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Ronald N. Jones, Rodrigo E. Mendes, Helio S. Sader, Mariana Castanheira, In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008–2009) Gram-Positive Organisms Collected in the United States, Clinical Infectious Diseases, Volume 52, Issue suppl_7, June 2011, Pages S477–S486, https://doi.org/10.1093/cid/cir163
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Abstract
Fusidic acid has a long history of consistent activity against staphylococcal pathogens including methicillin-resistant Staphylococcus aureus (MRSA). Fusidic acid (CEM-102) was susceptibility tested against a surveillance study collection of 12,707 Gram-positive pathogens (2008–2009) from the United States. Reference broth microdilution method results demonstrated the following MIC50/90 results: S. aureus (.12/.25 μg/mL), coagulase-negative staphylococci (.12/.25 μg/mL), enterococci (4/4 μg/mL), Streptococcus pyogenes (4/8 μg/mL), and viridans group Streptococcus spp. (>8/>8 μg/mL). At a proposed susceptible breakpoint (≤1 μg/mL), fusidic acid inhibited 99.7% of MRSA strains and 99.3% to 99.9% of multidrug-resistant phenotypes of S. aureus. Furthermore, S. aureus strains nonsusceptible to fusidic acid (.35%) generally had detectable resistance mechanisms (fusA, B, C, and E). Reviews of in vitro susceptibility test development confirm the accuracy and intermethod reproducibility of various fusidic acid methods. Fusidic acid is a promising oral therapy for staphylococcal skin and skin structure infections in the United States, where the contemporary S. aureus population remains without significant resistance.
Fusidic acid, also known as CEM-102, is a steroid-class antimicrobial agent initially identified from Fusidium coccineum by Godtfredsen et al [1–3] in 1960. That organism was found in a primate (monkey) stool culture. Such steroidal agents, however, have no corticosteroid activity, yet exhibit a well-characterized potency against staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococcal species (CoNS) [4]. Fusidic acid was introduced into clinical trials in 1962 as a potential systemic and topical therapy for staphylococcal skin and skin structure infections [4–6].
The structure of fusidic acid (Figure 1) as a sodium salt is water soluble and active via the oral route (molecular weight, 538.7; pK, 5.35) [4]. Biedenbach and colleagues recently redefined the fusidic acid spectrum and activity against a wide range of pathogens as follows: S. aureus (minimum inhibitory concentration [MIC], .25 μg/mL), Micrococcus luteus (MIC, .25–.5 μg/mL), Corynebacterium spp. (MIC, .06–.12 μg/mL), Moraxella catarrhalis (MIC, .06–.12 μg/mL), and Neisseria meningitidis (MIC, .12–.25 μg/mL); Streptococcus spp., not S. pyogenes (MIC, 16–32 μg/mL), and enterococci (MIC, 2–8 μg/mL) were less susceptible with Gram-negative bacilli being frankly resistant at fusidic acid MIC values of ≥32 μg/mL [7]. This range of activity is the result of drug interactions with elongation factor G (EF-G) that prevents its release from the ribosome, thus compromising protein synthesis [8–10], a mode of action that continues to be actively studied [11–13].
Fusidic acid resistance has long been thought to be caused by mutations of the EF-G-encoding gene [12, 14]. More recently acquired mechanisms (fusB and C) were detected as mobile elements that can either be chromosome- or plasmid-mediated in staphylococci [15–21]. At least 5 mechanisms exist (fusA–E), producing staphylococcal resistance correlating with fusidic acid MIC values ≥2 μg/mL [22, 23]. As this antimicrobial was used clinically worldwide, microbiologists in some nations encountered Gram-positive pathogens with elevated fusidic acid resistance rates (eg, United Kingdom, Ireland, Greece); in contrast, in the United States (US), the US Food and Drug Administration (FDA) has not approved this agent for therapeutic use by any route of administration. Thus, this unique steroidal antimicrobial, if used in the US, would be prescribed for treatment of a naïve population of Staphylococcus species [22, 23], as compared with a country like Australia [22, 24, 25].
In this report, we summarize the results of a fusidic acid resistance surveillance study in the US for 2008 and 2009. We also describe the recently published investigations defining fusidic acid susceptibility rates globally when tested against various Gram-positive pathogens, as well as the status of in vitro diagnostic methods for clinical application.
MATERIALS AND METHODS
Bacterial Strains
A total of 7339 S. aureus strains collected in 51 US medical centers, located in the 9 census regions, were analyzed as part of the SENTRY Antimicrobial Surveillance Program (2008–2009). These isolates were obtained from bloodstream, respiratory tract infections, and skin and skin structure infections, according to defined protocols. An additional 5368 Gram-positive organisms were sampled as follows: CoNS (1352), enterococci (2448), β-hemolytic streptococci (1255), and viridans group Streptococcus spp. (313) (Table 2). Only 1 isolate per patient from documented infections was included. Species identification was confirmed by standard biochemical tests, the Vitek 2 System (bioMérieux), or 16S ribosomal RNA sequencing, when necessary.
Antimicrobial Susceptibility Testing
Isolates were susceptibility tested by a reference broth microdilution procedure as described by the Clinical and Laboratory Standards Institute (CLSI) [28] using validated microdilution panels (TREK Diagnostics). Categorical interpretations for all antimicrobials were those found in M100-S20-U [26], and quality control was performed using Escherichia coli (ATCC 25922), S. aureus (ATCC 29213), and Enterococcus faecalis (ATCC 29212). All quality control results were within specified ranges as published in CLSI documents [26]. For fusidic acid, the interpretive susceptibility criteria of the European Committee on Antimicrobial Susceptibility Testing (EUCAST; 2010) were applied at ≤1 μg/mL [27], and quality control ranges were used based on the recent study reported by Jones and Ross [29].
Detection of Fusidic Acid Resistance Mechanisms
All strains displaying fusidic acid MIC at ≥2 μg/mL (EUCAST resistant breakpoint) were tested for the presence of fusB, fusC, and fusD in a multiplex polymerase chain reaction approach. Detection of fusD (intrinsic in S. saprophyticus) was included in this reaction to detect strains that were incorrectly identified as other staphylococcal species.
Constitutive genes fusA and fusE were amplified and sequenced using Extensor Hi-Fidelity Master Mix (ABgene) as well as custom and previously described oligonucleotides [22, 23]. Sequencing was performed in 5 and 2 reactions, respectively. The nucleotide sequences and deduced amino acid sequences were analyzed using Lasergene software version 8.1.5 (DNASTAR) and compared with sequences available through the internet using BLAST, the Basic Local Alignment Search Tool (http://www.ncbi.nlm.nih.gov/blast/).
RESULTS AND DISCUSSION
Fusidic Acid Activity Against S. aureus
A total of 7339 S. aureus strains among 12,707 Gram-positive pathogens tested in the US SENTRY surveillance program in 2008–2009 were analyzed here. Of the S. aureus strains, 3876 (52.8%) were MRSA and the sample numbers were 3962 (2008) and 3377 (2009) (Table 1). Most of the S. aureus strains were from bacteremias (46.0%), skin and skin structure infections (31.5%), and lower respiratory tract cultures (16.6%).
