Linezolid and Other Oxazolidinones

CLASS

The oxazolidinones are a unique class of synthetic antibiotics, chemically distinct from any commercially available agent (45,136) The first oxazolidinones were reported in the late 1970s by researchers at E.I. Dupont de Nemours & Company (45,86) Further chemical modifications resulted in two 3-aryl-oxazolidinones compounds, DuP-721 and DuP-105, in 1987. These agents demonstrated potent in vitro and in vivo activity versus a variety of antibiotic-susceptible and -resistant gram positive organisms (13,34,72,90,109) However, toxicity issues in animals led to the abandonment of further development of these compounds. Pharmacia Corporation (currently Pfizer, Inc.) revisited this class and examined hundreds of different oxazolidinone subclasses in an effort to find those with good antibacterial activity and low toxicity (134). Two lead compounds, eperezolid (PNU-100592) and linezolid (PNU-100766), were selected for further study (20,22,136) Only linezolid continued beyond Phase I development, and is the first oxazalodinone approved for clinical use in more than 50 countries. AZD-2563 (AstraZeneca) is a newer oxazolidinone with a similar spectrum of activity to that of linezolid and completed phase I trials before it was discontinued in July 2002. The oxazolidinones have several noteworthy attributes including 1) a novel mechanism of action, 2) a spectrum of activity that includes multidrug-resistant gram-positive bacteria, 3) excellent oral bioavailability, 4) difficulty in selecting resistance in vitro, and 5) lack of cross resistance with other antimicrobial agents (12,136).

Chemical Structure

The oxazolidinones are heterocyclic molecules with a nitrogen and oxygen in a five membered ring bridged with a carbonyl group (109). Linezolid is a member of the 3-aryl-2-oxzalidinones, which possess good antibacterial activity. These agents have an acetamidomethyl group attached to the C (5) position of the oxazolidinone ring. Their antibacterial activity is enhanced by the hydroxyactetyl group on the heterocyclic nitrogen and fluorine substitutions at the phenyl 3 position (20). AZD-2563 is a member of a series of compounds which have the C-5 acetamidomethyl group replaced by O- or N-linked 5- or 6-member aromatic heterocycles (58). The chemical structures of DuP-721, DuP105, erperezolid, linezolid, and AZD-2563 are shown in Figure 1.

ANTIMICROBIAL ACTIVITY

Spectrum

Oxazolidinones are active mainly against gram-positive organisms, but they also display modest activity against certain gram negative and anaerobic pathogens. Representativein vitro susceptibilities of various gram-positive, gram-negative and anaerobic bacteria are listed in Table 1.

Gram Positive Activity

The testing of several thousand clinical isolates have demonstrated that the 90% minimum inhibitory concentrations (MIC90 ) of both linezolid and AZD2563 for susceptible and multi-drug resistant enterococci, staphylococci and streptococci are ≤ 4 µg/ml. Linezolid and AZD-2563 are highly effective against methicillin-resistant Staphylococcus aureus (MRSA) with MIC90s ranging from 1-4 and 2 µg/ml, respectively. Both compounds possess activity against methicillin-resistant Staphylococcus epidermidis (MRSE) with MIC90s of 1-4 and 1µg/ml, respectively (23,44,48,72,73,88,91,102,103,122,127,136). In addition, clinical isolates of vancomycin/glycopeptide-intermediate S. aureus (VISA/GISA, vancomycin MIC 8 to 16 µg/mL), and vancomycin-resistant S. aureus (VRSA, vancomycin MIC≥ 32 µg/mL) isolates were susceptible to linezolid with MICs ranging from 1-2 µg/ml (4,25,103). Unlike quinupristin-dalfopristin, oxazolidinones also demonstrate activity against both vancomycin-resistant Enterococcus (VRE) faecalis and faecium. Linezolid and AZD-2563 have consistently reported MIC90s of 1-4 and 2 µg/ml for these organisms, respectively (23,39,40,131,136). Against methicillin-resistant Streptococcus pneumoniae both linezolid and AZD-2563 demonstrate excellent in vitro activity with MIC90’s ≤ 2 µg/ml (15,23,95,110,136). Susceptibility breakpoints for linezolid against enterococci, staphylococci, and streptococci are listed in Table 2. The spectrum of activity of the oxazolidinones also includes unusual gram positive species including Bacillus spp., Corynebacterium spp., Listeria monocytogenes, and Micrococcus spp. (70,72,136)

Gram Negative Activity

Oxazolidinones are less active against aerobic gram-negative pathogens due to rapid efflux mechanisms. Linezolid is not active against Acinetobacter spp, Escherichia coli,Klebsiella pneumoniae, Proteus penneri, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia (72,116,136). In addition, linezolid displays minimal activity against Haemophilus influenzae and Neisseria gonorrhea, with MIC90s of 16 µg/ml (72,130). However, linezolid displays modest activity against Bordetella pertussis, Flavobacterium menigosepticum, Moraxella catarrhalis, and Pasteurella multocida with MIC90s of ≤4 µg/ml (35,53,66,130,136).

Anaerobic Activity

Oxazolidinones display activity against select gram-positive anaerobic bacteria. Linezolid has modest activity against Bacteroides fragilis, Clostridium difficile, Clostridium perfringens, Fusobacterium spp., Peptostreptococcus spp., and Prevotella spp. (29,36,54,55,94,97,127,136). AZD-2563 displays greater activity against Clostridium difficile, Clostridium perfringens, and Peptostreptococcus spp. with MIC90s of ≤2 µg/ml against these species (36).

Miscellaneous Activity

Oxazolidinones possess significant activity against Legionella spp. and Mycobacterium tuberculosis. Oxazolidinones inhibited growth of five multidrug-resistant isolates of M. tuberculosis at concentrations of ≤2 µg/ml (136). Against clinical isolates of M. tuberculosis resistant to first line drugs, the MIC90 of linezolid was 0.5 µg/ml (3). In addition, linezolid has activity against Mycobacterium avium complex as well as several rapidly growing mycobacteria such as M. fortuitum third biovariant complex , M. mucogenicum and M. smegmatisgroup (96,124).

Effects on Virulence Factors

S. aureus produces a number of virulence factors such as α-hemolysin, δ-hemolysin, and coagulase, which play an important role in the infection process. S. pyogenesproduces streptolysin O (SLO), which displays toxic activity for a variety of cell types, and deoxyribonuclease (DNase). Subinhibitory concentrations of linezolid at 1/2, 1/4, and 1/8-fold the MIC impaired the production of α-hemolysin, δ-hemolysin, and coagulase in S. aureus and SLO and DNase in S. pyogenes. In addition, in both S. aureus and S. pyogenes,susceptibility to phagocytosis was enhanced by linezolid at concentrations below the MIC (49). S. pyogenes also produces streptococcal pyrogenic exotoxin A (SPE A), which plays an important role in the pathogenesis of severe group A streptococcal infections. Increasing concentrations of SPE A have been associated with increases in IL-6, which is a marker for systemic inflammation (30). In an in vitro pharmacodynamic model using S. pyogenes, linezolid alone and in combination with penicillin significantly reduced the early release of SPE A and was as effective as clindamycin in reducing its overall production (31).

