CEM-102 (Fusidic Acid) In Vitro Activity and Evaluation of Molecular Resistance Mechanisms Among European Gram-positive Isolates (2008-2009) (2010)

Fusidic acid (CEM-102) is an antimicrobial agent isolated from Fusidium coccineum that has been used in clinical practice in Europe since the early 1960s for the treatment of skin and skin structure infections (SSSI) as well as bone and joint infections, caused by indicated Gram-positive organisms. Only limited contemporary understanding of fusidic acid resistance at genetic, epidemiological and clinical levels is available, and prescribing practices are mostly based on outmoded data obtained from studies with small numbers of patients. Fusidic acid binds to elongation factor G (EF-G) preventing its release from the ribosome and thus, stalling protein synthesis. For several years, mutations on fusA, the gene encoding EF-G was postulated to be the primary cause of resistance against this antimicrobial agent, although strains carrying these mutations were predominantly laboratory mutants that were exposed to this compound. Plasmid-mediated resistance has also been described and genes encoding proteins that play a protective role on EF-G have more recently been identified. The genes encoding these proteins are known as fusB, fusC and fusD, the latter identified to cause intrinsic fusidic acid resistance in Staphylococcus saprophyticus. Novel dosing regimens to maximize pharmacodynamic features and minimize the selection of resistant mutants have been designed achieving at least 80 mg/L concentrations of fusidic acid at trough. In this study, we evaluated the activity of fusidic acid against 7,504 Gram-positive strains collected during 2008 and 2009 from European countries. Additionally, mechanisms of fusidic acid resistance were evaluated among 336 staphylococcal strains collected in 2008. Objectives: To evaluate the activity of fusidic acid (FA) among Gram-positive bacteria collected in European medical centres in the 2008-2009 period and to analyze the prevalence of FA resistance (R) mechanisms among staphylococci (2008). Methods: A total of 7,504 strains collected from 29 European (EU) medical sites located in 13 countries were susceptibility (S) tested by CLSI reference broth microdilution against FA and comparator agents. 336 Staphylococcus spp. (2008 only) displaying FA MIC at ≥2 mg/L were tested for the presence of fusB, fusC and fusD and mutations on fusA and fusE (FA primary and secondary active site). Results: FA was very active against all staphylococci displaying a MIC 50 of 0.12 mg/L regardless of methicillin-resistant (MR) profile. Applying EUCAST breakpoints (none available for CLSI), 90.7% of S. aureus (SA) strains were S to FA, with lower rates observed among MRSA (77.9%). Coagulase-negative staphylococci (CoNS) demonstrated 36.7% R against FA (14/867 S. saprophyticus with intrinsically elevated FA MIC). MRCoNS displayed 40.5% of FA-R. FA demonstrated moderate activity against enterococci and streptococci, with MIC 50 values for beta-haemolytic, group A, B and viridians group streptococci, S. pneumoniae and enterococci ranging from 4 to >8 mg/L. Among 336 staphylococci (FA MIC, ≥2 mg/L), the presence of acquired FA-R genes was detected in 64.9% of the strains (36.6% fusB and 28.3% fusC). fusB and fusC rates among FA-R strains were 10.1 and 16.9% for SA and 26.5 and 11.3% for CoNS, respectively. fusA mutations were detected in 56 of 62 FA-R SA, most common being aminoacid alterations on position 461 (Leu to Lys/Ser). One SA showed a mutation on fusE (Q140L). Ireland and Greece showed the highest SA FA-R rates with high prevalence of L461K fusA mutation (clinical outbreaks). Low staphylococci FA-R rates (1.4-3.1%) were observed in Israel, Italy, Poland, Spain and Sweden.