Number (cumulative %) inhibited at MIC (μg/mL) | MIC (μg/mL) % | ||||||||||
Organism/resistance patterna(no. tested/% of total) | ≤.06 | 0.12 | .25 | .5 | 1 | 2 | 4 | 8 | 50% | 90% | ≤1 μg/mLb |
All S. aureus (7339/100.0) | 1070 (14.6) | 5327 (87.2)c | 826 (98.4) | 70 (99.4) | 20 (99.7) | 10 (99.8) | 8 (99.9) | 8 (100.0) | .12 | .25 | 99.7 |
2008 S. aureus (3962/54.0) | 397 (10.0) | 3066 (87.4) | 434 (98.4) | 48 (99.6) | 5 (99.7) | 3 (99.8) | 3 (99.8) | 6 (100.0) | .12 | .25 | 99.7 |
2009 S. aureus (3377/46.0) | 673 (19.9) | 2261 (86.9) | 392 (98.5) | 22 (99.1) | 15 (99.6) | 7 (99.8) | 5 (99.9) | 2 (100.0) | .12 | .25 | 99.6 |
MRSA (3876/52.8) | 493 (12.7) | 2884 (87.1) | 435 (98.3) | 38 (99.3) | 15 (99.7) | 8 (99.9) | 2 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
MSSA (3463/47.2) | 577 (16.7) | 2443 (87.2) | 391 (98.5) | 32 (99.4) | 5 (99.6) | 2 (99.6) | 6 (99.8) | 7 (100.0) | .12 | .25 | 99.6 |
OX, ER, CP (1364/18.6) | 149 (10.9) | 1017 (85.5) | 184 (99.0) | 9 (99.6) | 3 (99.9) | 2 (100.0) | - | - | .12 | .25 | 99.9 |
OX, ER, CL, CP (1156/15.7) | 97 (8.4) | 859 (82.7) | 168 (97.2) | 20 (99.0) | 7 (99.6) | 4 (99.9) | 1 (100.0) | - | .12 | .25 | 99.6 |
OX, ER (751/10.2) | 141 (18.8) | 574 (95.2) | 27 (98.8) | 3 (99.2) | 4 (99.7) | 0 (99.7) | 2 (100.0) | - | .12 | .12 | 99.7 |
ER (729/10.0) | 115 (15.8) | 523 (87.5) | 83 (98.9) | 5 (99.6) | 1 (99.7) | 1 (99.9) | 1 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
ER, CP (177/2.4) | 27 (15.3) | 125 (85.9) | 20 (97.2) | 2 (98.3) | 2 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
OX, CL, CP (137/1.9) | 23 (16.8) | 104 (92.7) | 7 (97.8) | 2 (99.3) | 0 (99.3) | 0 (99.3) | 0 (99.3) | 1 (100.0) | .12 | .12 | 99.3 |
ER, CL, CP (112/1.5) | 12 (10.7) | 83 (84.8) | 16 (99.1) | 1 (100.0) | - | - | - | - | .12 | .25 | 100.0 |
Pan-R (170/2.4) | 31 (18.2) | 116 (86.5) | 22 (99.4) | 0 (99.4) | 0 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
Number (cumulative %) inhibited at MIC (μg/mL) | MIC (μg/mL) % | ||||||||||
Organism/resistance patterna(no. tested/% of total) | ≤.06 | 0.12 | .25 | .5 | 1 | 2 | 4 | 8 | 50% | 90% | ≤1 μg/mLb |
All S. aureus (7339/100.0) | 1070 (14.6) | 5327 (87.2)c | 826 (98.4) | 70 (99.4) | 20 (99.7) | 10 (99.8) | 8 (99.9) | 8 (100.0) | .12 | .25 | 99.7 |
2008 S. aureus (3962/54.0) | 397 (10.0) | 3066 (87.4) | 434 (98.4) | 48 (99.6) | 5 (99.7) | 3 (99.8) | 3 (99.8) | 6 (100.0) | .12 | .25 | 99.7 |
2009 S. aureus (3377/46.0) | 673 (19.9) | 2261 (86.9) | 392 (98.5) | 22 (99.1) | 15 (99.6) | 7 (99.8) | 5 (99.9) | 2 (100.0) | .12 | .25 | 99.6 |
MRSA (3876/52.8) | 493 (12.7) | 2884 (87.1) | 435 (98.3) | 38 (99.3) | 15 (99.7) | 8 (99.9) | 2 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
MSSA (3463/47.2) | 577 (16.7) | 2443 (87.2) | 391 (98.5) | 32 (99.4) | 5 (99.6) | 2 (99.6) | 6 (99.8) | 7 (100.0) | .12 | .25 | 99.6 |
OX, ER, CP (1364/18.6) | 149 (10.9) | 1017 (85.5) | 184 (99.0) | 9 (99.6) | 3 (99.9) | 2 (100.0) | - | - | .12 | .25 | 99.9 |
OX, ER, CL, CP (1156/15.7) | 97 (8.4) | 859 (82.7) | 168 (97.2) | 20 (99.0) | 7 (99.6) | 4 (99.9) | 1 (100.0) | - | .12 | .25 | 99.6 |
OX, ER (751/10.2) | 141 (18.8) | 574 (95.2) | 27 (98.8) | 3 (99.2) | 4 (99.7) | 0 (99.7) | 2 (100.0) | - | .12 | .12 | 99.7 |
ER (729/10.0) | 115 (15.8) | 523 (87.5) | 83 (98.9) | 5 (99.6) | 1 (99.7) | 1 (99.9) | 1 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
ER, CP (177/2.4) | 27 (15.3) | 125 (85.9) | 20 (97.2) | 2 (98.3) | 2 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
OX, CL, CP (137/1.9) | 23 (16.8) | 104 (92.7) | 7 (97.8) | 2 (99.3) | 0 (99.3) | 0 (99.3) | 0 (99.3) | 1 (100.0) | .12 | .12 | 99.3 |
ER, CL, CP (112/1.5) | 12 (10.7) | 83 (84.8) | 16 (99.1) | 1 (100.0) | - | - | - | - | .12 | .25 | 100.0 |
Pan-R (170/2.4) | 31 (18.2) | 116 (86.5) | 22 (99.4) | 0 (99.4) | 0 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
Most prevalent resistance patterns noted among Staphylococcus aureus. MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; CL, clindamycin; CP, ciprofloxacin; ER, erythromycin; OX, oxacillin; Pan-R, Pan-resistant phenotype (resistance to 5 antimicrobial classes). Criteria for susceptibility were those published by the Clinical and Laboratory Standards Institute (M100 - S20 - U, 2010) [26]. Intermediate and resistant results grouped as resistant.
Fusidic acid minimum inhibitory concentration breakpoint published by the European Committee on Antimicrobial Susceptibility Testing (2010) [27].
Modal MIC value (0.12 μg/ml)
Number (cumulative %) inhibited at MIC (μg/mL) | MIC (μg/mL) % | ||||||||||
Organism/resistance patterna(no. tested/% of total) | ≤.06 | 0.12 | .25 | .5 | 1 | 2 | 4 | 8 | 50% | 90% | ≤1 μg/mLb |
All S. aureus (7339/100.0) | 1070 (14.6) | 5327 (87.2)c | 826 (98.4) | 70 (99.4) | 20 (99.7) | 10 (99.8) | 8 (99.9) | 8 (100.0) | .12 | .25 | 99.7 |
2008 S. aureus (3962/54.0) | 397 (10.0) | 3066 (87.4) | 434 (98.4) | 48 (99.6) | 5 (99.7) | 3 (99.8) | 3 (99.8) | 6 (100.0) | .12 | .25 | 99.7 |
2009 S. aureus (3377/46.0) | 673 (19.9) | 2261 (86.9) | 392 (98.5) | 22 (99.1) | 15 (99.6) | 7 (99.8) | 5 (99.9) | 2 (100.0) | .12 | .25 | 99.6 |
MRSA (3876/52.8) | 493 (12.7) | 2884 (87.1) | 435 (98.3) | 38 (99.3) | 15 (99.7) | 8 (99.9) | 2 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
MSSA (3463/47.2) | 577 (16.7) | 2443 (87.2) | 391 (98.5) | 32 (99.4) | 5 (99.6) | 2 (99.6) | 6 (99.8) | 7 (100.0) | .12 | .25 | 99.6 |
OX, ER, CP (1364/18.6) | 149 (10.9) | 1017 (85.5) | 184 (99.0) | 9 (99.6) | 3 (99.9) | 2 (100.0) | - | - | .12 | .25 | 99.9 |
OX, ER, CL, CP (1156/15.7) | 97 (8.4) | 859 (82.7) | 168 (97.2) | 20 (99.0) | 7 (99.6) | 4 (99.9) | 1 (100.0) | - | .12 | .25 | 99.6 |
OX, ER (751/10.2) | 141 (18.8) | 574 (95.2) | 27 (98.8) | 3 (99.2) | 4 (99.7) | 0 (99.7) | 2 (100.0) | - | .12 | .12 | 99.7 |
ER (729/10.0) | 115 (15.8) | 523 (87.5) | 83 (98.9) | 5 (99.6) | 1 (99.7) | 1 (99.9) | 1 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
ER, CP (177/2.4) | 27 (15.3) | 125 (85.9) | 20 (97.2) | 2 (98.3) | 2 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
OX, CL, CP (137/1.9) | 23 (16.8) | 104 (92.7) | 7 (97.8) | 2 (99.3) | 0 (99.3) | 0 (99.3) | 0 (99.3) | 1 (100.0) | .12 | .12 | 99.3 |
ER, CL, CP (112/1.5) | 12 (10.7) | 83 (84.8) | 16 (99.1) | 1 (100.0) | - | - | - | - | .12 | .25 | 100.0 |
Pan-R (170/2.4) | 31 (18.2) | 116 (86.5) | 22 (99.4) | 0 (99.4) | 0 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
Number (cumulative %) inhibited at MIC (μg/mL) | MIC (μg/mL) % | ||||||||||
Organism/resistance patterna(no. tested/% of total) | ≤.06 | 0.12 | .25 | .5 | 1 | 2 | 4 | 8 | 50% | 90% | ≤1 μg/mLb |
All S. aureus (7339/100.0) | 1070 (14.6) | 5327 (87.2)c | 826 (98.4) | 70 (99.4) | 20 (99.7) | 10 (99.8) | 8 (99.9) | 8 (100.0) | .12 | .25 | 99.7 |
2008 S. aureus (3962/54.0) | 397 (10.0) | 3066 (87.4) | 434 (98.4) | 48 (99.6) | 5 (99.7) | 3 (99.8) | 3 (99.8) | 6 (100.0) | .12 | .25 | 99.7 |
2009 S. aureus (3377/46.0) | 673 (19.9) | 2261 (86.9) | 392 (98.5) | 22 (99.1) | 15 (99.6) | 7 (99.8) | 5 (99.9) | 2 (100.0) | .12 | .25 | 99.6 |
MRSA (3876/52.8) | 493 (12.7) | 2884 (87.1) | 435 (98.3) | 38 (99.3) | 15 (99.7) | 8 (99.9) | 2 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
MSSA (3463/47.2) | 577 (16.7) | 2443 (87.2) | 391 (98.5) | 32 (99.4) | 5 (99.6) | 2 (99.6) | 6 (99.8) | 7 (100.0) | .12 | .25 | 99.6 |
OX, ER, CP (1364/18.6) | 149 (10.9) | 1017 (85.5) | 184 (99.0) | 9 (99.6) | 3 (99.9) | 2 (100.0) | - | - | .12 | .25 | 99.9 |
OX, ER, CL, CP (1156/15.7) | 97 (8.4) | 859 (82.7) | 168 (97.2) | 20 (99.0) | 7 (99.6) | 4 (99.9) | 1 (100.0) | - | .12 | .25 | 99.6 |
OX, ER (751/10.2) | 141 (18.8) | 574 (95.2) | 27 (98.8) | 3 (99.2) | 4 (99.7) | 0 (99.7) | 2 (100.0) | - | .12 | .12 | 99.7 |
ER (729/10.0) | 115 (15.8) | 523 (87.5) | 83 (98.9) | 5 (99.6) | 1 (99.7) | 1 (99.9) | 1 (99.9) | 1 (100.0) | .12 | .25 | 99.7 |
ER, CP (177/2.4) | 27 (15.3) | 125 (85.9) | 20 (97.2) | 2 (98.3) | 2 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
OX, CL, CP (137/1.9) | 23 (16.8) | 104 (92.7) | 7 (97.8) | 2 (99.3) | 0 (99.3) | 0 (99.3) | 0 (99.3) | 1 (100.0) | .12 | .12 | 99.3 |
ER, CL, CP (112/1.5) | 12 (10.7) | 83 (84.8) | 16 (99.1) | 1 (100.0) | - | - | - | - | .12 | .25 | 100.0 |
Pan-R (170/2.4) | 31 (18.2) | 116 (86.5) | 22 (99.4) | 0 (99.4) | 0 (99.4) | 1 (100.0) | - | - | .12 | .25 | 99.4 |
Most prevalent resistance patterns noted among Staphylococcus aureus. MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; CL, clindamycin; CP, ciprofloxacin; ER, erythromycin; OX, oxacillin; Pan-R, Pan-resistant phenotype (resistance to 5 antimicrobial classes). Criteria for susceptibility were those published by the Clinical and Laboratory Standards Institute (M100 - S20 - U, 2010) [26]. Intermediate and resistant results grouped as resistant.