 

PHARMACODYNAMICS

Parameters Correlating With Outcome

The percentage of the dosing interval that drug concentrations remain above the MIC (T>MIC) and area under the plasma concentration-time curve to MIC ratio (AUC/MIC) are pharmacodynamic parameters which have been shown to be predictors of outcomes for oxazolidinones. Peak drug concentration level in serum to MIC ratio (peak/MIC) has not been shown to be a predictor of efficacy. In a rat pneumococcal pneumonia model, the major parameters predicting efficacy for linezolid were T>MIC of greater than 39% of the dosing interval and an AUC/MIC ratio of >147 (50). In addition, a T>MIC of ≥40% for linezolid was associated with positive outcomes in a gerbil model of acute S. pneumoniae infection (84). However, in a murine-thigh model of infection, Andes et al demonstrated that the 24-h AUC/MIC ratio was the major parameter determining the efficacy of linezolid against eight different strains of penicillin-susceptible S. pneumoniae. The coefficient of determination (R2) was the highest for the 24 h AUC/MIC in comparison with other pharmacodynamic parameters (R2 = 82% for AUC/MIC, 57% for T>MIC and 59% for peak/MIC, respectively) (Figure 2). In methicillin-susceptible S. aureus, the most relevant pharmacodynamic parameter was difficult to determine; however, a 24 h AUC/MIC demonstrated a slightly better correlation with outcomes in comparison with the other parameters (R2 = 75% for AUC/MIC, 74% for T>MIC, and 65% for peak/MIC, respectively). The mean 24 h AUC/MIC ratio required for a bacteriostatic effect with linezolid over 24 h was 48 for S. pneumoniae and 83 for S. aureus (7). In a similar study by Craig et al, the 24 h AUC/MIC ratio was also highly correlated with efficacy for AZD-2563 in both S. aureus, and S. pneumoniae. (R2 = 84-94% for AUC/MIC, 46-73% for T>MIC, and 59% for peak/MIC, respectively) (32).

In 231 patients treated with linezolid for community acquired pneumonia, T>MIC and AUC/MIC ratio were evaluated as predictors of clinical and microbiologic failure. As serum concentrations of linezolid were above the MIC for 100% of the dosing interval, T>MIC could not be analyzed. However, a low 24 h AUC/MIC was shown to be a significant predictor of failure in these patients (28). In 241 seriously ill patients participating in a compassionate use program for gram positive infections, time to pathogen eradication, pathogen eradication, and clinical cure were predicted by both 24 h AUC/MIC and T>MIC. A T > MIC of ≥85% or a 24 h AUC/MIC ratio of >100 was associated with maximal efficacy (84).

Bactericidal Activity

Time-kill experiments have demonstrated that oxazolidinones are predominately bacteriostatic against staphylococci and enterococci irrespective of the presence of resistance to other drugs (34,72,73,102,103,109,127,136). At concentrations of two, four, ten fold the MIC, linezolid has been shown to have bacteriostatic activity against numerous strains of staphylococci and enterococci (102,103,127,136). In an in vitro pharmacodynamic model by Allen et al, linezolid 600mg every 12 h was bacteriostatic against MRSA, MRSE, and vancomycin-resistant E. faecalis and E. faecium. However, against one strain of GISA modest bactericidal activity was achieved (a 3.52 log10 CFU/mL reduction in colony counts at 48 h) (4). In a similar in-vitro model by Cha et al., linezolid demonstrated significant bactericidal activity against multidrug-resistant and vancomycin-tolerant Streptococcus pneumoniae (24). In time kill experiments employing S. pneumoniae, modest bactericidal activity was also achieved by linezolid (127,136). Other time kill experiments have shown that linezolid demonstrated bactericidal activity against B. fragilis, C. perfringens, and S. pyogenes (136). Data from animal models support some of the in vitro findings. In a murine-thigh model of infection by Andes et al, linezolid demonstrated bacteriostatic activity, producing modest reductions in colony counts of ≤ 0.5 log10 CFU/mL in S. aureus and ≤ 2 log10 CFU/mL in S. pneumonia (7). More recently, AZD-2563 has been shown to have concentration independent, bacteriostatic activity against staphylococci and streptococci (68).

Post-antibiotic Effects

Oxazolidinones exhibit a modest to prolonged post antibiotic effect (PAE) against staphylococci and enterococci. In an in vitro pharmacodynamic model linezolid exhibited a minimal to modest PAE against clinical strains of S. aureus, S. epidermidis, E. faecalis, and E. faecium. The PAE was shown to increase with increasing concentrations, greater at 4-fold the MIC (range, 0.2 to 1.4 h) than at the MIC (range, 0.1 to 0.8 h) (102). In vivo, the PAE of linezolid was slightly longer than when determined using in vitro models and was not concentration dependant. Linezolid exhibited a PAE of 3.2 to 3.4 h in a murine-thigh model against S. aureus at both 20 and 80 mg/kg doses. However, against S. pneumoniae linezolid did not exhibit a post antibiotic effect in vivo (7). In contrast, AZD-2563 exhibits a prolonged in vivo PAE. Against S. aureus and S. pneumoniae, PAE’s for AZD-2563 ranged from 7.4-17.0 h, and 1.6 to 12h, respectively, which support the rationale for once-daily dosing with this agent (32).

Synergy

Several in vitro and in vivo studies have investigated combination therapy with oxazolidinones against a variety of resistant gram-positive pathogens. Sweeney et al examined the effects of linezolid in combination with 35 antimicrobial agents against various strains of gram positive bacteria using the checkerboard technique of detecting synergy. Against multidrug-resistant and –susceptible strains of S. aureus, S. pneumoniae, E. faecalis, and E. faecium greater than 90% of the antimicrobial combinations with linezolid showed indifference. However, against S. aureus linezolid plus amoxicillin and linezolid plus imipenem was synergistic against MRSA and methicillin-susceptible S. aureus (MSSA), respectively. Against vancomycin-susceptible E. faecalis linezolid plus teicoplanin was synergistic. In addition, linezolid plus imipenem or tetracycline demonstrated synergy against vancomycin-resistant E. faecium. In the case of penicillin-intermediate S. pneumoniae, linezolid also achieved synergy with erythromycin (116). Time-kill experiments also have demonstrated synergistic combinations with linezolid. Grohs et al analyzed the effect of linezolid in combination with various antimicrobials against ten strains of S. aureus. Against MRSA and MSSA, no synergy was observed when linezolid was combined with fusidic acid, gentamicin, or rifampin at 4- and 8-fold the MIC. However, when linezolid was combined with vancomycin and ciprofloxacin slight antagonism was observed (60).

