Fusidic Acid

Authors: Keryn J. Christiansen, MBBS

CLASS
Fusidic acid is a member of the fusidane class. The sodium salt was introduced into clinical practice in 1962.

Chemical Structure (Figure 1 )

Fusidic acid is a tetracyclic triterpenoid that is structurally related to cephalosporin P1 (named because of its origin

from Cephalosporium acremonium – it is not related to the beta lactam cephalosporins). Fusidic acid is derived from

the fungus Fusidium coccineum and differs from cephalosporin P1 by the addition of a few acetyl groups, which

increase antibacterial activity. The fusidic acid nucleus has properties common to other tetracyclic structures such as

the adrenocorticoids and bile salts, especially cholate and taurocholate (26). Fusidic acid is related to other antibiotic

groups including the helvolic acids and the viridominic acids. Antibiotics similar or identical to fusidic acid are

produced by dermatophytes such as Microsporum canis, Microsporum gypseum, and Epidermophyton

floccosum (63).
Structure-Activity Relationship
The essential parts of the fusidic acid molecule related to activity are the alpha, beta – unsaturated carboxylic acid at

position C20 and the acetoxyl group at C16. Other functional groups although contributory, are less vital. Many

chemical modifications have been made with only 24, 25 dihydrofusidic acid having activity equivalent to fusidic acid

(95).

ANTIMICROBIAL ACTIVITY
Spectrum

Fusidic acid has good in vitro activity against staphylococci, including both methicillin sensitive and resistant strains. It

also has useful activity against Neisseria spp, Bordetella pertussis, Corynebacterium spp and Gram positive

anaerobes such as Clostridium difficile and C. perfringens, Peptostreptococcus spp and Propionibacterium

acnes (19). The MIC’s for streptococci, enterococci and Gram negative anaerobes are generally higher but at <8

mg/L may provide some activity clinically. Table 1 shows in vitro susceptibility data for the above organisms. It is not

active against the Enterobacteriacae (23, 80, 82, 83). Resistance in vitro has been demonstrated for Borrelia

burgdorferi (34) (MIC90 >4), and Yersinia enterocolitica (81).

Pharmacodynamic Effects
Bactericidal Effects

Fusidic acid is slowly bactericidal in vitro against S. aureus (71) and concentration-dependent inhibition has been

demonstrated against Escherichia coli (25).

Effects of Subinhibitory Concentrations 

There are no data on the effects of subinhibitory concentrations.

Postantibiotic Effects 

At achievable serum concentrations there is a post antibiotic effect of 0.8 – 1.75 hours for S. aureus and  1hour

for Streptococcus pyogenes (51).
Effects on Host Immunity 

Fusidic acid immunomodulatory effects as a result of suppression of cytokine production have been shown in animal

models of septic shock and insulin dependent diabetes. The clinical utility of these properties has not been verified

(16).
Pharmacodynamic Correlates with Outcome

The pharmacodynamic predictors of efficacy (AUC/MIC ratio or time above MIC) have not been determined for this

drug.

MECHANISMS OF ACTION
Fusidic acid interferes with the function of elongation factor G (EF-G), leading to the inhibition of protein synthesis.

Elongation factor G hydrolyses GTP to GDP to provide energy for the translocation of the peptidyl – tRNA from the A

site to the P site on the 50S subunit of the ribosome. In the presence of fusidic acid, EF-G remains bound to the

ribosome after GTP hydrolysis, sterically blocking the next stage of protein synthesis.

MECHANISMS OF RESISTANCE
Organisms Commonly Resistant

Fusidic acid is inactive against the Enterobacteriacae and has only marginal activity against streptococci and

enterococci. The prevalence of resistance in methicillin susceptibleStaphylococcus aureus varies in different

countries with generally low rates reported in studies conducted up to the mid 1990’s (Denmark 0 – 1%, Australia 1-

3%, Canada 0.6%) (89). Since then however, increasing resistance has been reported, particularly in the United

Kingdom with reports of increases from 6 - 8% in 1995/1998 to 11.5 – 17.3% in 2001 (11, 10). An increase in the use

of topical fusidic acid for skin infections has been recorded over this period suggesting resistance selection (47). In

Scandinavia clonal spread of fusidic acid resistant staphylococci has been documented with an increase in resistance

prevalence in Norway of 3% in 1992 to 36% in 2001. Resistance rates for methicillin resistant Staphylococcus

aureus (2 -12%) (89) have remained more stable with the exception that specific clones (EMRSA –17) are reliably

resistant to fusidic acid (3).