Fusidic acid minimum inhibitory concentration breakpoint published by the European Committee on Antimicrobial Susceptibility Testing (2010) [27].
Modal MIC value (0.12 μg/ml)
Overall, fusidic acid (MIC50/90, .12/.25 μg/mL) inhibited 99.65% of S. aureus strains at ≤1 μg/mL [27]; only .22% had MIC results at ≥8 μg/mL (Table 1). No significant differences were noted in MIC50, MIC90, or percentage of strains at ≤1 μg/mL between years, but a slight trend toward more strains with fusidic acid MIC values at ≥2 μg/mL was observed among methicillin-susceptible S. aureus (MSSA) strains. The fusidic acid MIC distributions (Table 1) were analyzed for 8 different resistance phenotypes/patterns and showed that the MIC50 results remained the same, and the MIC90 values were either .12 or .25 μg/mL. S. aureus strains having resistance to 5 or more drug classes (Pan-resistant phenotype) were also fusidic acid susceptible (MIC, ≤1 μg/mL) for 99.4% of the samples.
Other tested parenteral agents exhibiting >95.0% coverage (Table 2) of these S. aureus strains at CLSI [26] breakpoints were quinupristin/dalfopristin (99.8% susceptible), gentamicin (97.9% susceptible), daptomycin (99.9% susceptible), and vancomycin (100.0% susceptible). Among potential orally administered treatments, only tetracyclines (95.5% susceptible), trimethoprim/sulfamethoxazole (98.6%), and linezolid (99.9%) showed high activity vs S. aureus; and linezolid (MIC90, 2 μg/mL) was 8-fold less potent when compared with fusidic acid (MIC90, .25 μg/mL) (Table 2). In contrast, β-lactams, erythromycin, clindamycin, and fluoroquinolones (levofloxacin results shown here) inhibited only 34.7% to 78.3% of tested S. aureus.
MIC (μg/mL) | % by Categorya | ||||
Organism (No. tested) | 50% | 90% | Range | Susceptible | Resistant |
S. aureus (7339) | |||||
Fusidic acid | .12 | .25 | ≤.06–8 | 99.7 | .2 |
Oxacillin | >2 | >2 | ≤.25->2 | 47.2 | 52.8 |
Penicillin | 16 | >32 | ≤.015->32 | 9.7 | 90.3 |
Ceftriaxone | 16 | >32 | ≤.25->32 | 47.2b | 52.8 |
Imipenem | ≤.12 | 8 | ≤.12->8 | 47.2b | 52.8 |
Erythromycin | >2 | >2 | ≤.25->2 | 34.7 | 64.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 78.3 | 21.3 |
Quinupristin/dalfopristin | .5 | .5 | ≤.25–>2 | 99.8 | <.1 |
Gentamicin | ≤2 | ≤2 | ≤2–>8 | 97.9 | 1.8 |
Levofloxacin | ≤.5 | >4 | ≤.5–>4 | 56.5 | 42.8 |
Tetracycline | ≤2 | ≤2 | ≤2–>8 | 95.5 | 3.8 |
TMP/SMXd | ≤.5 | ≤.5 | ≤.5–>2 | 98.6 | 1.4 |
Linezolid | 2 | 2 | ≤.06->8 | 99.9 | <.1 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.9 | -c |
Vancomycin | 1 | 1 | ≤.12–2 | 100.0 | .0 |
CoNS (1352)e | |||||
Fusidic acid | .12 | .25 | ≤.06–>8 | 92.2 | 7.0 |
Oxacillin | >2 | >2 | ≤.25–>2 | 27.5 | 72.5 |
Penicillin | 2 | 16 | ≤.015–>32 | 17.2 | 82.8 |
Ceftriaxone | 8 | >32 | ≤.25–>32 | 27.5b | 72.5 |
Imipenem | ≤.12 | >8 | ≤.12–>8 | 27.5b | 72.5 |
Erythromycin | >2 | >2 | ≤.25–>2 | 32.5 | 66.5 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 66.6 | 31.6 |
Quinupristin/dalfopristin | ≤.25 | ≤.25 | ≤.25–2 | 99.9 | .0 |
Gentamicin | ≤2 | >8 | ≤2–>8 | 71.5 | 22.4 |
Levofloxacin | 4 | >4 | ≤.5–>4 | 45.0 | 43.1 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 86.5 | 12.9 |
TMP/SMXd | ≤.5 | >2 | ≤.5–>2 | 59.4 | 40.6 |
Linezolid | 1 | 1 | .12->8 | 98.0 | 2.0 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.8 | -c |
Vancomycin | 1 | 2 | ≤.12–4 | 100.0 | .0 |
Enterococci (2448)f | |||||
Fusidic acid | 4 | 4 | .12–>8 | -c | -c |
Ampicillin | ≤1 | >16 | ≤1->16 | 68.3 | 31.7 |
Gentamicin (HL)g | ≤500 | >1000 | ≤500–>1000 | 75.1 | -c |
Erythromycin | >2 | >2 | ≤.25–>8 | 8.3 | 72.2 |
Quinupristin/dalfopristin | >2 | >2 | ≤.25–>2 | 31.4 | 64.3 |
Levofloxacin | >4 | >4 | ≤.5–>4 | 46.5 | 52.4 |
Tetracycline | >8 | >8 | ≤2–>8 | 32.6 | 67.0 |
Linezolid | 1 | 2 | .12–>8 | 99.4 | .5 |
Daptomycin | 1 | 2 | ≤.06–>8 | 99.7 | -c |
Teicoplanin | ≤2 | >16 | ≤2–>16 | 72.4 | 26.2 |
Vancomycin | 2 | >16 | .25–>16 | 71.2 | 28.7 |
β-hemolytic streptococci (1255)h | |||||
Fusidic acid | 8 | >8 | .12–>8 | -c | -c |
Penicillin | .03 | .06 | ≤.015–.12 | 100.0 | -c |
Ceftriaxone | ≤.25 | .5 | ≤.25–.5 | 100.0 | -c |
Meropenem | ≤.12 | ≤.12 | ≤.12–.25 | 100.0 | -c |
Erythromycin | ≤.25 | >2 | ≤.25–>2 | 66.4 | 32.3 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 83.5 | 16.1 |
Quinupristin/dalfopristin | ≤.25 | .5 | ≤.25–1 | 100.0 | .0 |
Levofloxacin | ≤.5 | 1 | ≤.5–>4 | 98.3 | 1.5 |
Tetracycline | >8 | >8 | ≤2–>8 | 44.2 | 53.6 |
Linezolid | 1 | 1 | ≤.06–2 | 100.0 | -c |
Daptomycin | .12 | .25 | ≤.06–.5 | 100.0 | -c |
Vancomycin | .5 | .5 | ≤.12–1 | 100.0 | -c |
Viridans group streptococci (313) | |||||
Fusidic acid | >8 | >8 | 1–>8 | -c | -c |
Penicillin | .06 | 1 | ≤.015–32 | 71.9 | 4.8 |
Ceftriaxone | ≤.25 | 1 | ≤.25–16 | 92.0 | 3.5 |
