665-3370; fax: ⫹1-319-6653371. E-mail address: [email protected] (R. Jones).

are valuable in preventing serious endogenous infection and transfer between patients and/or health care workers. Mupirocin (pseudomonic acid) was first marketed for clinical use in the United Kingdom (UK) in 1985 and in the United States (US) in 1988 (Mehtar, 1998). In addition to preventing the spread of staphylococcal infections from nasal passages (Scully et al., 1992), mupirocin has been used as a topical agent to prevent staphylococcal dialysis exit-site infections (Bloom et al., 1996), post-operative and skin infections, and infections of burn wounds. The 2% (20,000 ␮g/mL) mupirocin ointment has been used as therapy for superficial skin infections such as impetigo, infected eczema and wound infections (Poupard, 1995).

0732-8893/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 2 - 8 8 9 3 ( 0 1 ) 0 0 3 2 8 - 5

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Two types of mupirocin resistance are recognized, the first a low-level pattern (MIC, 8 –256 ␮g/mL), has been attributed to mutations of chromosomally encoded IRS protein. The second, a high-level mupirocin resistance (mup A), is caused by plasmid-encoded isoleucine t-RNA synthetase, a second resistant IRS enzyme (Gilbart et al., 1993; Nunes et al., 1999). Low-level resistance is generally not transferable (Ramsey et al., 1996) and of less clinical concern, but transmission between strains or species remains highly probable for the high-level resistance genes (Woodford et al., 1998). With the wide use of mupirocin came reports of resistance from different parts of the world such as Australia (Riley et al., 1994), Brazil (Ramos et al., 1999), Canada (Miller et al., 1996), New Zealand (Hefferman et al., 1995; Skellen et al., 1998), Poland (Leski et al., 1999), Saudi Arabia (Rich et al., 1999), Spain (Alarcon et al., 1998), UK (Wise & Johnson, 1991; Connolly et al., 1993), US (Bradley et al., 1995), and the concern that mupirocin-resistant staphylococci may evolve into a serious threat to hospital or community infection control (Cookson, 1998). Also mupirocin resistance has emerged during treatment or prophylaxis of indicated infections (Henkel & Finlay, 1998; Zakrzewska-Bode et al., 1995). In the year 2000 SENTRY Antimicrobial Surveillance Program (Pfaller et al., 1998), we investigated the incidence of mupirocin resistance in staphylococci isolated from blood stream and other hospital-acquired infections. We believe this report represents the first global assessment of emerging resistance to this valuable topical agent.

2. Materials and methods 2.1. Bacteria A total of 2,159 isolates of S. aureus and 617 isolates of CoNS were screened for resistance to mupirocin using a reference broth microdilution format. The isolates were from the SENTRY Program 2000 collection and represented strains from bloodstream infections (Objective A), pneumonia in hospitalized patients (Objective C), skin and soft tissue infections (Objective D), and urinary tract infections (Objective E; see Tables 2 and 3). Strains were submitted from 57 participating medical centers in the US (25 centers), Canada (5 centers), Latin America (9 centers) and Europe (18 centers). Based on broth microdilution MIC testing, 131 S. aureus and 171 CoNS were determined to be resistant to mupirocin (MIC, ⱖ16 ␮g/mL). From these 302 strains, a subset of 80 S. aureus and 88 CoNS were used in subsequent studies. An additional 59 mupirocin-susceptible strains of staphylococci were included as susceptible test controls.

Table 1 Distribution of mupirocin-resistant (MIC, ⱖ16 ␮g/mL) strains and resistance rates among 2,776 staphylococcal isolates in the SENTRY Antimicrobial Surveillance Program (2000) Region

Europe Latin America North America Total

CoNSa

S. aureus OxacillinS (1,345)

OxacillinR (814)

OxacillinS (130)

OxacillinR (487)

1.9 0.0 1.5 1.3

17.8 4.6 14.1 13.8

6.7 5.9 6.0 6.2

14.0 33.7 43.1 32.4

a CoNS ⫽ coagulase-negative staphylococci. OxacillinS ⫽ oxacillin-susceptible (MIC, ⱕ2 ␮g/mL [S. aureus] or ⱕ0.25 ␮g/mL [CoNS]) OxacillinR ⫽ oxacillin-resistant (MIC, ⱖ4 ␮g/mL [S. aureus] or ⱖ0.5 ␮g/mL [CoNS]) per NCCLS [2002].