Other time-kill experiments support the notion of indifference with linezolid combination therapy. Three strains of MRSA and MRSE showed indifference when linezolid was combined with vancomycin or rifampin at one quarter the MIC (88). Against 10 multidrug-resistant strains of staphylococci and streptococci, AZD-2563 in combination with gentamicin but not vancomycin demonstrated synergy (69). Jacqueline et al evaluated the in vitro activity of linezolid alone and in combination with gentamicin, vancomycin, or rifampicin at one-, four-, and eight-fold the MIC against MRSA by time kill methods in conjunction with scanning electron microscopy. Time kill curves demonstrated that the combination of linezolid and rifampin was additive; however, the addition of linezolid resulted in a decrease of antibacterial activity for vancomycin and gentamicin. Only the combination of linezolid and gentamicin was antagonistic. Scanning electron micrographs of an MRSA strain exposed to linezolid alone and in combination with various antimicrobials display similar results to the time kill curves, shown in  3 (67).

Allen et al evaluated the activities of linezolid simulated at 600 mg every 12 hours in combination with a number of antimicrobials against a variety of multi-drug resistant gram positive bacteria in an in vitro pharmacodynamic model. The combinations of linezolid plus cefepime or vancomycin demonstrated additivity against both MRSA, and MSSA. In addition, against MRSE, VRE faecalis, and VRE faecium linezolid plus vancomycin, quinupristin-dalfopristin, or doxycycline demonstrated additivity. Synergy was also demonstrated with the combinations of linezolid plus quinupristin-dalfopristin against MRSA, cefepime against MRSE, and doxycycline against VRE faecalis (4). Similar studies in vancomycin-tolerant S. pneumoniae also suggest synergistic bactericidal activity with linezolid plus rifampin (24). However, contrary to in vitro studies two recent analyses of combination therapy in rabbit models of MRSA endocarditis have demonstrated antagonism with linezolid plus vancomycin, and indifference with linezolid plus rifampin (26,33).

 

MECHANISM OF ACTION

The oxazolidinones have a unique mechanism of action that involves the inhibition of bacterial ribosomal protein synthesis at a very early stage (34,41,80,109). Oxazolidinones bind to the 23S portion of the 50S ribosomal subunit preventing the formation of a functional 70S initiation complex formed with the 30S subunit, fMet-RNA, initiation factors (IF2, IF3) and mRNA (34,41,80,109,115). While oxazolidinones may compete with chloramphenicol and lincomycin at the 50S subunit, they have no effect on petidyl transferase or translation termination (80). This mechanism of action differs from that of existing protein synthesis inhibitors such as chloramphenicol, aminoglycosides, pristinamycin, lincosamides, macrolides, and tetracycline, which inhibit peptide elongation (81). Due to this novel mechanism of action, cross resistance between the oxazolidinones and other antimicrobial agents is not expected (43). The mechanism of action of oxazolidinones is illustrated in Figure 4.

 

MECHANISM OF RESISTANCE

Specific point mutations in the central loop of domain V of 23S rRNA of the 50S subunit of the ribosome have been associated with oxazolidinone resistance in S. aureus, E. faecalis, and E. faecium in clinical and laboratory strains (76,98,107,129). Guanosine is replaced by uracil at nucleotide 2576 (G2576U) of the 23SrRNA in linezolid-resistant E. faecalis. Mutations that have been associated with linezolid resistance in S. aureus include G2447U and G2576U, and in E. faecium G2505A and G2576U (81,98). Domain V is one of the most highly conserved rRNA segments, and is an integral part of the ribosomal peptidyl transferase center (38). Most organisms have multiple copies of the 23S rRNA gene, and the degree of linezolid resistance observed correlates with the ratio of wild type to mutant 23S rRNA (107,135). Interestingly, it has been shown that radiolabeled chloramphenicol and lincomycin are capable of partially competing with the binding of oxazolidinones to the 50S subunit of the ribosome (80). Both of these drugs inhibit the peptidyl transferase reaction, whereas oxazolidinones do not (42,80). Thus, even though the mechanism of protein synthesis inhibition for chloramphenicol, lincosamides, and oxazolidinones differ, their binding site(s) on the 23S rRNA may overlap ( 4).

Video: Mechanism of Resistance -- Mutation

In Vitro

In vitro selection of resistant mutants is difficult to induce with oxazolidinones (73,136). In a study by Zurenko et al, after exposure to linezolid at concentrations 2-fold the MIC, no resistant mutants were found in MRSA and MRSE. The frequency of spontaneous resistance for these organisms was <1 X 10-9 (73). Supporting these results, in an analysis by Kaatz et al, after exposure to linezolid at 2-, 4-, and 8-fold the MIC no resistant mutants were found in S. aureus. The frequency of spontaneous resistance in this study was <8 X 10-11 (136).

In Vivo

Resistance to the oxazolidinones is rare among patients receiving linezolid for VRE or MRSA infections. However, in cases of linezolid-resistant organisms indwelling prosthetic devices, undrained abscesses, prior linezolid therapy, and prolonged duration of therapy appear to be risk factors (11,56,65,93,118). Resistance to linezolid has been reported more frequently in enterococci than in staphylococci. Mutnick et al analyzed 9833 gram-positive cocci during 2001-2002, and identified eight (0.08%) linezolid-resistant strains. Of the eight linezolid-resistant strains, four E. faecium, two E. faecalis, and one each of Streptococcus oralis and S. epidermidis were identified (89). During phase III clinical trials, 15 cases of linezolid-resistant enterococci (14 cases with E. faecium and one with E. faecalis) were encountered (81,135). Several subsequent cases of linezolid-resistant E. faecalis and E. faecium have also been reported (11,56,65,71,89,93). Auckland et al described the first three cases of linezolid-resistant enterococci isolated in the United Kingdom. The MICs were 64 µg/mL inE. faecium and E. faecalis. All resistant isolates demonstrated G2576U mutations of the 23SrRNA subunit. Pulsed-field gel electrophoresis (PGFE) along with sequence analysis of rRNA indicated that resistance developed in previously susceptible strains (11). Gonzales et al reported 5 cases of linezolid-resistant E. faecium. Four cases occurred in transplant patients and all patients received prolonged courses of linezolid ranging from 21 to 40 days. Three cases of linezolid resistance were associated with treatment failure (56). Herrero et al described the nosocomial spread of linezolid-resistant E. faecium isolated from seven transplant patients. One strain was first identified in a liver transplant patient with a VRE intra-abdominal infection, receiving linezolid. This strain was subsequently nosocomially transmitted to six other patients, none of whom had prior treatment with linezolid. All isolates had a G2576T mutation in the 23SrRNA subunit, and exhibited indistinguishable patterns on SmaI PFGE (65). Surprisingly, in a report by Jones et al, a linezolid-resistant E. faecium strain from a bloodstream infection in a diabetic patient with end-stage renal disease was unassociated with prior linezolid treatment. This isolate had a G2676U mutation in the 23SrRNA subunit and the linezolid MIC was 8 µg/ml (71). In the case of linezolid resistance in other oxazolidinones, several isolates of enterococci resistant to linezolid also demonstrated cross-resistance to AZD-2563 (68,93).