Meropenem | ≤.12 | .25 | ≤.12–4 | 94.3 | -c |
Erythromycin | 1 | >2 | ≤025–>2 | 40.9 | 55.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 88.5 | 10.2 |
Quinupristin/dalfopristin | .5 | 1 | ≤.25–>2 | 97.1 | .6 |
Levofloxacin | 1 | 4 | ≤.5–>4 | 89.5 | 8.9 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 60.1 | 33.5 |
Linezolid | 1 | 1 | .12–2 | 100.0 | -c |
Daptomycin | .25 | 1 | ≤.06–2 | 99.0 | -c |
Vancomycin | .5 | 1 | ≤.12–1 | 100.0 | -c |
MIC (μg/mL) | % by Categorya | ||||
Organism (No. tested) | 50% | 90% | Range | Susceptible | Resistant |
S. aureus (7339) | |||||
Fusidic acid | .12 | .25 | ≤.06–8 | 99.7 | .2 |
Oxacillin | >2 | >2 | ≤.25->2 | 47.2 | 52.8 |
Penicillin | 16 | >32 | ≤.015->32 | 9.7 | 90.3 |
Ceftriaxone | 16 | >32 | ≤.25->32 | 47.2b | 52.8 |
Imipenem | ≤.12 | 8 | ≤.12->8 | 47.2b | 52.8 |
Erythromycin | >2 | >2 | ≤.25->2 | 34.7 | 64.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 78.3 | 21.3 |
Quinupristin/dalfopristin | .5 | .5 | ≤.25–>2 | 99.8 | <.1 |
Gentamicin | ≤2 | ≤2 | ≤2–>8 | 97.9 | 1.8 |
Levofloxacin | ≤.5 | >4 | ≤.5–>4 | 56.5 | 42.8 |
Tetracycline | ≤2 | ≤2 | ≤2–>8 | 95.5 | 3.8 |
TMP/SMXd | ≤.5 | ≤.5 | ≤.5–>2 | 98.6 | 1.4 |
Linezolid | 2 | 2 | ≤.06->8 | 99.9 | <.1 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.9 | -c |
Vancomycin | 1 | 1 | ≤.12–2 | 100.0 | .0 |
CoNS (1352)e | |||||
Fusidic acid | .12 | .25 | ≤.06–>8 | 92.2 | 7.0 |
Oxacillin | >2 | >2 | ≤.25–>2 | 27.5 | 72.5 |
Penicillin | 2 | 16 | ≤.015–>32 | 17.2 | 82.8 |
Ceftriaxone | 8 | >32 | ≤.25–>32 | 27.5b | 72.5 |
Imipenem | ≤.12 | >8 | ≤.12–>8 | 27.5b | 72.5 |
Erythromycin | >2 | >2 | ≤.25–>2 | 32.5 | 66.5 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 66.6 | 31.6 |
Quinupristin/dalfopristin | ≤.25 | ≤.25 | ≤.25–2 | 99.9 | .0 |
Gentamicin | ≤2 | >8 | ≤2–>8 | 71.5 | 22.4 |
Levofloxacin | 4 | >4 | ≤.5–>4 | 45.0 | 43.1 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 86.5 | 12.9 |
TMP/SMXd | ≤.5 | >2 | ≤.5–>2 | 59.4 | 40.6 |
Linezolid | 1 | 1 | .12->8 | 98.0 | 2.0 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.8 | -c |
Vancomycin | 1 | 2 | ≤.12–4 | 100.0 | .0 |
Enterococci (2448)f | |||||
Fusidic acid | 4 | 4 | .12–>8 | -c | -c |
Ampicillin | ≤1 | >16 | ≤1->16 | 68.3 | 31.7 |
Gentamicin (HL)g | ≤500 | >1000 | ≤500–>1000 | 75.1 | -c |
Erythromycin | >2 | >2 | ≤.25–>8 | 8.3 | 72.2 |
Quinupristin/dalfopristin | >2 | >2 | ≤.25–>2 | 31.4 | 64.3 |
Levofloxacin | >4 | >4 | ≤.5–>4 | 46.5 | 52.4 |
Tetracycline | >8 | >8 | ≤2–>8 | 32.6 | 67.0 |
Linezolid | 1 | 2 | .12–>8 | 99.4 | .5 |
Daptomycin | 1 | 2 | ≤.06–>8 | 99.7 | -c |
Teicoplanin | ≤2 | >16 | ≤2–>16 | 72.4 | 26.2 |
Vancomycin | 2 | >16 | .25–>16 | 71.2 | 28.7 |
β-hemolytic streptococci (1255)h | |||||
Fusidic acid | 8 | >8 | .12–>8 | -c | -c |
Penicillin | .03 | .06 | ≤.015–.12 | 100.0 | -c |
Ceftriaxone | ≤.25 | .5 | ≤.25–.5 | 100.0 | -c |
Meropenem | ≤.12 | ≤.12 | ≤.12–.25 | 100.0 | -c |
Erythromycin | ≤.25 | >2 | ≤.25–>2 | 66.4 | 32.3 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 83.5 | 16.1 |
Quinupristin/dalfopristin | ≤.25 | .5 | ≤.25–1 | 100.0 | .0 |
Levofloxacin | ≤.5 | 1 | ≤.5–>4 | 98.3 | 1.5 |
Tetracycline | >8 | >8 | ≤2–>8 | 44.2 | 53.6 |
Linezolid | 1 | 1 | ≤.06–2 | 100.0 | -c |
Daptomycin | .12 | .25 | ≤.06–.5 | 100.0 | -c |
Vancomycin | .5 | .5 | ≤.12–1 | 100.0 | -c |
Viridans group streptococci (313) | |||||
Fusidic acid | >8 | >8 | 1–>8 | -c | -c |
Penicillin | .06 | 1 | ≤.015–32 | 71.9 | 4.8 |
Ceftriaxone | ≤.25 | 1 | ≤.25–16 | 92.0 | 3.5 |
Meropenem | ≤.12 | .25 | ≤.12–4 | 94.3 | -c |
Erythromycin | 1 | >2 | ≤025–>2 | 40.9 | 55.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 88.5 | 10.2 |
Quinupristin/dalfopristin | .5 | 1 | ≤.25–>2 | 97.1 | .6 |
Levofloxacin | 1 | 4 | ≤.5–>4 | 89.5 | 8.9 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 60.1 | 33.5 |
Linezolid | 1 | 1 | .12–2 | 100.0 | -c |
Daptomycin | .25 | 1 | ≤.06–2 | 99.0 | -c |
Vancomycin | .5 | 1 | ≤.12–1 | 100.0 | -c |
Categorical breakpoints of the Clinical and Laboratory Standards Institute [26]. Susceptibility for fusidic acid was defined as ≤1 μg/mL from the European Committee on Antimicrobial Susceptibility publication criteria [27].
Susceptibility guided by the oxacillin test results [26].
- = no published breakpoint for this category.
TMP/SMX, trimethoprim/sulfamethoxazole.
CoNS, coagulase-negative staphylococci.
Includes Enterococcus faecalis (1552 strains), E. faecium (814 strains), and 82 other enterococcal species.
HL, high-level; susceptibility predicts possible synergy when combined with cell-wall-active agents.
Includes Streptococcus pyogenes (group A; 448 strains), S. agalactiae (group B; 623 strains), and other species (184 strains).