Mechanisms of Resistance
A number of mechanisms conferring resistance to fusidic acid have been reported.
Chromosomally mediated resistance is due to point mutations within the fusA gene encoding EF-G (7). Although

mutations occur across a number of loci on EF-G, changes in the conserved region centered on residues 451-464

and in particular H457 (56, 58, 54) seem to be most important, suggesting a possible fusidic acid binding site. Some

mutations are associated with low fitness however selected resistant clinical isolates have been shown to have a

variety of compensatory mutations that restore fitness. In vitro studies suggest that compensation is more likely than

reversion to the sensitive wild type thereby stabilising the resistant bacterial population. These compensatory

mutations probably act by restoring the balance between the GDP and GTP conformations of EF-G of the ribosome

(54, 36, 42). This type of resistance has been demonstrated in S. aureus with mutation frequencies of between one in

106 and one in 108 (89). Although not clinically relevant, altered elongation factor has also been demonstrated in

Gram-negative bacteria which have MICs much higher than wild type strains (72) and inSalmonella typhimurium this

has been shown to result from mutations in the fusA gene (37). The frequency of mutations in S.

aureus demonstrated in vitro has lead to the recommendation for combination therapy particularly for MRSA

infections. In vitro studies support this with undetectable mutations when fusidic acid is combined with rifampicin (59).

Fusidic acid resistance in S. aureus has also been demonstrated to be plasmid mediated. This is the predominant

form of resistance for S. aureus being found in about 70% of resistant strains. This resistance, carried on a plasmid

(pUB101) which also encodes a betalactamase and cadmium resistance, does not involve drug modification or

protein inhibition in a cell free model. Earlier studies have described alteration in membrane permeability however

alterations in membrane composition have not been observed. More recently genetic characterisation of the plasmid

borne fusidic acid resistance has identified an inducible resistance gene, far1, which has similarities with fibronectin

binding protein sequences in other organisms (57).

An efflux resistance mechanism has been described for both Enterobacteriacae and S. aureus. A multidrug tripartite

complex, consisting of an efflux pump (AcrB), a membrane fusion protein (AcrA) and an outer membrane channel

(TolC) has been shown in E. coli to confer resistance to a large number of drugs including fusidic acid, tetracycline,

chloramphenicol, fluoroquinolones, beta-lactams, erythromycin, together with a number of dyes and detergents. The

AcrD transporter has a more limited substrate range but includes aminoglycosides in addition to fusidic acid. The

pump, AcrB or AcrD, captures its substrates from within the cytoplasmic membrane with extrusion directly into the

extracellular medium via the combined action of AcrA and TolC (23). A novel efflux system, MdeA, has been

described for S. aureus (31). When over expressed, resistance to fusidic acid, virginiamycin and novobiocin occurs

but unlike NorA the pump does not confer resistance to fluoroquinolones. Over expression has been demonstrated to

occur by spontaneous mutations in the mdeA promoter region.

Drug sequestration has been described in Enterobacteriacae that are also resistant to chloramphenicol. Type 1

chloramphenicol acetyltransferase (CAT-I) competitively binds to fusidic acid resulting in inactivation by sequestration

(6). The structural basis for the binding of fusidic acid to CAT-1 has been reported (53) and is due to the presence of

specific residues in the chloramphenicol binding pocket of the enzyme. Differing residues in other CAT variants result

in a low binding affinity for fusidic acid and therefore a lack of resistance.

Drug inactivation of fusidic acid has been described in  Streptomyces spp. The enzyme responsible is an esterase

which desacetylates fusidic acid at the C16 position resulting in the inactive lactone derivative (96).
Methods to Overcome or Prevent Resistance

Selection for resistance has been demonstrated during fusidic acid monotherapy (15). In principle combination

therapy may prevent resistance selection (102). Fusidic acid most often is combined clinically with beta-lactams or

rifampicin. Combination therapy has been investigated in vitro with conflicting results for synergy, indifference or

antagonism (19). ForStaphylococcus aureus, resistant mutant selection, in vitro, is prevented for both fusidic acid and

rifampicin when these drugs are used in combination (59). Linezolid also prevents in vitroselection of fusidic acid

resistant mutants for S. aureus (28). Specific clinical data are lacking.

 
PHARMACOKINETICS
Absorption

Sodium fusidate absorption is not very rapid as can be seen from the Tmax values in Table 2. The consistency of the

Cmax values and comparable AUC values indicate that it is predictably absorbed. Food reduces the Cmax and delays

the Tmax but does not alter the AUC (46). The oral formulation has a high bioavailability (91%) (84). Penetration of

fusidic acid applied topically to the skin is minimal with studies showing absorption of 2% or less (94). When applied

topically to the eye significant penetration occurs into the cornea, aqueous humour but not vitreous humour (86, 29).

A single subconjunctival injection of 100 mg of fusidic acid produces levels above the MICs of most organisms in the

cornea, aqueous, and vitreous and persists for over 24 hours, but at this concentration results in conjunctival necrosis

and corneal decompensation (86).

Distribution
Fusidic acid has modest penetration into bone (16 – 24%) and synovial fluid (28-88%) and achieves levels in pus that

are marginally below those in serum. Skin exudate and burn studies show good Cmax values and high fluid/serum

ratios (88, 77). After systemic administration intraocular penetration is low (99, 14).