Only 2 cases of linezolid-resistant S. aureus have been reported to date (118,126). Tsiodras et al reported the first case of a linezolid-resistant strain in an 85 year old man undergoing peritoneal dialysis who developed MRSA peritonitis and was treated with linezolid. After 1 month of receiving linezolid, and having cultured 11 linezolid-susceptible isolates of MRSA (MIC of 2 µg/mL), 3 MRSA isolates recovered from the peritoneal fluid were resistant to linezolid (MIC of > 32 µg/mL). PGFE revealed that this strain was unrelated to previously identified linezolid-susceptible MRSA, and all isolates showed a G2576T mutation in the 23SrRNA subunit (118). More recently, in a report by Wilson et al a 52 year old man received linezolid for a post-operative MRSA infection for 21 days. Three weeks after completion of linezolid therapy, MRSA resistant to linezolid (MIC 32 µg/mL) was isolated from a wound swab of the drain site and the empyema fluid. However, during treatment, the MIC of linezolid for MRSA was 2 µg/mL. In contrast to the previous report, the linezolid-resistant strain developed from a susceptible strain as PGFE revealed identical banding patterns in both isolates. All linezolid-resistant isolates also demonstrated a G2576T mutation in the 23SrRNA subunit (126).

 

PHARMACOKINETICS

Absorption

Pharmacokinetic data for linezolid are available from two randomized, double-blind, placebo-controlled phase I trials in 42 adult healthy volunteers (111). Linezolid is rapidly and completely absorbed after oral administration, with a mean absolute bioavailability of approximately 100%. Maximum plasma concentrations (C_max) are reached 1 to 2 hours after administration (T_max). Linezolid may be administered without regard to the timing of meals; however, when linezolid is given with high fat food T_max is delayed from 1.5 hours to 2.2 hours and C_max is decreased by approximately 17%. The area under the concentration–time curve (AUC) is not affected (137). Linezolid exhibits linear pharmacokinetics as plasma concentrations and AUC increased proportionally with dose, irrespective of the route of administration (111). The dose-normalized mean pharmacokinetic values for linezolid after multiple doses were given intravenously and orally are shown in Table 3.

Distribution

Animal and human data have demonstrated that linezolid readily distributes into well-perfused tissues (47). In healthy adult volunteers, its volume of distribution at steady state is 40 to 50 L (0.6-0.7L/kg) (84,137). Linezolid is moderately bound to plasma proteins (31%) and its binding is independent of drug concentration (84,111,137).

Mean linezolid tissue fluid/plasma concentration ratios in sweat and saliva (C_max) are 0.55 and 1.2 µg/ml, respectively (137). Lovering et al examined the penetration of intravenously-administered linezolid into fat, bone, and muscle before and after surgery in 12 patients undergoing hip arthroplasty. Linezolid penetrated these tissues rapidly with approximately 30, 50 and 90% penetration, respectively (83).

Penetration of linezolid into cerebrospinal fluid is adequate in patients with severe infections. In a patient with VRE faecium meningitis linezolid 600mg administered intravenously every 12 hours produced a CSF:plasma ratio of 0.8 (61). In some cases of meningitis, CSF concentrations of linezolid can even exceed those found in serum. In a report of 5 patients with post-neurosurgical central nervous system infections due to gram positive pathogens, multiple doses of linezolid 600 mg intravenously produced a mean CSF:plasma ratio of 1.6 (121).

Metabolism

Linezolid is metabolized by non-enzymatic oxidation of the morpholine ring into two inactive carboxylic acid metabolites (PNU-142586 and PNU-142300) which do not possess any antibacterial activity. In a study by Slatter et al in 8 healthy volunteers, the disposition of linezolid following a 500 mg oral dose of radioactive drug was determined. Linezolid circulates in plasma mainly as the parent compound (108). Linezolid is not detectably metabolized by human cytochrome P450 (111,137).

Elimination

The elimination half life of linezolid is 4.5 to 5.5 hours under single dose and steady state conditions (137). Its primary route of elimination is non-renal, accounting for approximately 65% of the total clearance, with the renal route accounting for the remainder (clearance rate 40ml/min) (137). The low renal clearance suggests that linezolid undergoes tubular reabsorption. Under steady state conditions approximately 30% of an administered dose appears in the urine as unchanged drug and 50% as the two inactive carboxylic acid metabolites mentioned previously. Virtually no parent drug appears in the feces, while approximately 9% of the dose appears in the feces as PNU-142586 and PNU 142300. Formation of PNU-142586 is the rate-limiting step in the clearance of linezolid (108).

 

DOSAGE

Normal

For patients with VRE and MRSA infections the recommended dosage of linezolid is 600 mg every 12 h intravenously or orally for 14 to 28 days (VRE) or 7 to 28 days (MRSA). For patients with nosocomial or community-acquired pneumonia or complicated skin and skin structure infections, the recommended dosage of linezolid is 600 mg every 12 hours for 10 to 14 days. In patients with uncomplicated skin and skin structure infections, the recommended dose is 400 mg orally every 12 h for 10 to 14 days. No dosage adjustment is necessary when switching from intravenous to oral administration. The intravenous formulation of linezolid should be infused over 30 to 120 minutes (137).

Pediatric Patients

The disposition of linezolid in pediatric patients has been studied in 58 children (3 months to 16 years of age) who received a single 10mg/kg or 1.5mg/kg intravenous dose. The pharmacokinetics of linezolid are age dependant, with infants and children having greater plasma clearance, larger volumes of distribution, and lower serum concentrations and serum AUC (75,84). Overall, there is limited data on the pharmacokinetics of linezolid in pediatric patients of any age. Pediatric dosing regimens that provide a pharmacokinetic profile similar to adults have not been determined (137). However, 10mg/kg two to three times a day may be effective (75).

For patients on continuous renal replacement, dosages should be modified (Table 5).

