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Current Drug Metabolism, 2009, 10, 2-12

Association of Pharmacokinetic and Pharmacodynamic Aspects of Linezolid with Infection Outcome K.Z. Vardakas1, I. Kioumis2 and M.E. Falagas1,3,* 1

Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece; 2Department of Pulmonary Medicine, Aristotle University School of Medicine, Thessaloniki, Greece; 3Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA Abstract: Linezolid is the first antibiotic of a new class (oxazolidinones). It inhibits protein synthesis by binding to the bacterial 23S ribosomal RNA of the 50S subunit, thus blocking the formation of the functional 70S initiation complex, but it does not inhibit peptidyl transferase. Therefore, its mechanism of action is unique and cross resistance is unlikely to occur; however, resistant strains have already been reported, but the rate of resistance is low in surveillance programs. Linezolid has a favorable pharmacokinetic profile. It is rapidly absorbed when administered orally, and it is 100% bioavailable, thus allowing early switch from intravenous to oral administration. The maximum plasma concentration (range between 13.1±1.8 to 19.5±4.5 μg/ml according to the route of administration, studied population and dosages administered to subjects) is achieved 1-2 hours after the first dosage. It penetrates readily to most tissues of the human body at concentrations much higher than that of the minimal inhibitory concentrations of the targeted pathogens. It is metabolized by oxidation in two major inactive metabolites and is eliminated mainly through the kidneys. Linezolid is bacteriostatic for staphylococci and enterococci but bactericidal for pneumococci and kills bacteria in a time-dependent fashion. It has been studied in several randomized controlled trials and has been approved for the treatment of patients with Gram positive bacterial infections (community-acquired and nosocomial pneumonia, skin and soft tissue infections, and infections due to vancomycin-resistant enterococci) including these due to multidrug-resistant strains. Careful and judicious use is warranted to preserve the activity of this important antibiotic.

Keywords: Minimal inhibitory concentration, resistance, multidrug-resistant bacteria, staphylococcus. LINEZOLID - SPECTRUM AND RESISTANCE Linezolid (Zyvox®, Pfizer, in most countries) is the first approved compound of a new class of antibiotics called oxazolidinones that were developed and marketed mainly for the treatment of patients with Gram positive infections. The effectiveness of linezolid against staphylococcal (both Staphylococcus aureus and coagulase negative staphylococci- CoNS), enterococcal and streptococcal spp (including multi-drug resistant isolates) has been shown in several clinical trials [1-5]. In addition, several in vitro studies demonstrated that linezolid is also active against anaerobic bacteria (Clostridium spp, Peptostreptococci spp, Prevotella spp, Bacteroides fragilis, Fusobacterium nucleatum and F. meningosepticum) and has limited activity against Gram negative micro-organisms (Pasteurella multocida, Moraxella catarhallis, and Haemophilus influenzae) and atypical organisms (Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae) [6-8]; linezolid is not approved for Gram negative infections. A variety of other clinically significant pathogens including mycobacteria and Nocardia spp may be sensitive to linezolid [9-11]. Finally, resent research has revealed that a number of uncommonly isolated Gram-positive organisms, such as Enterococci other than E. faecalis and E. faecium, Micrococcus luteus, Aerococcus spp, Rothia mucilaginosa, Listeria monocytogenes and Corynobacterium spp. maybe also effectively inhibited by clinically achievable concentrations [12]. Linezolid has been approved for the treatment of patients with community-acquired and nosocomial pneumonia, complicated skin and soft tissue infections and infections due to vancomycinresistant E. faecium. Finally, it has been used successfully for the treatment of patients with endocarditis and bacteremia [13-15], osteomyelitis and joint infections [16-18], urinary tract infections [5,19], central nervous system infections [20] and tuberculosis [21]. Linezolid is a synthetic antibiotic that is not related structurally to any older antimicrobial agent [22,23]. It is a protein synthesis inhibitor; RNA and DNA synthesis are not affected [24]. It binds to the bacterial 23S ribosomal RNA of the 50S subunit, thus blocking the formation of the functional 70S initiation complex that is essen*Address correspondence to this author at the Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Greece; Tel: +30 (694) 611-0000; Fax: +30 (210) 683-9605; E-mail: [email protected] 1389-2002/09 $55.00+.00