MIC (μg/mL) | % by Categorya | ||||
Organism (No. tested) | 50% | 90% | Range | Susceptible | Resistant |
S. aureus (7339) | |||||
Fusidic acid | .12 | .25 | ≤.06–8 | 99.7 | .2 |
Oxacillin | >2 | >2 | ≤.25->2 | 47.2 | 52.8 |
Penicillin | 16 | >32 | ≤.015->32 | 9.7 | 90.3 |
Ceftriaxone | 16 | >32 | ≤.25->32 | 47.2b | 52.8 |
Imipenem | ≤.12 | 8 | ≤.12->8 | 47.2b | 52.8 |
Erythromycin | >2 | >2 | ≤.25->2 | 34.7 | 64.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 78.3 | 21.3 |
Quinupristin/dalfopristin | .5 | .5 | ≤.25–>2 | 99.8 | <.1 |
Gentamicin | ≤2 | ≤2 | ≤2–>8 | 97.9 | 1.8 |
Levofloxacin | ≤.5 | >4 | ≤.5–>4 | 56.5 | 42.8 |
Tetracycline | ≤2 | ≤2 | ≤2–>8 | 95.5 | 3.8 |
TMP/SMXd | ≤.5 | ≤.5 | ≤.5–>2 | 98.6 | 1.4 |
Linezolid | 2 | 2 | ≤.06->8 | 99.9 | <.1 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.9 | -c |
Vancomycin | 1 | 1 | ≤.12–2 | 100.0 | .0 |
CoNS (1352)e | |||||
Fusidic acid | .12 | .25 | ≤.06–>8 | 92.2 | 7.0 |
Oxacillin | >2 | >2 | ≤.25–>2 | 27.5 | 72.5 |
Penicillin | 2 | 16 | ≤.015–>32 | 17.2 | 82.8 |
Ceftriaxone | 8 | >32 | ≤.25–>32 | 27.5b | 72.5 |
Imipenem | ≤.12 | >8 | ≤.12–>8 | 27.5b | 72.5 |
Erythromycin | >2 | >2 | ≤.25–>2 | 32.5 | 66.5 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 66.6 | 31.6 |
Quinupristin/dalfopristin | ≤.25 | ≤.25 | ≤.25–2 | 99.9 | .0 |
Gentamicin | ≤2 | >8 | ≤2–>8 | 71.5 | 22.4 |
Levofloxacin | 4 | >4 | ≤.5–>4 | 45.0 | 43.1 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 86.5 | 12.9 |
TMP/SMXd | ≤.5 | >2 | ≤.5–>2 | 59.4 | 40.6 |
Linezolid | 1 | 1 | .12->8 | 98.0 | 2.0 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.8 | -c |
Vancomycin | 1 | 2 | ≤.12–4 | 100.0 | .0 |
Enterococci (2448)f | |||||
Fusidic acid | 4 | 4 | .12–>8 | -c | -c |
Ampicillin | ≤1 | >16 | ≤1->16 | 68.3 | 31.7 |
Gentamicin (HL)g | ≤500 | >1000 | ≤500–>1000 | 75.1 | -c |
Erythromycin | >2 | >2 | ≤.25–>8 | 8.3 | 72.2 |
Quinupristin/dalfopristin | >2 | >2 | ≤.25–>2 | 31.4 | 64.3 |
Levofloxacin | >4 | >4 | ≤.5–>4 | 46.5 | 52.4 |
Tetracycline | >8 | >8 | ≤2–>8 | 32.6 | 67.0 |
Linezolid | 1 | 2 | .12–>8 | 99.4 | .5 |
Daptomycin | 1 | 2 | ≤.06–>8 | 99.7 | -c |
Teicoplanin | ≤2 | >16 | ≤2–>16 | 72.4 | 26.2 |
Vancomycin | 2 | >16 | .25–>16 | 71.2 | 28.7 |
β-hemolytic streptococci (1255)h | |||||
Fusidic acid | 8 | >8 | .12–>8 | -c | -c |
Penicillin | .03 | .06 | ≤.015–.12 | 100.0 | -c |
Ceftriaxone | ≤.25 | .5 | ≤.25–.5 | 100.0 | -c |
Meropenem | ≤.12 | ≤.12 | ≤.12–.25 | 100.0 | -c |
Erythromycin | ≤.25 | >2 | ≤.25–>2 | 66.4 | 32.3 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 83.5 | 16.1 |
Quinupristin/dalfopristin | ≤.25 | .5 | ≤.25–1 | 100.0 | .0 |
Levofloxacin | ≤.5 | 1 | ≤.5–>4 | 98.3 | 1.5 |
Tetracycline | >8 | >8 | ≤2–>8 | 44.2 | 53.6 |
Linezolid | 1 | 1 | ≤.06–2 | 100.0 | -c |
Daptomycin | .12 | .25 | ≤.06–.5 | 100.0 | -c |
Vancomycin | .5 | .5 | ≤.12–1 | 100.0 | -c |
Viridans group streptococci (313) | |||||
Fusidic acid | >8 | >8 | 1–>8 | -c | -c |
Penicillin | .06 | 1 | ≤.015–32 | 71.9 | 4.8 |
Ceftriaxone | ≤.25 | 1 | ≤.25–16 | 92.0 | 3.5 |
Meropenem | ≤.12 | .25 | ≤.12–4 | 94.3 | -c |
Erythromycin | 1 | >2 | ≤025–>2 | 40.9 | 55.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 88.5 | 10.2 |
Quinupristin/dalfopristin | .5 | 1 | ≤.25–>2 | 97.1 | .6 |
Levofloxacin | 1 | 4 | ≤.5–>4 | 89.5 | 8.9 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 60.1 | 33.5 |
Linezolid | 1 | 1 | .12–2 | 100.0 | -c |
Daptomycin | .25 | 1 | ≤.06–2 | 99.0 | -c |
Vancomycin | .5 | 1 | ≤.12–1 | 100.0 | -c |
MIC (μg/mL) | % by Categorya | ||||
Organism (No. tested) | 50% | 90% | Range | Susceptible | Resistant |
S. aureus (7339) | |||||
Fusidic acid | .12 | .25 | ≤.06–8 | 99.7 | .2 |
Oxacillin | >2 | >2 | ≤.25->2 | 47.2 | 52.8 |
Penicillin | 16 | >32 | ≤.015->32 | 9.7 | 90.3 |
Ceftriaxone | 16 | >32 | ≤.25->32 | 47.2b | 52.8 |
Imipenem | ≤.12 | 8 | ≤.12->8 | 47.2b | 52.8 |
Erythromycin | >2 | >2 | ≤.25->2 | 34.7 | 64.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 78.3 | 21.3 |
Quinupristin/dalfopristin | .5 | .5 | ≤.25–>2 | 99.8 | <.1 |
Gentamicin | ≤2 | ≤2 | ≤2–>8 | 97.9 | 1.8 |
Levofloxacin | ≤.5 | >4 | ≤.5–>4 | 56.5 | 42.8 |
Tetracycline | ≤2 | ≤2 | ≤2–>8 | 95.5 | 3.8 |
TMP/SMXd | ≤.5 | ≤.5 | ≤.5–>2 | 98.6 | 1.4 |
Linezolid | 2 | 2 | ≤.06->8 | 99.9 | <.1 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.9 | -c |
Vancomycin | 1 | 1 | ≤.12–2 | 100.0 | .0 |
CoNS (1352)e | |||||
Fusidic acid | .12 | .25 | ≤.06–>8 | 92.2 | 7.0 |
Oxacillin | >2 | >2 | ≤.25–>2 | 27.5 | 72.5 |
Penicillin | 2 | 16 | ≤.015–>32 | 17.2 | 82.8 |
Ceftriaxone | 8 | >32 | ≤.25–>32 | 27.5b | 72.5 |
Imipenem | ≤.12 | >8 | ≤.12–>8 | 27.5b | 72.5 |
Erythromycin | >2 | >2 | ≤.25–>2 | 32.5 | 66.5 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 66.6 | 31.6 |
Quinupristin/dalfopristin | ≤.25 | ≤.25 | ≤.25–2 | 99.9 | .0 |
Gentamicin | ≤2 | >8 | ≤2–>8 | 71.5 | 22.4 |
Levofloxacin | 4 | >4 | ≤.5–>4 | 45.0 | 43.1 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 86.5 | 12.9 |
TMP/SMXd | ≤.5 | >2 | ≤.5–>2 | 59.4 | 40.6 |
Linezolid | 1 | 1 | .12->8 | 98.0 | 2.0 |
Daptomycin | .25 | .5 | ≤.06–4 | 99.8 | -c |
Vancomycin | 1 | 2 | ≤.12–4 | 100.0 | .0 |
Enterococci (2448)f | |||||
Fusidic acid | 4 | 4 | .12–>8 | -c | -c |
Ampicillin | ≤1 | >16 | ≤1->16 | 68.3 | 31.7 |
Gentamicin (HL)g | ≤500 | >1000 | ≤500–>1000 | 75.1 | -c |
Erythromycin | >2 | >2 | ≤.25–>8 | 8.3 | 72.2 |
Quinupristin/dalfopristin | >2 | >2 | ≤.25–>2 | 31.4 | 64.3 |
Levofloxacin | >4 | >4 | ≤.5–>4 | 46.5 | 52.4 |
Tetracycline | >8 | >8 | ≤2–>8 | 32.6 | 67.0 |
Linezolid | 1 | 2 | .12–>8 | 99.4 | .5 |
Daptomycin | 1 | 2 | ≤.06–>8 | 99.7 | -c |
Teicoplanin | ≤2 | >16 | ≤2–>16 | 72.4 | 26.2 |
Vancomycin | 2 | >16 | .25–>16 | 71.2 | 28.7 |
β-hemolytic streptococci (1255)h | |||||
Fusidic acid | 8 | >8 | .12–>8 | -c | -c |
Penicillin | .03 | .06 | ≤.015–.12 | 100.0 | -c |
Ceftriaxone | ≤.25 | .5 | ≤.25–.5 | 100.0 | -c |
Meropenem | ≤.12 | ≤.12 | ≤.12–.25 | 100.0 | -c |
Erythromycin | ≤.25 | >2 | ≤.25–>2 | 66.4 | 32.3 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 83.5 | 16.1 |
Quinupristin/dalfopristin | ≤.25 | .5 | ≤.25–1 | 100.0 | .0 |
Levofloxacin | ≤.5 | 1 | ≤.5–>4 | 98.3 | 1.5 |
Tetracycline | >8 | >8 | ≤2–>8 | 44.2 | 53.6 |
Linezolid | 1 | 1 | ≤.06–2 | 100.0 | -c |
Daptomycin | .12 | .25 | ≤.06–.5 | 100.0 | -c |
Vancomycin | .5 | .5 | ≤.12–1 | 100.0 | -c |
Viridans group streptococci (313) | |||||
Fusidic acid | >8 | >8 | 1–>8 | -c | -c |
Penicillin | .06 | 1 | ≤.015–32 | 71.9 | 4.8 |
Ceftriaxone | ≤.25 | 1 | ≤.25–16 | 92.0 | 3.5 |
Meropenem | ≤.12 | .25 | ≤.12–4 | 94.3 | -c |
Erythromycin | 1 | >2 | ≤025–>2 | 40.9 | 55.6 |
Clindamycin | ≤.25 | >2 | ≤.25–>2 | 88.5 | 10.2 |
Quinupristin/dalfopristin | .5 | 1 | ≤.25–>2 | 97.1 | .6 |
Levofloxacin | 1 | 4 | ≤.5–>4 | 89.5 | 8.9 |
Tetracycline | ≤2 | >8 | ≤2–>8 | 60.1 | 33.5 |
Linezolid | 1 | 1 | .12–2 | 100.0 | -c |
Daptomycin | .25 | 1 | ≤.06–2 | 99.0 | -c |
Vancomycin | .5 | 1 | ≤.12–1 | 100.0 | -c |
Categorical breakpoints of the Clinical and Laboratory Standards Institute [26]. Susceptibility for fusidic acid was defined as ≤1 μg/mL from the European Committee on Antimicrobial Susceptibility publication criteria [27].