Hepatic Insufficiency

In a matched control study of 7 patients with mild to moderate hepatic insufficiency (Childs-Pugh class A or B) compared with 8 healthy volunteers, no significant differences of the pharmacokinetic parameters of linezolid were observed (64). Based on these data, no dosage adjustment for patients with mild-to-moderate hepatic insufficiency is recommended (137). In patients with severe hepatic insufficiency (Childs-Pugh class C) the pharmacokinetics of linezolid have not been evaluated.

Renal Insufficiency

In a study of 24 patients with varying degrees of renal impairment (creatinine clearance ≥80, 40-79, or 10-39 mL/min and patients on hemodialysis) the AUC, C_max, T_max, V, and CLTOTAL of linezolid did not change with decreased renal function (21). However, depending on the degree of renal impairment the two carboxylic acid metabolites of linezolid did accumulate, with the amount increasing with the severity of renal function (137). In patients with severe renal insufficiency, a 7 to 8-fold increase in exposure to both metabolites occurred (84). The clinical significance of the accumulation of PNU-142586 and PNU-142300 has not been determined. Based on these observations, the manufacturer recommends that no dosage adjustment is necessary for linezolid in patients with renal insufficiency; however, the risks of using linezolid in this population must be weighed against the potential benefit (137). Hemodialysis removes approximately 30% of the linezolid dose and in this situation continued administration of the standard every 12 h dosing is recommended and should be scheduled after hemodialysis (84).

Critically Ill Patients

The pharmacokinetics of linezolid was studied in 24 critically ill patients in an intensive care unit who received linezolid 600 mg intravenously every 12 hours. The mean C_maxand C_min in these patients were slightly lower than that of healthy volunteers at 12.8±5.0 and 4.7±4.3 g/mL, respectively. The first-dose half life of 3.5 hours was shorter than that of healthy volunteers (84). In 318 patients participating in a compassionate use program the intrinsic clearance of linezolid was increased by 60% and the maximum rate of metabolism was 2-fold higher in these debilitated patients compared to previously studied healthy adult volunteers (p < 0.001), resulting in lower AUC values (18).

Pregnancy

There are no adequate well-controlled studies of oxazolidinones in pregnant women or nursing mothers. In mice and rats linezolid was not teratogenic at 4-fold the human exposure level, based on AUC. However, embryo and fetal toxicities were seen. In lactating rats, linezolid and its metabolites were excreted into milk (137).

ADVERSE EFFECTS

Effects on Hematology

Oxazolidinones have shown the potential for reversible myelosuppression in animals (87). Preclinical phase I and II trials have noted hematologic effects with linezolid administration (100). In animal studies, linezolid caused moderate decreases in white blood cell (WBC), red blood cell (RBC) and platelet counts. In human volunteers, 2.4% of those receiving high doses (>1 g/day) developed significant changes in hematocrit, platelet or RBC counts but these changes were reversible when linezolid was discontinued (46). Post-marketing surveillance data gathered during the first 6 months of approved use of linezolid (55,000 treated patients) indicate that the overall incidence of hematologic abnormalities, thrombocytopenia, leukopenia, and neutropenia was 0.13, 0.06, 0.03, 0.004, and 0.006%, respectively (77, 100).

In phase III trials the incidence of abnormalities of hemoglobin, neutrophils, and WBC were not significantly different from that of the comparator group. However, the incidence of thrombocytopenia (defined as less than 75% of lower limit of baseline) was higher in the linezolid group than in the comparator group, at 2.4 versus 1.5%, only close to statistical significance (p=0.066) (51,100). Thrombocytopenia began at approximately 2 weeks of linezolid therapy, but was reversible upon discontinuation of therapy. Several case studies also suggest that while thrombocytopenia associated with linezolid is reversible, it may occur earlier and at a higher incidence (10,59,92). Attassi et al found that the incidence of thrombocytopenia was as high 32% of patients who received linezolid 600mg twice daily for greater than 10 days. Gastrointestinal bleeding occurred in 5% of patients, and 21% of patients who received linezolid required platelet transfusions. Four to 13 days after linezolid therapy was discontinued, platelet counts returned to normal values (10). In addition to thrombocytopenia, there has also been cases of linezolid-induced pancytopenia. In two patients described by Halpern et al, after seven to 21 days of receiving linezolid 600mg twice daily, WBC and hemoglobin levels decreased significantly from baseline. While there was no evidence of bleeding, one patient required erythropoietin alfa, and both patients required blood transfusions (62). Several other cases of reversible myelosuppression, with anemia, reticulocytopenia and increasing iron saturation have been described in patients receiving more than two weeks of linezolid therapy (2,59).

Safety

The safety profile of linezolid was evaluated in seven multi-center, phase III, comparator-controlled trials involving 4047 adult patients with gram positive bacterial infections (100). A total of 2046 patients were treated with linezolid 600 or 400 mg intravenous and orally twice daily for up to 28 days and 2001 patients were treated with comparator agents including cefpodoxime, ceftriaxone, clarithromycin, dicloxacillin, and vancomycin. The linezolid and comparator groups were similar with respect to age, sex, race, presenting infection, and geographic distribution. Adverse drug events occurred more often in the linezolid group than in the comparator group (21.7 vs 15.7%, respectively [p=0.001]). However, the incidence of serious adverse events, treatment discontinuation due to adverse drug events, and patients who died were not significantly different between the two groups. The most common adverse effects of linezolid, which occurred at rates not significantly different from the comparator group, were diarrhea, nausea, and headache (4.3, 3.4, and 2.2 %, respectively) (Table 4) Few patients (≤0.5%) required discontinuation of the study medication due to these effects. Overall, linezolid has generated little toxicity and produced few adverse effects in phase III clinical trial (46,87,100,137).

 

MONITORING REQUIREMENTS

Since linezolid causes mild, reversible, time-dependant myelosuppression, monitoring of complete blood counts in patients who receive linezolid is now recommended (100,137). Monitoring is especially important in patients receiving the drug for more than 2 weeks, those with preexisting myelosuppression or receiving concomitant drugs that produce myelosuppression, and those with chronic infections who have received previous antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression (137).

Prolonged use of 28 days or longer is a risk factor for peripheral neuropathy (which is usually irreversible), and optic neuropathy which can lead to blindness. 

Lactic acidosis can occur and is not associated with duration of therapy.

 

DrUG INTERACTIONS

Cytochrome P450

Linezolid does not inhibit human cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. Linezolid also does not induce hepatic microsomal CYP 450 1A, 3A, or 4A (84). Concomitant administration of linezolid did not alter substantially the pharmacokinetics of (S)-warfarin. Drug substrates of the CYP2C9 system may be administered with linezolid without changes in dosages. No drug interactions with the CYP450 system are expected (137).