tial for the bacterial translation process [25-27]. More specifically, linezolid inhibits the formation of the initiation complex constructed with 30S ribosomes, mRNA, initiation factors (IF) IF2 and IF3, and fMet-tRNA [28-30]. Although several other classes of antibiotics (including macrolides, lincosamides, chloramphenicol) exhibit their function by binding to the same 50S subunit of bacterial ribosomes, linezolid’s mechanism of action differs in binding to the specific 23S ribosomal RNA. Chloramphenicol binds to protein L16 of the 50S ribosomal subunit and blocks procaryotic protein translation primarily by inhibiting peptidyl transferase and thus blocking elongation [31]. More specifically, it prevents the attachment of the amino acidcontaining end of the amino acyl-tRNA complex to the ribosome, hence inhibiting the formation of the peptide bond [32]. Lincomycin (and clindamycin) inhibits peptidyl transferase but has also been shown to inhibit translation termination [33]. Linezolid’s action is not exerted by inhibition of peptidyl transferase [30]. Finally, chlorampenicol and lincomycin inhibit the puromycin reaction (a tRNA analogue that has been used to release nascent peptides from the ribosome), but linezolid does not. However, the binding of linezolid to 50S ribosomes is inhibited by chloramphenicol and lincomycin [27,30]. Thus, it has been postulated that cross-resistance is unlikely to occur; but if it does, it will be infrequent [34,35]. However, de novo development of resistant has been described; most of them were associated with prolonged linezolid administration [36-38], but reports suggesting the opposite have also been published [39]. However, we should emphasize that resistance to linezolid is generally rare in surveillance programs [38]. In addition, it has been suggested that the co-administration of linezolid with doxycycline may have a protective effect in the selection of linezolid-resistant E. faecium strains [40]. Similar findings were reported for subinhibitory concentrations of rifampicin and fusidic acid for S. aureus [41]. Several mutations leading to resistance or reduced susceptibility to linezolid have been described. A total of seven mutations (A2062C, C2452U, A2453C, A2453G, C2499U, U2500C, U2504C) affecting six different positions in the central loop of the domain V of 23S rRNA were found to confer resistance to linezolid [42]. The G2576U transversion is responsible for the reduced susceptibility to linezolid in microorganisms including S. aureus, © 2009 Bentham Science Publishers Ltd.

Association of Pharmacokinetic and Pharmacodynamic Aspects of Linezolid

CoNS, viridans group streptococci, E. faecium and E. faecalis [4345]. The G2447U transversion has been related with the development of resistance in Escherichia coli and S. aureus laboratory strains. Other reported mutations conferring resistance to linezolid include a G2032A transversion and a A2160G transversion [46,47]. Non-susceptibility to linezolid has also been described in S. pneumoniae isolates; six base pair deletions resulting in the deletion of two aminoacids from the riboprotein L4 (65WR66, 68KG69) were found in these isolates [48]. PHARMACOKINETICS Absorption Pharmacokinetics of linezolid after either oral or intravenous administration are comparable. Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations (C max) are reached rapidly after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment [8]. This implies that the type of treated infection is not the decisive factor for oral or intravenous administration, but the ability of the patient to receive oral medications. Following single or multiple dose administration, linezolid reaches maximum concentrations within 1–2 h after oral administration. Under steady-state conditions linezolid is again rapidly absorbed within 1–2 h after oral administration. When administered intravenously, C max is achieved at the end of infusion (half an hour is required); the same is true at the steady-state condition. In both the oral and intravenous administration, steady-state conditions are achieved after fewer than 2 days of dosing. In addition, concentrations at steady-states remain above the MIC90 (minimal inhibitory concentration) of 4 μg/L for target pathogens for 10–16 h following oral dosing and for 9–10 h following intravenous dosing; Cmax values vary between 12-21 μg/ml after oral administration and 13-15 μg/ml after intravenous administration [8,49]. C max and the area under the curve (AUC) increase proportionally with dose for both oral and intravenous administration [50]. A slightly longer time to reach peak plasma levels is required when linezolid is given orally with high-fat containing food (2.2 in fed vs 1.5 h in fasted volunteers). This increase, although statistically significant, is not likely to affect the effectiveness of linezolid. Additionally, the C max measured in subjects following the high-fat meal was 23% lower than the Cmax measured in the same volunteers when fasted. The fact that comparable AUC values were measured under both conditions indicates that the overall extent of absorption is the same [51]. The role of enteral feeding in the absorption of linezolid was also studied. No statistically significant differences were observed between patients who received continuous enteral feedings via the nasogastric or gastrostomy tubes and those who were able to tolerate oral intake. Patients receiving enteral feedings were older (p=0.05). The Cmax and the time to achieve the C max (T max) values differed by less than 10% between study groups. The AUC appeared larger in patients receiving oral linezolid than for those receiving enteral administration of linezolid; however, a statistically significant difference was not found. The overall extent of absorption was nearly complete in both groups [52]. In contrast to the studies performed in healthy volunteers, the pharmacokinetics of linezolid were slightly worse in patients enrolled in a compassionate use program [53]. In this analysis, the mean linezolid concentrations, during the first week of treatment, were 3.28 μg/ml, in contrast to that found in a study of healthy volunteers in whom the average concentration was 13.9 μg/ml.1 These findings were mainly attributed to the increased clearance of line-