2.2. Susceptibility testing All isolates were tested initially by the microdilution method in cation-adjusted Mueller-Hinton broth (NCCLS, 2000b). Mupirocin powder was obtained from the manufacturer (GlaxoSmithKline, Collegeville, PA) and the microdilution trays were prepared by TREK Diagnostic Systems, Inc. (Westlake, OH). Potential co-resistances to an additional 11 antimicrobial agents (tetracycline, rifampin, trimethoprim/sulfamethoxazole, gentamicin, erythromycin, clindamycin, chloramphenicol, ciprofloxacin, vancomycin, quinupristin/dalfopristin, and linezolid) were also determined by broth microdilution performed according to reference guidelines (NCCLS, 2000a). Mupirocin-resistant (168 isolates) and -susceptible (59 isolates; 38 S. aureus and 21 CoNS) isolates were also tested using the mupirocin Etest (AB BIODISK, Solna, Sweden) and a 5-␮g mupirocin disk (BD Microbiology Systems, Cockeysville, MD) on Mueller-Hinton agar plates (PML Microbiologicals, Wilsonville, OR) (NCCLS, 2000b). Interpretations of susceptibility test results were those of the NCCLS (2002) or those recommended by the mupirocin manufacturer (Finlay et al., 1997; Poupard, 1999). 2.3. Molecular typing Mupirocin-resistant strains were further characterized by automated ribotyping (RiboPrinterTM, Qualicon, Wilmington, DE) and pulsed-field gel electrophoresis (PFGE).

3. Results The geographic distribution of mupirocin-resistant strains among 2776 staphylococci, isolated from the 2000 SENTRY Program is shown in Table 1. For S. aureus, mupirocin resistance rates ranged from 0% to 1.9% in oxacillin-susceptible strains and from 4.6% to 17.8% in oxacillin-resistant strains (814 strains, 37.6% of S. aureus

L.M. Deshpande et al. / Diagnostic Microbiology and Infectious Disease 42 (2002) 283–290 Table 2 Mupirocin resistance rates among Staphylococcus aureus isolates listed by geographic region and site of infectiona Region

United States

No of centers

Objectivea (no. tested)

% mupirocin-resistant Average

Rangeb

24

A (625) C (594) D (58) E (8) Total (1,285) A (96) C (101) D (14) Total (211) A (154) C (11) D (140) E (9) Total (314) A (170) C (169) D (13) E (1) Total (353)

5.6 8.2 5.2 12.5 6.8 4.2 3.9 7.0 4.3 1.9 0.0 0.7 0.0 1.3 3.5 14.1b 6.7 0.0 8.7b

0.0–17.1 0.0–30.2 0.0–8.1 0.0–100.0 0.0–100.0 0.0–13.3 0.0–14.3 7.0 0.0–14.3 0.0–5.6 0.0 0.0–4.2 0.0 0.0–5.6 0.0–9.1 0.0–64.2 0.0–33.3 0.0 0.0–64.2

Canada

4

Latin America

9

Europe

18

a

SENTRY Program objectives: A, blood stream infections; C, pneumonia in hospitalized patients; D, skin and soft tissue infections; E, urinary tract infections. b High resistance rate heavily influenced by one epidmeic cluster (see Figure 1). Range among monitored medical centers.

were oxacillin-resistant). In contrast, mupirocin resistance rates were much higher among CoNS isolates, ranging from 5.9% to 6.7% in oxacillin-susceptible strains and from 14.0% to 43.1% in oxacillin-resistant strains (487 strains, 78.9% CoNS were oxacillin-resistant). Resistance to mupirocin was generally more prevalent among oxacillin-resistant isolates as well as greater in North America or European isolates of S. aureus. The largest number of samples screened for mupirocin resistant strains were from the blood stream infection isolates (1045/2163, 48%, for S. aureus, and 542/617, 88% for CoNS) and pneumonia isolates (876/2163, 40.5% for S. aureus, and 22/617, 3.6%, for CONS). Average resistance rates for blood stream infections in S. aureus ranged from 1.9% to 5.6% (Table 2), contrasting sharply with the results in CoNS (12.2% in Europe to 39.9% in the US; Table 3). The range of average resistance rates in pneumonia for S. aureus was wider (0%–14.1%), but one region provided only 11 isolates (0% mupirocin resistance), making interpretation of the results difficult. Mupirocin resistance rates in pneumonia isolates were highest in Europe (14.1%), followed by the US (8.2%). The largest number of mupirocin-resistant S. aureus (Table 2) came from the US (87 strains; 6.8% of all isolates) followed by Europe (31 strains; 8.7% of all isolates). Latin America only had four mupirocin-resistant strains and an overall resistance rate of only 1.3%. The high rate in Europe was adversely effected by an ongoing epidemic in one medical center in the UK. For the