Monamine Oxidase

Oxazolidinones are weak, non-selective, reversible inhibitors of monoamine oxidase. Therefore, these agents have the potential to interact with adrenergic and serotonergic agents. Coadministration of linezolid with adrenergic, vasopressor, or dopaminergic agents may result in a reversible enhancement of their pressor response. Following coadministration of linezolid in normotensive healthy volunteers, minimal yet significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations. Increases in blood pressure were also observed following coadministrationm (63). When linezolid was administered with dextromethorphan in healthy volunteers, minimal yet significant decreases were observed in dextrophan (the primary metabolite of dextromethorphan, a serotonin reuptake inhibitor) plasma concentrations. Coadministration was not associated with a serotonin syndrome such as confusion, delirium, restlessness, tremor, blushing or hyperexia and no effects on blood pressure were observed (63).

In phase III trials, the incidence of MAO-related adverse events was similar between patients who received linezolid or comparator agents. 30.9% of patients in the linezolid group versus 30.3% in the comparator group received potentially MAO-interacting medications. When specific drug classes were examined, there was no clear pattern indicating a MAO-inhibitory interaction effect with linezolid (100).

There can be significant interactions between linezolid and food. An exaggerated pressor response may be seen with the ingestion of foods high in tyramine content such as aged cheeses (up to 15 mg tyramine per ounce), tap beers (4 mg tyramine per 12 ounces), and red wines (up to 6 mg tyramine per 6 ounces). No significant pressor response was observed in patients receiving both linezolid and <100 mg tyramine concurrently (9). Therefore, ingestion of more than 100 mg of tyramine at a single meal should be avoided (119,123). It is recommended that linezolid should only be administered to patients receiving serotonin reuptake inhibitors, vasopressor agents, dopaminergic agents, pethidine or buspirone if there are facilities to monitor blood pressure (84). Initial doses of adrenergic agents should be reduced and titrated to achieve the desired response (137).

 

CLINICAL INDICATIONS

Linezolid is currently approved in more than 50 countries for clinical use. FDA approved indications include VRE infections, including those instances of concurrent bacteremia, nosocomial pneumonia caused by S. aureus (including methicillin-resistant strains) and S. pneumoniae (penicillin-susceptible strains), complicated skin and skin structure infections caused by S. aureus (including methicillin-resistant strains), Streptococcus pyogenes, and Streptococcus agalactiae, uncomplicated skin and skin structure infections caused by S. aureus(methicillin-susceptible strains) or S. pyogenes, and community-acquired pneumonia caused by S. pneumoniae or S. aureus (penicillin- and methicillin-susceptible strains, respectively). There have been several phase II and III trials evaluating the effectiveness of linezolid in these infections.

Community Acquired Pneumonia

A multicenter randomized, open label, phase III trial was conducted in 747 hospitalized patients to compare the effectiveness of linezolid versus a cephalosporin regimen for the treatment of community acquired pneumonia (CAP). 381 patients received intravenous linezolid 600 mg twice daily, followed by 600mg orally twice daily, while 366 patients received intravenous ceftriaxone 1 g twice daily, followed by oral cefpodoxime, 200 mg twice daily. Following 12 to 28 days of treatment, microbiologic and clinical efficacy was assessed. Clinical cure was significantly higher in the linezolid group than in the cephalosporin group in all patients (83 vs 76.4%; p=0.04). In the case of all patients who had S. pneumoniaeisolated at baseline, no significant differences in eradication rates were demonstrated between linezolid and ceftriaxone/cefpodoxime (both groups approximately 90%). However, when analyzing a subgroup of patients with bacteremia due to S. pneumoniae, linezolid demonstrated a significantly higher clinical cure rate in comparison to the cephalosporin combination (93.1 vs 68.2%; p=0.021) (104).

Consistent witth adult data a phase II, an open label, multicenter trial was conducted in 66 hospitalized children (12 months to 17 years of age) with CAP, who were treated with intravenous linezolid 10mg/kg every 12 h followed by an oral regimen. Linezolid was administered intravenously for a mean of 4.8 ± 4.3 days, and the mean total duration of therapy was 12.2 ±6.2 days. At the end of therapy a successful outcome was observed in 94% of children. Only one patient failed therapy (74).

Despite the fact that oxazolidinones have demonstrated good cure rates in clinical trials and are indicated for treatment of CAP, based on the limited clinical data presented above it is difficult to recommend the use of linezolid as a first-line agent. It is important to remember that the activity of linezolid against H. influenzae and atypical respiratory pathogens is limited (87). It will be of interest to evaluate newer oxazolidinones with increased H. influenzae activity in the treatment of CAP.

Nosocomial Pneumonia

The efficacy of linezolid in 396 hospitalized patients with nosocomial pneumonia was evaluated in a multi-center, randomized, double-blinded comparator-controlled trial. 203 adult patients empirically received intravenous linezolid 600mg twice daily, plus aztreonam and 193 patients received intravenous vancomycin, 1g twice daily plus aztreonam for 7-21 days. Both groups of patients were severely ill as assessed by their mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores of more than 15. The majority of patients were over 65 years of age, and more than 40% were on a ventilator before enrollment. Clinical and microbiologic outcomes were evaluated 12 to 28 days after treatment. The clinical outcome was not significantly different between groups, as 66.4% of patients in the linezolid group versus 68.1% of patients in the vancomycin group were cured (p=0.79). In the case of microbiologic outcome, there were no significant differences between groups. 67.9% of linezolid-treated patients versus 71.8% of vancomycin-treated patients demonstrated microbiologic success (p=0.69). In addition, eradiation rates of MRSA and S. pneumoniae did not differ significantly (99). In a subsequent continuation study, linezolid and vancomycin were again compared using similar methods and identical regimens of linezolid and vancomycin as described above. However, patients from the previous analysis were not included in this continuation study. 321 patients were treated in the linezolid group and 302 in the vancomycin group. Patients in the continuation study were also severely ill as APACHE II scores were >14 and mean ages were >60 years of age. Supporting the results of the first study, there were no significant differences in cure rates between the treatment groups. Clinical cure rates were 67.9% and 64.9%, and microbiologic success rates were 61.8% and 53.2% in the linezolid and vancomycin groups, respectively (128). Both clinical trials have demonstrated that in severely ill patients linezolid is an effective treatment option for adults with gram-positive nosocomial pneumonia.

Skin and Skin Structure

A randomized, double-blinded, multi-center comparator-controlled trial was performed to evaluate the efficacy of linezolid versus oxacillin-dicloxacillin in 826 patients with complicated skin and soft tissue infections. 403 patients were randomized to receive 600 mg linezolid intravenously every 12 h and 423 patients were to receive oxacillin 2 g intravenously every 6 h, followed by oral linezolid or oral dicloxacillin, respectively. Cure rates were not significantly different between the groups in clinically evaluable patients. Clinical cure rates were 88.6% versus 85.8% for patients treated with linezolid or oxacillin-dicloxacillin, respectively (p=0.30). Similarly, microbiologic cure rates were 88.1% in patients in the linezolid group versus 86.1% in patients in the oxacillin-dicloxacillin group. This study supports the use of linezolid for the treatment of adults with complicated skin and soft tissue infections (113).