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Turnak M.R., Forrest A, Hyatt JM, Ballow CH, Stalker DJ, Welshman IR,; Schentag JJ. Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A51, 1998

Current Drug Metabolism, 2009, Vol. 10, No. 1

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zolid, which resulted in lower AUC values for linezolid in this study. Despite these findings, linezolid was highly effective in this study [19]. Distribution and Penetration to Tissues Animal and human pharmacokinetic studies have shown that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent [53]. The volume of distribution of linezolid at steady-state approximate those of total body water (averaged 40 to 50 liters) in healthy adult volunteers [8,53]. Several studies showed that linezolid readily penetrates to both healthy and inflamed tissues. Table 1 summarizes the data regarding the distribution of linezolid to these tissues [54-62]. High tissue concentrations of linezolid have been observed in most of these studies, while in specific tissues its concentration may be similar or even higher than that of blood. For example, in non-smoking healthy individuals, concentrations (means ± standard deviations) in plasma, epithelial lining fluid (ELF), and alveolar cells (AC), were 7.3 ± 4.9, 64.3 ± 33.1, and 2.2 ± 0.6 μg/ml at the 4-h bronchoalveolar lavage (BAL), respectively [54]. In smoking individuals with possible chronic obstructive pulmonary disease the mean concentrations were 13.4 mg/L in serum, 25.1 μg/ml in ELF, 8.1 μg/ml in alveolar macrophages and 10.7 mg/kg in lung mucosa [55]. In a mechanically ventilated rat model, the administration of linezolid through the respiratory tract significantly increased the levels of the drug in lung tissue and ELF. In addition, the decrease in respiratory rate (30 rspm vs 60 rspm) together with the increase in tidal volume (4 ml vs 2 ml) favoured the distribution of linezolid in pulmonary tissues and fluids. The levels of linezolid in blood were very low after inhalation. Administration of linezolid through the respiratory tract might be a promising strategy to increase drug levels in pulmonary fluid and tissue without significant increases in systemic exposure to the antibiotic [63]. Metabolism and Elimination Linezolid is metabolized by nonenzymatic chemical oxidation mainly into two inactive metabolites, PNU-142586 and PNU142300 [8,53]. Cytochrome P450-induced drug interactions are not expected with linezolid. Linezolid is devoid of any inhibitory activity toward the following CYP enzyme isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) [64]. In addition, linezolid does not induce hepatic microsomal CYP1A, CYP3A or CYP4A [65]. Its metabolites do not possess significant potential to inhibit various CYP450 enzymes or monoamine oxidase [66]. Therefore, drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen. In vitro studies excluded the possibility of flavin-containing monooxygenase and monoamine oxidase as potential enzymes responsible for metabolite formation. However, metabolite formation was found to be optimal under basic (pH 9.0) conditions, which suggests the potential involvement of either an uncharacterized P-450 enzyme or an alternative microsomal mediated oxidative pathway [64]. Excretion in urine is the dominant route of elimination, accounting on average for 83 to 84% of linezolid dose. The three major excreted compounds are linezolid and the carboxylic acid morpholine ring-metabolites PNU-142586 and PNU-142300. Individuals with lower total clearance excrete less PNU-142586 and more linezolid, thus limiting the rate of linezolid’s clearance. Fecal excretion accounts for 10 to 11% of dose. The three major peaks in the feces are the carboxylic acid metabolites PNU-142586, PNU142300, and PNU-173558. Linezolid accounts for less than 0.2% of the dose in feces, in accord with 100% bioavailability. Seventeen minor metabolites - mainly by-products of PNU-142586 or PNU142300, which arose in the separate “lactone” and “lactam” pathways - account for the remaining of the dose [67].

4 Current Drug Metabolism, 2009, Vol. 10, No. 1 Table 1.

Vardakas et al.