Susceptibility guided by the oxacillin test results [26].
- = no published breakpoint for this category.
TMP/SMX, trimethoprim/sulfamethoxazole.
CoNS, coagulase-negative staphylococci.
Includes Enterococcus faecalis (1552 strains), E. faecium (814 strains), and 82 other enterococcal species.
HL, high-level; susceptibility predicts possible synergy when combined with cell-wall-active agents.
Includes Streptococcus pyogenes (group A; 448 strains), S. agalactiae (group B; 623 strains), and other species (184 strains).
Fusidic acid MIC (μg/mL) | |||
Organism (no. tested) | MIC50 | MIC90 | Range |
Streptococcus pyogenes (131) | 4 | 8 | 2–8 |
S. agalactiae (25) | 16 | 16 | 16 |
Group C (10) | 8 | 16 | 4–16 |
Group G (10) | 8 | 8 | 8–16 |
Fusidic acid MIC (μg/mL) | |||
Organism (no. tested) | MIC50 | MIC90 | Range |
Streptococcus pyogenes (131) | 4 | 8 | 2–8 |
S. agalactiae (25) | 16 | 16 | 16 |
Group C (10) | 8 | 16 | 4–16 |
Group G (10) | 8 | 8 | 8–16 |
Fusidic acid MIC (μg/mL) | |||
Organism (no. tested) | MIC50 | MIC90 | Range |
Streptococcus pyogenes (131) | 4 | 8 | 2–8 |
S. agalactiae (25) | 16 | 16 | 16 |
Group C (10) | 8 | 16 | 4–16 |
Group G (10) | 8 | 8 | 8–16 |
Fusidic acid MIC (μg/mL) | |||
Organism (no. tested) | MIC50 | MIC90 | Range |
Streptococcus pyogenes (131) | 4 | 8 | 2–8 |
S. agalactiae (25) | 16 | 16 | 16 |
Group C (10) | 8 | 16 | 4–16 |
Group G (10) | 8 | 8 | 8–16 |
Fusidic Acid Activity Against Other Staphylococci
In Table 2 the results from testing 1352 CoNS strains are shown for fusidic acid and 14 other antimicrobials. A total of 980 CoNS were methicillin resistant (72.5%) and the fusidic acid susceptibility (MIC, ≤1 μg/mL) rate was 90.2% compared with 97.6% for methicillin-susceptible CoNS (data not shown). For fusidic acid–nonsusceptible strains, MIC results were generally 2, 4, or 8 μg/mL with only 1.4% of these CoNS having MIC values >8 μg/mL, that is, dominant low-level resistance [22, 23].
Quinupristin/dalfopristin (99.9% susceptible), linezolid (98.0% susceptible), daptomycin (99.8% susceptible), and vancomycin (100.0% susceptible) were the only other agents with more than 90% susceptibility rates (Table 2). Fusidic acid (MIC90, .25 μg/mL) was 4-fold more active than linezolid (MIC90, 1 μg/mL), the only other orally administered agent with wide coverage.
Fusidic Acid Activity Against Enterocococci and Streptococci
When tested against 2448 enterococci (1552 E. faecalis and 814 E. faecium; Table 2), fusidic acid only inhibited 9.0% of strains at ≤1 μg/mL, but measured MIC values were rarely (.2%) more than 8 μg/mL (data not shown). The overall vancomycin-resistant rate was 28.7% (91.3% VanA phenotype), and the most active agents at CLSI breakpoints [26] were linezolid (99.4% susceptible) and daptomycin (99.7% susceptible). The ampicillin susceptibility rate was 68.3%, and high-level gentamicin resistance minimizing potential co-drug therapies was nearly 25% (Table 2).
Streptococci, both β-haemolytic (1255; group A [S. pyogenes], 448 and group B [S. agalactiae], 623) and viridans group, were less susceptible to fusidic acid when compared with the demonstrated anti-staphylococcal activity (Table 2). However, a subset analysis of S. pyogenes (group A; Figure 2) and a review of prior work by Pfaller et al, [30] revealed moderate susceptibility to fusidic acid (MIC50, 8 μg/mL) with MIC values reported over a narrow range of 2–8 μg/mL (Table 3). The fusidic acid MIC90 values for S. pyogenes in Canada (8 μg/mL) [30] and in the 2008–2009 surveillance (8 μg/mL) were identical, as were the modal MIC results (4 μg/mL; Figure 2). The occurrences of high-level (MIC, >8 μg/mL) resistance of S. pyogenes vs fusidic acid was extremely rare. In contrast to the fusidic acid MIC50 of 8 μg/mL when tested against β-haemolytic streptococci, MIC50 results for all other tested agents except tetracyclines were ≤1 μg/mL (Table 2). These results were consistent with earlier studies [30] that utilized a broader MIC dilution range to define the upper limit of β-haemolytic streptococcal MIC distribution. Susceptibility rates for the comparators ranged from 44.2% (tetracycline) to 100.0% for all β-lactams, quinupristin/dalfopristin, linezolid, daptomycin, and vancomycin. Levofloxacin resistance was 1.5% (Table 2). Like the enterococci, fusidic acid MIC results when testing β-haemolytic streptococci were uncommonly >8 μg/mL (12.8%), with no occurrences at that high level for S. pyogenes (data not shown).
Like other streptococci, viridans group species (313 strains) had fusidic acid MIC results ranging from 1 to >8 μg/mL (Table 3). These α-hemolytic streptococci were less susceptible to nearly all tested compounds when compared with the β-hemolytic species. Erythromycin susceptibility was limited (40.9%) and clindamycin resistance was 10.2%, results similar to those of levofloxacin (8.9%).
Fusidic Acid Resistance in S. aureus Detected in US Surveillance Studies (2008–2009)
Table 4 lists the 26 S. aureus strains (only .35% of all S. aureus) detected with fusidic acid MIC values ≥2 μg/mL, that is, potential resistance [27]. The organisms were studied by molecular methods described earlier [22, 23] and fusidic acid resistance mechanisms were documented in 21 strains (80.8%). Those strains having no detectable mechanism had fusidic acid MIC results at only 2 μg/mL (50.0% negative for strains at that MIC level); all strains with MIC results of 4 μg/mL (8 of 8) and 8 μg/mL (8 of 8) had documented fusA–E mechanisms of resistance (Table 4). High-level resistance (MIC >32 μg/mL) was not observed among the US strains, even those with fusA mutations [22, 23, 31].
No. by resistance mechanism typea | ||||||
Year (No.) | % MRSAb | No. sites | fusAc | fusB | fusC | fusE |
2008 (12) | 33.3 | 7 | M453I | 1 | 7 | 2d |
2009 (14) | 50.0 | 12 | L461S, A71V+P404L(2)e | 2 | 5 | - |
MRSA (11) | - | 8 | L461S, M453I, A71V+P404L(2)e | - | - | 2d |
MSSAf (15) | - | 11 | - | 3 | 12 | - |
No. by resistance mechanism typea | ||||||
Year (No.) | % MRSAb | No. sites | fusAc | fusB | fusC | fusE |
2008 (12) | 33.3 | 7 | M453I | 1 | 7 | 2d |
2009 (14) | 50.0 | 12 | L461S, A71V+P404L(2)e | 2 | 5 | - |
MRSA (11) | - | 8 | L461S, M453I, A71V+P404L(2)e | - | - | 2d |
MSSAf (15) | - | 11 | - | 3 | 12 | - |
fusD only observed in coagulase-negative Staphylococcus spp. (S. saprophyticus).
MRSA, methicillin-resistant S. aureus.
fusA mutation site.
Clonal occurrence of 2 strains with G78 - Q99 deletions in fusE from a Michigan hospital.
Clonal occurrence of 2 strains in an Oregon site.
MSSA, methicillin-susceptible S. aureus.
No. by resistance mechanism typea | ||||||
Year (No.) | % MRSAb | No. sites | fusAc | fusB | fusC | fusE |
2008 (12) | 33.3 | 7 | M453I | 1 | 7 | 2d |
2009 (14) | 50.0 | 12 | L461S, A71V+P404L(2)e | 2 | 5 | - |
MRSA (11) | - | 8 | L461S, M453I, A71V+P404L(2)e | - | - | 2d |
MSSAf (15) | - | 11 | - | 3 | 12 | - |
No. by resistance mechanism typea | ||||||
Year (No.) | % MRSAb | No. sites | fusAc | fusB | fusC | fusE |
2008 (12) | 33.3 | 7 | M453I | 1 | 7 | 2d |
2009 (14) | 50.0 | 12 | L461S, A71V+P404L(2)e | 2 | 5 | - |
MRSA (11) | - | 8 | L461S, M453I, A71V+P404L(2)e | - | - | 2d |
MSSAf (15) | - | 11 | - | 3 | 12 | - |
fusD only observed in coagulase-negative Staphylococcus spp. (S. saprophyticus).
MRSA, methicillin-resistant S. aureus.
fusA mutation site.
Clonal occurrence of 2 strains with G78 - Q99 deletions in fusE from a Michigan hospital.
Clonal occurrence of 2 strains in an Oregon site.
MSSA, methicillin-susceptible S. aureus.
The fusidic acid–nonsusceptible (MIC ≥2 μg/mL) strains were found in 14 states (1–4 organisms per state; most in Michigan) and were slightly more common among MSSA and in 2009 (14 vs 12 strains). Mechanisms were distributed differently between MRSA and MSSA, with fusA and fusE noted exclusively in MRSA [30], and acquired fusB and fusC [22, 23] found in MSSA (Table 4). Clonal occurrences were documented by pulsed field gel electrophoresis in some medical centers in Michigan (fusE with a G78-Q99 deletion) and Oregon (fusA, A71V and D404L mutations). None of these case isolates had known exposures to fusidic acid.