285

CoNS strains (Table 3), nearly nine of 10 isolates were from blood cultures and the mupirocin resistance rates for this infection site ranged from 12.2% (Europe) to 39.9% (US). The highest numbers of mupirocin-resistant strains and rates overall was observed in the US (38.8% resistant) (Table 3). The percentages of resistance for these infections in the monitored medical centers are illustrated in Fig. 1. There were marked differences in the distribution of mupirocinresistant isolates among the different medical centers. Approximately one-half of these medical centers (25 for Objective A and 26 for Objective C) did not observe any mupirocin-resistant isolates. An analysis by medical center revealed that up to one-half of center participants reporting blood stream infection cases recorded resistance levels between 3% and 17%. An ongoing epidemic cluster from one European site (pneumonia, S. aureus) accounted for the highest percentage (64%) of resistant isolates (Fig. 1). Three other centers had mupirocin resistance rates of 20% to ⬎30% among S. aureus. There were some clusters with 2 to 4 isolates, while based on Ribotyping and PFGE patterns, other isolates were totally different from each other. A large number of the mupirocin-resistant isolates that occurred in clusters were also resistant to oxacillin or multiple antimicrobial agents. Predominant among them was a set of 17 S. aureus isolates (UK medical center epidemic), all of which were oxacillinresistant as well as mupirocin-resistant. Upon molecular typing these strains were found to share the same PFGE pattern (Fig. 3). Only one isolate showed a slightly different subtype. These results clearly indicated clonal disseminaTable 3 Mupirocin resistance among CoNS isolates listed by geographic region and site of infectiona Region

United States

No of centers

Objectivea (no. tested)

% mupirocin-resistant Average

Range

22

A (233) C (10) D (2) E (7) Total (252) A (63) C (4) D (8) E (4) Total (79) A (75) C (1) D (24) E (6) Total (106) A (171) C (7) D (2) Total (180)

39.9 16.7 100.0 33.3 38.8 28.5 0.0 12.5 0.0 24.1 28.0 100.0 37.5 0.0 29.2 12.2 14.3 50.0 12.7

0.0–52.4 0.0–50.0 100.0 25.0–50.0 0.0–100.0 20.0–41.2 0.0 12.5 0.0 0.0–41.2 0.0–100.0 100.0 0.0–80.0 0.0 0.0–100.0 0.0–66.7 0.0–50.0 50.0 0.0–66.7

Canada

5

Latin America

8

Europe

15

a SENTRY Program objectives: A, blood stream infections; C, pneumonia in hospitalized patients; D, skin and soft tissue infections; E, urinary tract infections.

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Fig. 1. Number of medical centers having mupirocin resistance rates (%) for isolates from blood stream infections and pneumonia patients.

tion of the mupirocin-resistant S. aureus within this institution. As shown in Table 4, oxacillin susceptibility among S. aureus had a substantial impact on the susceptibility/spectrum of mupirocin and the other drugs. The S. aureus isolates within the oxacillin-resistant subset (both mupirocin-resistant and mupirocin-susceptible) were significantly more resistant to 8 of the 11 classes of drugs tested (Table 4). Linezolid, quinupristin/dalfopristin and vancomycin were relatively unaffected by the resistance patterns for mupirocin or oxacillin. The highest resistance rates (ciprofloxacin, clindamycin, erythromycin) were observed among mupirocin-resistant, oxacillin-resistant isolates. The testing results for CoNS listed by oxacillin and mupirocin resistance patterns are displayed in Table 5. For this group of staphylococci, only the resistance to erythromycin approximated the pattern observed with S. aureus. Overall, antimicrobial activity was equivalent to, or higher for all tested compounds by analysis group when compared to the results for S. aureus (Table 4). Essentially all isolates were susceptible to linezolid and vancomycin, and ⬎98% of strains were susceptible to quinupristin/dalfopristin (no resistance). All isolates with a mupirocin MIC of ⱖ8 ␮g/mL had zone diameters of 6 mm (Fig. 3). There was excellent correlation between disk diffusion and Etest results and a highly acceptable prediction of resistance. All the suscepti-