VRE

A randomized, double-blinded, multi-center, dose-comparative, phase III study was conducted to evaluate the efficacy of linezolid in patients with VRE infections. 79 patients received 600 mg of intravenous or oral linezolid and 66 patients received 200 mg of intravenous or oral linezolid twice daily for 7 to 28 days. The mean duration of linezolid therapy was similar between groups, ranging from 15.0 to 16.1 days. Clinical cure rates were slightly higher in the high dose linezolid group in patients with bacteremia, urinary tract infections, pneumonia, and all other infections, but the differences were not statistically significant. However, microbiologic cure was significantly greater for the high dose linezolid group (88 vs 62%; p=0.007) (125,137). The results of a compassionate use program in 796 patients with a variety of gram-positive infections treated with linezolid support the above findings. VRE was the causative pathogen in 66.3% of cases. In intention to treat analysis, clinical cure and microbiologic cure were 73.3% and 82.4%, suggesting that linezolid has similar efficacy in controlled clinical and real world environments. (18,125) Another study analyzed 15 patients who were treated with linezolid 600 mg every 12 hours for a mean duration of 20.5 days against a variety of VRE infections. Microbiologic cure occurred in all 10 patients who completed therapy, and all 7 patients alive at long term follow up were considered clinically cured (27).

MRSA

A randomized, open label trial in 240 hospitalized patients compared up to 4 weeks of linezolid or vancomycin in the treatment of known or suspected MRSA infections. 56 patients who received linezolid 600 mg twice daily and 60 patients who received vancomycin 1 g twice daily were evaluated in this study. S. aureus was isolated from 53% of patients, and 93% of isolates were methicillin-resistant. Skin and soft tissue was the common infection site, followed by pneumonia and urinary tract infections. The linezolid treated group showed no significant differences versus the vancomycin treated group, as clinical cure and microbiologic success was 73.2% versus 73.1% (p=0.99) and 58.9% versus 63.2% (p=0.65), respectively. MRSA eradication rates were similar in both groups (112).

In addition to the clinical utility in using linezolid for MRSA infections, a number of studies support its use to reduce length of stay (LOS) if therapy is switched to the oral route of administration. In 468 hospitalized patients with known or suspected MRSA infections, for patients who received intravenous followed by oral linezolid instead of vancomycin, the median LOS for patients with skin and soft tissue infections was 8 days shorter for the linezolid-treated group (p=0.003) (78,79). Finally, in patients with serious gram positive bacterial infections, including those caused by MRSA, patients treated with intravenous to oral linezolid demonstrated a 1.6-day shorter LOS and a 66% greater odds of early discharge compared with patients treated with teicoplanin (P = 0.049) (82).

Other Infections

The efficacy of linezolid has also been evaluated against a number of other gram positive infections. A growing number of case reports cite success when linezolid is used for meningitis caused by VRE (57,61,106,120). In addition, the evidence of successfully treating CSF infections due MRSE with linezolid is also growing (52,120). Prosthetic hip infections associated with osteomyelitis due to VRE faecium and MRSA have also been successfully treated with linezolid (14,117). In the case of endocarditis there have been reports of clinical success when linezolid was used as part of combination therapy against multi-drug resistant pathogens. In a 52 year old patient with mitral-valve endocarditis due to GISA clinical response was achieved only after linezolid was added to vancomycin (8). Other successful cases of treatment with linezolid for VRE endocarditis have been reported (27). However, there are also a number of case reports citing failures of linezolid as monotherapy in MRSA and E. faecalis endocarditis (101,133). 

Future Oxazolidinones

Oxazolidinones fill an important void in infectious disease chemotherapy. Within the past few years gram-positive organisms have emerged that are resistant to nearly every available antimicrobial agent. The oxazolidinones include such organisms within their spectrum of activity. Oxazolidinones have many favorable attributes with activity against multidrug-resistant bacteria, 100% bioavailability, a long serum half life allowing twice-daily dosing, a low incidence of the emergence of primary resistance and no cross-resistance to existing compounds. AZD-2563 also has favorable characteristics, with a spectrum of activity similar to that of linezolid and a prolonged post antibiotic effect, allowing for once a day dosing. However, as resistance appears to be a class effect with the oxazolidinones, pathogens resistant linezolid are likely to be resistant to other oxazolidinones, including AZD-2563. Several other oxazolidinones exist as potential candidates in the battle against multidrug-resistant pathogens, but other than AZD-2563 and linezolid none have progressed to clinical trials. PNU-183247 (Pfizer) and VRC 3599 (Versicor) are two newer oxazolidinones which have increase anti-Haemophilus activity and good activity against S. pneumoniae (81). RBX7644 (Ranbaxy) is a newer oxazolidinone which demonstrates very good activity against both gram negative and gram positive anaerobic pathogens (37). The development these second generation oxazolidinones and other new oxazolidinones is anxiously awaited.

 

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Tables

Table 1. In Vitro Susceptibility of Multi-Drug Resistant and Susceptible Gram-Positive, Gram Negative and Anaerobic Pathogens to Linezolid and AZD-2563.    