Routes of Elimination
Metabolism

Hepatic metabolism with biliary excretion is the most likely route of elimination, although renal elimination of hepatic

conjugates or metabolites has not been specifically reported. Examination of biliary metabolites of fusidic acid shows
that the main metabolites are a glucuronide conjugate and a dicarboxylic derivative, accounting respectively for 15%

and 10% of the drug in bile. A variety of minor metabolites are produced, including a possible hydroxy metabolite, a

3-keto metabolite and three that are yet to be identified (88).

Renal Excretion

Elimination is mostly non-renal. Only very low levels have been detected in the urine in pharmacokinetic studies with

< 0.5% being calculated to be excreted by the renal route following IV administration (66). Faecal excretion is

similarly low.
Pharmacokinetic Parameters

The pharmacokinetic parameters, Cmax, Tmax, AUC, half life, clearance and volume of distribution, for different studies

after oral and IV administration (88), are shown in Table 2. Due to its slow clearance the drug accumulates with

repeated administration. When given as a 500mg dose 8 hourly the trough levels increase with reported

concentrations on 4 successive days of 21mg/l, 30mg/l, 47mg/l, and 73mg/l (26). Similarly increases occur in the

AUC (76). Accumulation is not demonstrated when dosing is reduced to 250mg 12 hourly (52) although a higher than

expected AUC is obtained using 500mg 12 hourly (90).

Fusidic acid is highly protein bound (91-98%) and with distinct binding sites on human albumin (73) is a potent

displacer of bilirubin (9).

CNS/CSF Disposition

Low levels of penetration are found in uninflamed brain (7% of the corresponding serum concentration), and

uninflamed CSF (<1% of serum concentration) in humans (49). In a rabbit model percentage penetration using

AUCCSF/AUCserum is 1.9% in uninflamed and 4.5% in purulent CSF (60).

Effect of Disease States
The pharmacokinetics of fusidic acid in patients with severe renal failure requiring dialysis (12) are not substantially

different to patients with normal renal function as would be expected for a drug that has minimal renal clearance. The

drug is not removed by haemodialysis and concentrations in peritoneal dialysis fluid are low (< 2.3mg/l).

Accumulation of metabolites has not been demonstrated in these patients.

The pharmacokinetics of fusidic acid are altered in patients with coeliac disease with the AUC and Cmax being

increased by 60 – 70% compared to normal subjects (61). Patients with low albumin states have increased

clearance, presumably because the reduced capacity for protein binding results in greater drug availability for

metabolism. Conversely decreased clearance occurs with severe cholestasis, the suggested mechanism being

competition by the excess bilirubin for glucuronidation (64).

 
DOSAGE
Adults and Children
Oral Film Coated Tablet

The conventional dosing for adults is 250 to 500mg 8 hourly. Given the documented accumulation at these doses and

greater adverse reactions, a 12 hourly dosing interval can be considered. Clinical trials in skin and soft tissue

infections show similar efficacy for 8 hourly and 12 hourly dosing regimens (13, 55).
Oral Suspension

This is an aqueous suspension containing fusidic acid hemihydrate (250mg/5ml – equivalent sodium fusidate

175mg). Regimens based on conventional 8 hourly dosing are:

< 1 year: 1mL/kg/day in three divided doses,

1-5 years: 5mL 3 times daily,

6-12 years: 10mL 3 times daily

Children > 12, adults: 15mL 3 times daily

As for the tablet formulation 12 hourly dosing can be used.

Intravenous Infusion

This contains the sodium salt equivalent to 500mg of fusidic acid per vial. It is infused over no less than 2 hours. Adult

dose: 500mg 8 to 12 hourly, Children: 12mg/kg up to 500mg 12 hourly or 20mg/kg/daily in three divided doses.

Topical Preparations 

There are three preparations, 2% fusidic acid cream, 2% fusidic acid ointment, 2% fusidic acid gel all for use on skin

surfaces twice daily. An ophthalmic preparation, 1% viscous drops, is available for instillation twice daily into the

conjunctival sac.

Renal Failure

Dose modification is not required.

Hepatic Failure

As there are no safety data in patients with severely impaired hepatic function, opposing pharmacokinetics in patients

with low serum albumin and hyperbilirubinemia, and potential drug hepatotoxicity it is best avoided in these patients.

Body Composition (Obesity, Wasting, Various Body Builds)

There are no data on the effects of body composition.

Ascites/Edema

Low serum albumin states may have increased drug clearance requiring doses in the higher range.

Chronic Diarrhea/Malabsorption

Patients with coeliac disease may require dose reduction.

Malnutrition

There are no data on the effects of malnutrition.

Pregnancy

There is evidence that fusidic acid can penetrate the placental barrier. Fusidic acid may cause kernicterus in babies

during the first month of life by displacing bilirubin from plasma albumin. Fusidic acid should be avoided when

possible during the last month of pregnancy.

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