ble isolates showed zone diameters of ⱖ17 mm. For highlevel resistant strains (Etest MIC, ⬎256 ␮g/mL) the growth was confluent to the disk or Etest edge, whereas for the low-level resistance there was always a hazy zone of growth around the disk within a faint, but visible zone of inhibition. A comparison of the reference screening microdilution test results (NCCLS, 2000a) and the Etest showed excellent correlation (Table 6). The high- and low-level mupirocinresistant strains were easily recognized by the Etest with low-level strains having MIC values between 8 and 128 ␮g/ml and all high-level mupirocin-reistant strains producing MICs at ⱖ1024 ␮g/ml (90 of 168 resistant strains tested; 53.6%).

4. Discussion The first report of high-level resistance to mupirocin was by Rahman et al. [1987] in methicillin-susceptible S. aureus, although mupirocin resistance has also been described in isolates stored prior to the first clinical use of the drug (Cookson, 1994). Resistance has frequently been attributed to the clinical use of mupirocin over extended periods (Udo et al., 1997) or in areas of highly concentrated application, such as dermatology or burns units (Eltringham, 1997; Poupard, 1995). A recent report describes the emergence of low-level resistance to mupirocin in oxacillin-resistant S.

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287

Fig. 2. PFGE gel of the 17 mupirocin-resistant isolates from Europe. Lane 1, 48.5 ␭ ladder, lanes 2–18, PFGE pattern of the 17 mupirocin-resistant isolates.

aureus cultured from the pharynx of a patient treated with intranasal mupirocin ointment (Watanabe et al., 2001). The authors conclude that “ . . . nasal application of mupirocin at clinically effective concentrations may result in low levels of the antibiotic in the pharynx, which could consequently induce or select for the emergence of mupirocin-resistant MRSA.” This study is, we believe, the first to document the extent of global resistance to mupirocin, covering 57 centers in 20 countries as part of the SENTRY Program (Pfaller et al., 1998). The previous most complete survey of mupirocin resistance was described by Schmitz et al. (1998) and documented low- and high-level resistance from 19 hospitals in 12 countries These authors reported high-level resistance in 1.6% of S. aureus and 5.6% in CoNS strains and low-level resistance in 2.3% of S. aureus and 7.2% of CoNS isolates. In our study, average mupirocin resistance rates for S. aureus varied from 1.3% in Latin America to 7.0% in the US, and for CoNS from an average of 13.3% in Europe to 37.3% in the US; each rate a marked increase. Analysis of mupirocin resistance rates by region is made difficult by the wide variation between centers within a geographic region. The small numbers of samples collected for certain infection types also hampered analysis of these results. There was no clear correlation between the site of infection and the mupirocin resistance rate, a result that confirms the findings of others (Schmitz et al., 1998).

When the 2,776 strains of S. aureus and CoNS were tested against a panel of 11 antimicrobial agents, the highest resistance rates were documented for ciprofloxacin, clindamycin and erythromycin in both staphylococcal groups. Much lower susceptibilities to these three agents were documented in the oxacillin-resistant, mupirocin-resistant strains for both the S. aureus and CoNS groups. Linezolid, quinupristin/dalfopristin and vancomycin maintained high activity against essentially all staphylococcal isolates. The correlation between the reference broth microdilution and Etest (AB BIODISK) MIC values (Simpson et al., 1995) using a subset of 168 (80 S. aureus, 88 CoNS) mupirocin-resistant strains was excellent (Table 6), with a clear division into two groups (high- and low-level resistance). The 90 staphylococcal strains with mupirocin MICs at ⱖ1024 ␮g/mL all had heavy, confluent growth with no detectable zones around the disks or Etest strips. A correlation between Etest strips and reference broth microdilution/method results was reported in an evaluation of Etest strips and 5-, 25- and 100-␮g mupirocin disks (Palepou et al., 1998). These authors concluded that the 25 ␮g disks produced a good correlation with the Etest strips. The 5- and 100-␮g disk strengths were not reliable enough to detect all HLR S. aureus, or to discriminate between low- and highlevel resistances. In contrast, in our hands the results using the 5-␮g disk (Fig. 3) correlated well with the results obtained from the highly accurate and quantitatively precise

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Fig. 3. Scattergram comparing the results of Etest (MICs in ␮g/ml) with the zones around a 5-␮g mupirocin disk.