Organism	Linezolid MIC90	AZD-2563 MIC90	Reference
Gram-positive bacteria
Bacillus spp.	1	1	(72,136)
Corynebacterium spp.	0.5-2	0.25	(70,72,136)
Listeria monocytogenes	2	2	(70,136)
Micrococcus spp.	2	2	(70)
Enterococcus spp.
E. avium	2-4	1	(19,39,40)
E. casselliflavus	2-4	2	(19,39,40)
E. gallinarum	2-4	2	(19,40)
E. raffinosus	2-4	2	(39,40)
Enterococcus faecalis	1-4	2	(19,44,91,102,103,127)
Vancomycin – Susceptible	1-4	2	(23,39,40,72,114,131,136)
Vancomycin - Resistant	2-4	1	(23,39,40,131,136)
Enterococcus faecium	1-4	4	(19,44,91,102,103,127)
Vancomycin – Susceptible	1-2	2	(23,39,40,72,114,131)
Vancomycin - Resistant	2-4	2	(23,39,40,131,136)
Staphylococcus aureus
Methicillin – Resistant	1-4	2	(6,23,44,48,72,88,91,102,103,122,127,136)
Methicillin – Susceptible	1-4	2	(6,23,44,48,72;88,91,102,103,122,127,136)
Vancomycin – Intermediate	1-2a	--	(4,103)
Vancomycin – Resistant	2a	--	(25)
Staphylococcus epidermidis
Methicillin - Resistant	1-4	1	(44,48,72,73,91,102,103,122,127,136)
Methicillin - Susceptible	0.5-4	1	(44,48,72,73,91,102,122,127,136)
Streptococcus spp.
ß-Hemolytic	2	2	(5)
S. agalactiae	1-2	2	(17,44,72)
S. pyogenes	1-4	2	(17,44,72,127,136)
Viridans Group	1-2	1	(5,23)
Streptococcus pneumoniae	1-2	1	(1,17,44,72,85,91,127,132)
Penicillin - Susceptible	1-2	1	(15,23,95,110,136)
Penicillin - Intermediate	1	1	(15,23,95,110,136)
Penicillin - Resistant	1-2	1-2	(15,23,95,110,136)
Gram-negative bacteria
Bordetella pertussis	4	--	(66)
Flavobacterium menigosepticum	2	--	(35)
Haemophilus influenzae	16	--	(72,130)
Leigionella spp.	4	--	(105)
Moraxella catarrhalis	4	--	(130,136)
Neisseria gonorrhoeae	16	--	(72)
Pasteurella multocida	4	--	(53)
Anaerobic bacteria
Bacteroides fragilis group	4	>16	(16,29,36,97,127,136)
Clostridium difficile	2-16	2	(29,36,54,55,94,97,127,136)
Clostridium perfringens	2	2	(29,36,54,55,127,136)
Fusobacterium spp.	0.5-2	>16	(16,29,36,97,136)
Peptostreptococcus spp.	0.5-4	2	(29,36,54,55,72,97,136)
Prevotella spp.	1-4	16	(16,29,36,72,97,136)

MIC90 = minimum inhibitory concentration for 90% of strains tested

a =  reported as MIC

Table 2.  Susceptibility Breakpoints for Linezolid Approved by the National Committee for Clinical Laboratory Standards (NCCLS)(137).

SUSCEPTIBILITY BREAKPOINTS	Minimum Inhibitory Concentration (µg/mL)
	Susceptible	Intermediate	Resistant
Enterococcus spp.	≤2	4	≥8
Staphylococcus spp.	≤4	--	--
Streptococcus pneumoniae	≤2	--	--
Streptococcus spp. (other than Streptococcus pneumoniae)	≤2	--	--

 

Table 3.  Mean Pharmacokinetic Values for Linezolid After Intravenous and Oral Administration to Healthy Volunteers (137).

DOSE OF LINEZOLID	Cmax µg/mL	Cmin µg/mL	Tmax H	AUC µg•h/mL	t1/2 h	CL mL/min
400 mg tablet q 12h	11.00 ± 4.37	3.08 ± 2.25	1.12 ± 0.47	73.40 ± 33.50	4.69 ± 1.70	110 ± 49
600 mg tablet q 12h	21.20 ±5.78	6.15 ±2.94	1.03 ± 0.62	138.00 ± 42.10	5.40 ± 2.06	80 ± 29
600 mg IV injection	15.10 ±2.52	3.68 ±2.36	0.51 ±0.03	89.70 ±31.00	4.80 ±1.70	123 ±40

 ± = standard deviation C_max = Maximum plasma concentration; C_min = Minimum plasma concentration; T_max = Time to maximum plasma concentration; AUC = Area under concentration-time curve; t_½= Elimination half-life; CL = Systemic clearance 

 Table 4.   Adverse Events Summary Data In Phase III Comparator-Controlled Trials (46, 100).

Adverse Event Summary	Linezolid (n=2046)	Comparator (n=2001)	P value
Patients with one or more drug-related adverse event	21.7	15.7	0.001
Treatment discontinued due to drug-related event	2.4	5.2	0.230
Patients who died	4.8	4.9	0.596
Diarrhea	4.3	3.2	0.074
Nausea	3.4	2.3	0.036
Headache	2.2	1.3	0.047
Taste alteration	1.2	0.7	0.117
Vaginal moniliasis	1.2	0.6	0.85
Vomiting	1.1	0.4	0.008
Abnormal Liver Function Tests	1.0	0.3	0.010

 

Table 5.  Dosing during Continuous Renal Replacement Therapy.

Renal Replacement Therapy	Dose Adjustment
CVVH (Continuous venovenous hemofiltration):	600mg q12h
CVVHD (Continuous venovenous hemodialysis):	600mg q12h
CVVHDF (Continuous venovenous hemodiafiltration)	600mg q12h

Note: CVVH is mainly for fluid removal alone. Many institutions will employ more CVVHD or CVVHDF which combine dialysis with fluid removal.

Figure 1.  Structures of Extensively Evaluated Oxazolidinone Antimicrobial Agents.

Figure 2.  Relationship Between the Percentage of Time that Drug Concentrations Remain Above the MIC for the Dosing Interval (%T>MIC), Peak Drug Concentration Level in Serum To MIC Ratio (Peak/MIC), and the 24 H Area Under the Concentration Time Curve to MIC Ratio (AUC/MIC) and the Log10 Number Of CFU/Thigh After 24 H of Linezolid Therapy in a Murine-Thigh S. Aureus Infection Model (7).

R2 = Coefficient Of Determination.

Figure 3.   Scanning Electron Micrographs of a Methicillin-Resistant S. Aureus Strain Exposed to Linezolid Alone and in Combination with Gentamicin, Vancomycin Or Rifampicin. (a) Control (b) Linezolid (c) Gentamicin (d) Linezolid And Gentamicin (e) Vancomycin (f) Linezolid And Vancomycin (g) Rifampicin (h) Linezolid And Rifampicin (67).

Figure 4.  Mechanism of Action of the Oxazolidinone Antimicrobial Agents. 

Steps At Which Other Protein Synthesis Inhibitors Act Are Shown for Comparison.

What's New

Boak LM, et al. Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid.  Antimicrobial Agents Chemother 2014;58:2334-43.

Gu B, et al.  The Emerging Problem of Linezolid-resistant Staphylococcus.  J Antimicrob Chemother 2013;68:4-11.

Nukui Y, et al.  High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 2013: April [Epub ahead of publication].

Cattaneo D, et al.  Linezolid plasma concentrations and occurrence of drug-related haematological toxicity in patients with Gram-positive infections.  Int J Antimicrob Agents 2013;41:586-589.

Deresinski SC, In The Literature. What is the Linezolid Concentration? Clin Infect Dis 2013;57 (1 December):iii.

Butterfield JM, et al.  Can Linezolid be Safely Used in Patients Receiving Serotonergic Drugs?  In The Literature Section, Clin Infect Dis 2012;55:iii.

Long KS and Birte Vester. Resistance to Linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother. 2012;56(2):603-12.

Nambiar S, et al. Linezolid-Associated Peripheral and Optic Neuropathy in Children.Pediatrics. 2011 May 9. [Epub ahead of print]

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