The cited mutations were also correlated to the level of fusidic acid MIC. The fusA and fusE mutations were associated with fusidic acid MIC values at 2 or 4 μg/mL, and 13 of 16 strains with MIC results at 4 or 8 μg/mL had fusB (2) or fusC (11) mechanisms of resistance.
Fusidic Acid Resistance in Non-US Surveillance Samples
Castanheira and colleagues [22, 23, 30, 32] have updated the contemporary activity statistics for fusidic acid, including the rates of resistance among staphylococci in countries located in North America, Europe, and (Australia). Also the determination of fusidic acid resistance mechanisms (Table 5) was assessed for S. aureus and CoNS through 2008 [22, 23]. Table 5 shows results from a 2008 European sample of fusidic acid resistance mechanisms demonstrating a wide range of resistance rates among nations for S. aureus (1.4% [Spain] to 52.5% [Greece]) and CoNS (12.5% [Poland] to 50.0% [Ireland]) [23]. Acquired fusidic acid resistance genes (fusB and C) predominated overall, with only Ireland having more fusA and fusE mutations, as well as evidence for extensive clonal expansion [23]. Variations also existed between the types of acquired genes in S. aureus and CoNS, most evident for France where fusC and fusB were more common, respectively (Table 5). Twelve fusA mutation patterns were noted in Europe, but 75.0% of these were either L461K or L461 S. Conversely, through 2008, only 1 fusA mutation (M453I; Tables 4 and 5) was noted in a US MRSA strain. In Ireland, a unique alteration in ribosomal protein L6 was documented (Q140L) [23]. Comparisons of these findings from Europe to those noted in the United States (Table 4) leads to the conclusion that fusidic acid resistance mechanisms vary greatly in and between nations as well as among staphylococcal species. These findings are complicated by clonal spread [33–35], the level of elevation in the fusidic acid MIC, the fitness of the resistant organisms (especially fusE mutations/deletions) [15, 16, 19] and the fusidic acid use volume or routes of administration in each country [36, 37].
Location (No. overall S. aureus/CoNS) | S. aureus | CoNS | Acquired fusidic acid resistance genes (%) | ||||||
No. of strains showing fusidic acid MIC values ≥2 μg/mL (%) | fusB | fusC | No. of strains showing fusidic acid MIC values >2 μg/mL (%) | fusB | fusC | fusA mutations (No. tested) | fusE mutations (No. tested) | ||
Belgium (93/28) | 6 (6.5) | - | 1 | 12 (42.9) | 8 | 4 | 72.2 | 1 V90I, 1 L461K (3) | - (2) |
France (541/85) | 35 (6.5) | 2 | 16 | 42 (49.4) | 28 | 6 | 74.3 | 1 V90A, 1 A376 V, 1 P404L, 1 H457Y, 4 L461S, 1 T387I/E449K, 1 wt (10) | - (1) |
Germany (453/70) | 13 (2.9) | 3 | 1 | 23 (32.9) | 7 | 8 | 61.3 | 1 V90I, 1 H457Y, 1 L461K (3) | - (1) |
Greece (242/4) | 127 (52.5) | 18 | 4 | 1 (25.0) | 1 | - | 54.8 | 10 L461K (10) | NTa |
Ireland (241/4) | 48 (19.9) | 3 | 3 | 2 (50.0) | 1 | - | 15.6 | 17 L461K, 1 L461S, 1 D189V/L430S (21) | Q104L (6) |
Israel (70/25) | 2 (2.9) | - | - | 7 (28.0) | 5 | 1 | 66.7 | 1 L461S (1) | NT |
Italy (147/64) | 4 (2.7) | 1 | 4 | 14 (21.9) | 8 | 4 | 85.0 | 1 L461S (1) | NT |
Poland (66/24) | 1 (1.5) | - | - | 3 (12.5) | - | 1 | 50.0 | 1 L461S (1) | NT |
Spain (208/16) | 3 (1.4) | - | 1 | 4 (25.0) | 1 | 2 | 66.7 | - (1) | NT |
Sweden (163/24) | 5 (3.1) | 1 | 3 | 9 (37.5) | 7 | 2 | 92.9 | 1 A70V/A160V/H457Y (1) | - (1) |
Switzerland (59/19) | 4 (6.8) | 1 | 2 | 9 (47.4) | 7 | 2 | 92.3 | 1 F441Y (1) | - (1) |
Turkey (128/50) | 8 (6.3) | 1 | 3 | 16 (32.0) | 9 | 6 | 82.6 | 1 H457Y, 1 V90I/H457Q/L461K (2) | NT |
UK (289/21) | 34 (11.8) | 4 | 19 | 10 (47.6) | 7 | 2 | 74.4 | 1 P404L, 3 L461K, 2 L461S (6) | NT |
Location (No. overall S. aureus/CoNS) | S. aureus | CoNS | Acquired fusidic acid resistance genes (%) | ||||||
No. of strains showing fusidic acid MIC values ≥2 μg/mL (%) | fusB | fusC | No. of strains showing fusidic acid MIC values >2 μg/mL (%) | fusB | fusC | fusA mutations (No. tested) | fusE mutations (No. tested) | ||
Belgium (93/28) | 6 (6.5) | - | 1 | 12 (42.9) | 8 | 4 | 72.2 | 1 V90I, 1 L461K (3) | - (2) |
France (541/85) | 35 (6.5) | 2 | 16 | 42 (49.4) | 28 | 6 | 74.3 | 1 V90A, 1 A376 V, 1 P404L, 1 H457Y, 4 L461S, 1 T387I/E449K, 1 wt (10) | - (1) |
Germany (453/70) | 13 (2.9) | 3 | 1 | 23 (32.9) | 7 | 8 | 61.3 | 1 V90I, 1 H457Y, 1 L461K (3) | - (1) |
Greece (242/4) | 127 (52.5) | 18 | 4 | 1 (25.0) | 1 | - | 54.8 | 10 L461K (10) | NTa |
Ireland (241/4) | 48 (19.9) | 3 | 3 | 2 (50.0) | 1 | - | 15.6 | 17 L461K, 1 L461S, 1 D189V/L430S (21) | Q104L (6) |
Israel (70/25) | 2 (2.9) | - | - | 7 (28.0) | 5 | 1 | 66.7 | 1 L461S (1) | NT |
Italy (147/64) | 4 (2.7) | 1 | 4 | 14 (21.9) | 8 | 4 | 85.0 | 1 L461S (1) | NT |
Poland (66/24) | 1 (1.5) | - | - | 3 (12.5) | - | 1 | 50.0 | 1 L461S (1) | NT |
Spain (208/16) | 3 (1.4) | - | 1 | 4 (25.0) | 1 | 2 | 66.7 | - (1) | NT |
Sweden (163/24) | 5 (3.1) | 1 | 3 | 9 (37.5) | 7 | 2 | 92.9 | 1 A70V/A160V/H457Y (1) | - (1) |
Switzerland (59/19) | 4 (6.8) | 1 | 2 | 9 (47.4) | 7 | 2 | 92.3 | 1 F441Y (1) | - (1) |
Turkey (128/50) | 8 (6.3) | 1 | 3 | 16 (32.0) | 9 | 6 | 82.6 | 1 H457Y, 1 V90I/H457Q/L461K (2) | NT |
UK (289/21) | 34 (11.8) | 4 | 19 | 10 (47.6) | 7 | 2 | 74.4 | 1 P404L, 3 L461K, 2 L461S (6) | NT |
NOTE. CoNS, coagulase-negative Staphylococcus spp; MIC, minimum inhibitory concentration.
Used with permission from Castanheira et al [23]. Copyright © 2010, Oxford University Press.
NT, not tested.