Etest (AB BIODISK) strips. A rapid PCR method has also been developed to recognize the high-level mupirocin resistance pattern (Anthony et al., 1999). Mupirocin resistance appears to be increasing worldwide

with its escalated use, but varies greatly from institutionto-institution regardless of geographic region monitored. In vitro testing using a susceptible breakpoint of either ⱕ4 or ⱕ8 ␮g/mL functions very well, and the Etest (AB

Table 4 Antimicrobial activity/spectrum of 11 compounds tested against 2,159 strains of S. aureus categorized by oxacillin and mupirocin susceptibility patterns Antimicrobial agent

% susceptibility of all strains Oxacillin-susceptiblea

Chloramphenicol Ciprofloxacin Clindamycin Erythromycin Gentamicin Rifampin Tetracycline Trimethoprim/Sulfamethoxazole Linezolid Quinupristin/Dalfopristin Vancomycin a b

Oxacillin-resistanta

Mupirocin-susc.b (1,325)

Mupirocin-resist.b (18)

Mupirocin-susc.b (700)

Mupirocin-resist.b (116)

95.3 96.2 97.1 80.2 98.3 98.8 93.7 97.5 100.0 99.8 100.0

100.0 83.3 83.3 50.0 72.2 100.0 94.4 88.9 100.0 100.0 100.0

65.8 7.8 22.6 6.0 58.4 77.8 72.9 73.5 100.0 98.9 100.0

67.0 1.8 6.3 4.5 43.8 92.0 90.2 77.7 100.0 98.2 100.0

Susceptibility at ⱕ2 ␮g/mL and resistant at ⱖ4 ␮g/mL. Susceptible at ⱕ8 ␮g/mL and resistant at ⱖ16 ␮g/mL.

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Table 5. Antimicrobial activity/spectrum of 11 compounds tested against 617 strains of CoNSa categorized by oxacillin and mupirocin susceptibility patterns Antimicrobial agent

% susceptibility of all strains Oxacillin-susceptibleb

Chloramphenicol Ciprofloxacin Clindamycin Erythromycin Gentamicin Rifampin Tetracycline Trimethoprim/Sulfamethoxazole Linezolid Quinupristin/Dalfopristin Vancomycin

Oxacillin-resistantb

Mupirocin-susc.c (122)

Mupirocin-resist.c (8)

Mupirocin-susc.c (327)

Mupirocin-resist.c (160)

97.5 91.8 95.1 74.6 97.5 97.5 84.4 86.9 100.0 100.0 100.0

87.5 87.5 62.5 25.0 75.0 87.5 87.5 62.5 100.0 100.0 100.0

79.9 45.0 58.4 25.8 46.0 82.4 75.4 43.8 100.0 99.1 99.7

77.2 25.3 36.1 8.9 36.7 71.5 81.0 36.1 100.0 99.4 99.4

CoNS ⫽ coagulase-negative staphylococci. Susceptible at ⱕ0.25 ␮g/mL and resistant at ⱖ0.5 ␮g/mL. c Susceptible at ⱕ8 ␮g/mL and resistant at ⱖ16 ␮g/mL. a

b

BIODISK) accurately discriminates between high- and lowlevel resistance patterns (Table 6). Continued global surveillance for mupirocin resistance appears prudent, as well as, the local testing where institutions utilize large amounts for topical control of cutaneous or catheter-related infections. The practical use of a disk diffusion method as the initial screen supported by dilution or stable gradient confirming tests appears to be the best surveillance solution.

Acknowledgments The co-authors express their thanks to the following persons for support in bringing this manuscript to press: M.L. Beach, M.G. Stilwell, K.L. Meyer, D.J. Biedenbach, and D. Varnam. The SENTRY Program was funded by an educational/research grant from Bristol-Myers Squibb.

References

Table 6. Correlation between the reference broth microdilution (RBM) screen results and the Etest MICs for mupirocin when testing all staphylococci Etest MIC (␮g/mL)

ⱕ0.06 0.12 0.25 0.5 1 2 4a 8b 16 32 64 128 256c 512 ⱖ1024 a

RBM MIC (␮g/mL) ⱕ8

16

⬎16

4 31 22 1 -

1 11 16 -

1 13 27 8 1 90

Breakpoint often advocated by the mupirocin manufacturers. Assigned intermediate concentration for the SENTRY Program screen. c Concentration indicating the upper limit of so-called “low-level mupirocin resistance”. b

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