Location (No. overall S. aureus/CoNS) | S. aureus | CoNS | Acquired fusidic acid resistance genes (%) | ||||||
No. of strains showing fusidic acid MIC values ≥2 μg/mL (%) | fusB | fusC | No. of strains showing fusidic acid MIC values >2 μg/mL (%) | fusB | fusC | fusA mutations (No. tested) | fusE mutations (No. tested) | ||
Belgium (93/28) | 6 (6.5) | - | 1 | 12 (42.9) | 8 | 4 | 72.2 | 1 V90I, 1 L461K (3) | - (2) |
France (541/85) | 35 (6.5) | 2 | 16 | 42 (49.4) | 28 | 6 | 74.3 | 1 V90A, 1 A376 V, 1 P404L, 1 H457Y, 4 L461S, 1 T387I/E449K, 1 wt (10) | - (1) |
Germany (453/70) | 13 (2.9) | 3 | 1 | 23 (32.9) | 7 | 8 | 61.3 | 1 V90I, 1 H457Y, 1 L461K (3) | - (1) |
Greece (242/4) | 127 (52.5) | 18 | 4 | 1 (25.0) | 1 | - | 54.8 | 10 L461K (10) | NTa |
Ireland (241/4) | 48 (19.9) | 3 | 3 | 2 (50.0) | 1 | - | 15.6 | 17 L461K, 1 L461S, 1 D189V/L430S (21) | Q104L (6) |
Israel (70/25) | 2 (2.9) | - | - | 7 (28.0) | 5 | 1 | 66.7 | 1 L461S (1) | NT |
Italy (147/64) | 4 (2.7) | 1 | 4 | 14 (21.9) | 8 | 4 | 85.0 | 1 L461S (1) | NT |
Poland (66/24) | 1 (1.5) | - | - | 3 (12.5) | - | 1 | 50.0 | 1 L461S (1) | NT |
Spain (208/16) | 3 (1.4) | - | 1 | 4 (25.0) | 1 | 2 | 66.7 | - (1) | NT |
Sweden (163/24) | 5 (3.1) | 1 | 3 | 9 (37.5) | 7 | 2 | 92.9 | 1 A70V/A160V/H457Y (1) | - (1) |
Switzerland (59/19) | 4 (6.8) | 1 | 2 | 9 (47.4) | 7 | 2 | 92.3 | 1 F441Y (1) | - (1) |
Turkey (128/50) | 8 (6.3) | 1 | 3 | 16 (32.0) | 9 | 6 | 82.6 | 1 H457Y, 1 V90I/H457Q/L461K (2) | NT |
UK (289/21) | 34 (11.8) | 4 | 19 | 10 (47.6) | 7 | 2 | 74.4 | 1 P404L, 3 L461K, 2 L461S (6) | NT |
Location (No. overall S. aureus/CoNS) | S. aureus | CoNS | Acquired fusidic acid resistance genes (%) | ||||||
No. of strains showing fusidic acid MIC values ≥2 μg/mL (%) | fusB | fusC | No. of strains showing fusidic acid MIC values >2 μg/mL (%) | fusB | fusC | fusA mutations (No. tested) | fusE mutations (No. tested) | ||
Belgium (93/28) | 6 (6.5) | - | 1 | 12 (42.9) | 8 | 4 | 72.2 | 1 V90I, 1 L461K (3) | - (2) |
France (541/85) | 35 (6.5) | 2 | 16 | 42 (49.4) | 28 | 6 | 74.3 | 1 V90A, 1 A376 V, 1 P404L, 1 H457Y, 4 L461S, 1 T387I/E449K, 1 wt (10) | - (1) |
Germany (453/70) | 13 (2.9) | 3 | 1 | 23 (32.9) | 7 | 8 | 61.3 | 1 V90I, 1 H457Y, 1 L461K (3) | - (1) |
Greece (242/4) | 127 (52.5) | 18 | 4 | 1 (25.0) | 1 | - | 54.8 | 10 L461K (10) | NTa |
Ireland (241/4) | 48 (19.9) | 3 | 3 | 2 (50.0) | 1 | - | 15.6 | 17 L461K, 1 L461S, 1 D189V/L430S (21) | Q104L (6) |
Israel (70/25) | 2 (2.9) | - | - | 7 (28.0) | 5 | 1 | 66.7 | 1 L461S (1) | NT |
Italy (147/64) | 4 (2.7) | 1 | 4 | 14 (21.9) | 8 | 4 | 85.0 | 1 L461S (1) | NT |
Poland (66/24) | 1 (1.5) | - | - | 3 (12.5) | - | 1 | 50.0 | 1 L461S (1) | NT |
Spain (208/16) | 3 (1.4) | - | 1 | 4 (25.0) | 1 | 2 | 66.7 | - (1) | NT |
Sweden (163/24) | 5 (3.1) | 1 | 3 | 9 (37.5) | 7 | 2 | 92.9 | 1 A70V/A160V/H457Y (1) | - (1) |
Switzerland (59/19) | 4 (6.8) | 1 | 2 | 9 (47.4) | 7 | 2 | 92.3 | 1 F441Y (1) | - (1) |
Turkey (128/50) | 8 (6.3) | 1 | 3 | 16 (32.0) | 9 | 6 | 82.6 | 1 H457Y, 1 V90I/H457Q/L461K (2) | NT |
UK (289/21) | 34 (11.8) | 4 | 19 | 10 (47.6) | 7 | 2 | 74.4 | 1 P404L, 3 L461K, 2 L461S (6) | NT |
NOTE. CoNS, coagulase-negative Staphylococcus spp; MIC, minimum inhibitory concentration.
Used with permission from Castanheira et al [23]. Copyright © 2010, Oxford University Press.
NT, not tested.
Fusidic Acid Dosing and In Vitro Diagnostic Tests
The pharmacology and pharmacodynamics of fusidic acid [38] have been updated in an effort to maximize the duration of antimicrobial effects (inhibition or killing) and minimize/delay emerging resistance [39, 40]. These studies concluded that a loading dose oral regimen (≥1200 mg twice per day on day 1; 600 or 500 mg every day on subsequent days) would result in early, high trough levels (50–80 μg/mL) and by various in vitro models, delay regrowth of resistant mutants among studied staphylococci [41, 42].
Because the fusidic acid wild-type susceptible population has a clear modal MIC against S. aureus at .12 μg/mL, the epidemiologic cutoff value and susceptible staphylococcal breakpoint would be best chosen at ≤1 μg/mL, like that used by EUCAST [27]. Publications proposing or reviewing fusidic acid MIC and zone diameter breakpoints [6, 27, 43–46] have a general consensus as follows: (1) MIC breakpoint at ≤1 μg/mL; (2) use of a 10-μg fusidic acid disk concentration; and (3) a correlate zone diameter selected for susceptibility at ≥21 or ≥22 mm. Figure 3 (from Jones et al [46]) shows the fusidic acid MIC/zone diameter (10-μg disk) scattergram and proposed breakpoint criteria (broken lines) for susceptibility defined as ≤1 μg/mL and ≥22 mm [47]. This cited evaluation used 778 contemporary S. aureus isolates including molecularly characterized fusidic acid–resistant strains. The intermethod categorical agreement was 99.9% (r = .74), with only 1 minor interpretive error [46]. Correlations between CLSI [26] reference fusidic acid MIC results and those of Etest were also excellent at 99.7% ± 1 doubling dilution step [46].
The in vitro studies of fusidic acid resistance by Castanheira et al [22, 23] confirm those of Turnidge and Collignon [24] that resistance rates have generally remained low with some high national or resistance-based occurrences (cross or clonal infections), not trending toward high levels even with long-term (24 y) escalating use in some countries. Also, selection of resistant variants during treatment “does not occur at high frequency” [24]. The latter concern has been limited by co-drug (eg, rifampin), long-term treatments for serious staphylococcal infections such as endocarditis, osteomyelitis, and recurrent bacteremias. Surveillance to detect fusidic acid resistance emergence should be continued [22, 23, 32] in geographic areas where it may be introduced (US) or used more widely [24], utilizing the reference susceptibility test methods described above.
CONCLUSIONS
The continuing escalation of multidrug-resistant Gram-positive pathogens, especially MRSA, has fostered concerns about treatments of community-acquired infections [48]. Among these multidrug resistant infections, those challenging orally administered “drugs of last resort” (linezolid) have been documented, as yet in small but significant numbers [49, 50]. However, one possible high-level coverage (>99% susceptiblity rate) alternative has been fusidic acid, recognized by some for several decades [51, 52]. Wider acceptance of this old steroidal agent has been compromised by emerging resistance in S. aureus during treatment with the currently utilized dosing schedules [24, 38], granted, at low rates, but less than the combination (fusidic acid plus co-drug) treatment experience [51]. Given the single-step mutational rates (1.2 × 10−6 at 4 × MIC to 9.8 × 10−8 at 16 × MIC exposures) [7], fusidic acid resistance would be expected, but potentially controlled via novel, front-loading dosing strategies that maximize short-term drug exposure [40–42].
Initial application of systemic (not topical) fusidic acid doses for appropriate indications (skin and skin structure infections in ambulatory patients) based on modern concepts of pharmacodynamics appears promising [40–42, 53]. This has an even greater potential for success when used in a country, such as the US, where prior fusidic acid exposure has not occurred and the contemporary S. aureus population remains naïve, that is, 99.7% susceptible at ≤1 μg/mL (Tables 1 and 2). Furthermore, increasing knowledge about fusidic acid resistance mechanisms and rates of development [15–24, 30–32] now allows clinicians to have more confidence that combination therapies may not be required and that exposure-related resistance mechanisms (fusA and E) are uncommon and/or associated with reduced organism fitness [15, 16, 19]. Contemporary development of fusidic acid in any geographic area should be followed by structured surveillance programs and the expansion of indications to other emerging or problematic pathogens recently documented to be within its spectrum of activity (Neisseria spp., Bordetella pertussis, Moraxella catarrhalis, and Chlamydia trachomatis) [6, 32].
The coauthors wish to thank the following staff at JMI Laboratories: G.J. Moet, L.M. Deshpande, M.G. Stilwell, M.J. Janechek, P.R. Rhomberg, and D.J. Farrell for technical support and manuscript assistance.
Financial support. This work was supported by an educational/research grant from Cempra Holdings.
Supplement sponsorship. This article was published as part of a supplement entitled “Fusidic Acid Enters the United States” sponsored by Cempra Pharmaceuticals.
Potential conflicts of interest. R. N. J., R. E. M., H. S. S., and M. C. are employees of JMI Laboratories (North Liberty, Iowa), which has received research funding from API, Astellas, AstraZeneca, Bayer, Cerexa, Cubist, Durata, Forest, GlaxoSmithKline, Johnson & Johnson (Ortho McNeil), Nabriva, Novartis, Optimer, Ordway, Pfizer, RibX, Shionogi, The Medicines Co, Theravance, and TREK Diagnostics.
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