Penetration of Linezolid to Target Tissues in Selected Published Studies

First Author (reference)

Subjects

Pharmacokinetic parameters*

Organs Studied Plasma Cmax

Tissue Cmax

% of time over MIC

Conte 2002 [54]

Healthy humans, nonsmokers

Lungs

15.5 ± 4.9 μg/ml

ELF 64.3 ± 33.1μg/ml AC 2.2 ± 0.6 μg/ml

100

Honeybourne 2002 [55]

COPD humans, smokers

Lungs

13.4 μg/ml

ELF 25.1 μg/ml AM 8.1 μg/ml LM 10.7 mg/kg

NA

Bosseli 2005 [56]

VAP humans

Lungs

17.7 ± 4.0 μg/mL

ELF 14.4 ± 5.6 μg/mL

70-100

Dehghanyar 2005 [57] (single dose)

Healthy humans

Soft tissues

14.1 ± 2.8 μg/mL

SC 18.1 ± 4.8 μg/mL MS 13.5 ± 3.3 μg/mL

NA

Denghanyar 2005 [57] (multiple doses)

Healthy humans

Soft tissues

19.5 ± 4.6 μg/mL

SC 12.9 ± 2.4 μg/mL MS 15.4 ± 8.0 μg/mL

NA

Kutscha-Lissberg 2003 [58]

Osteomyelitis and joint infections, humans

Bone and soft tissues

17.1 ± 5.1 μg/ml

Bone 3.9 ± 2.0 μg/ml BM 10.5 ± 2.2 μg/ml GT 10.3 ± 1.4 μg/ml Tendon 14.5 ± 3.5μg/ml

NA

Lovering 2002 [59]

Arthroplasty, humans

Bone and soft tissues

14.3 (11.3–17.2)§

Bone 6.3 μg/mL (3.9–8.6)§ Fat 4.1 μg/ml (3.3–4.8)§ MS 12.0 μg/ml (9.2–14.8)§

NA

Myrianthefs 2006 [60]

Neurosurgical patients, humans

CSF

18.6 ± 9.6 μg/ml

CSF 10.8 ± 5.7 μg/ml

100

Prydal 2005 [61]

Healthy humans

Aqueous fluid

NA

AF 6.8 ± 1.2 μg/ml

100

Wagenlehner 2003 [62]

Healthy humans

Urine

13.1 ± 1.80 μg/ml

¶

Urine 192 μg/ml Urine 82 μg/ml¥

NA

Abbreviations: ELF epithelial lining fluid, AC alveolar cells, AUC area under the curve, MIC minimal inhibitory concentration, AM alveolar macrophage, LM lung mucosa, COPD chronic obstructive pulmonary disease, VAP ventilator-associated pneumonia, SC subcutis, MS muscles, JC knee/hip joint capsule, BM bone marrow, GT granulation tissue, CSF cerebrospinal fluid, AF aqueous fluid, NA not available Values are presented in mean ± standard deviation § Values are presented as mean (95% CI) ¥ The value refers to concentrations between 0-6h after the administration of linezolid ¶ The value refers to concentrations between 6-12h after the administration of linezolid

A wide variability in clearance that could be accounted for primarily by variability in non-renal clearance was observed with both oral and intravenous administration. Renal clearance demonstrated less variability with both routes of administration. The apparent elimination half-life of linezolid is approximately 5 h and is independent of either dose or route of administration. In addition, clearance values at steady state are lower than single dose administration (10–30% lower with oral administration and 11–19% lower with intravenous administration). This was again primarily due to lower non-renal clearance values at steady-state compared with those after a single dose. Clearance values are also less variable at steady-state than following single dose administration. Consequently, a small but statistically significant (oral, p = 0.0493; intravenous, p = 0.0274) increase in elimination half-life was seen at steady state compared with the half-life values after a single dose [50]. Finally, a high-fat diet results in changes in excretion of linezolid. In a study of 12 white, non-smoking healthy adults the rate of systemic clearance of linezolid measured in fasted and fed subjects were virtually identical, while both the renal clearance and the fraction of linezolid excreted in the urine were significantly higher in fed volunteers (p = 0.013), although the difference was only 14% [51]. SPECIAL POPULATIONS Renal Dysfunction and End Stage Renal Disease Neither the volume of distribution nor Cmax change with renal function. Renal dysfunction does not affect the total clearance of linezolid which ranges from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increases from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. However, renal clearance showed a significant (p99%) [103]. Linezolid has been found to be more active than macrolides against peptostreptococci and fusobacteria isolated from human and animal bite wounds [113]. For the new drug, no break-points for anaerobes are available, but appear to be quite active against a variety of anaerobes with 99% of isolates being susceptible to a concentration 4μg/mL. Species of Bacteroides, Eubacterium, and Clostridium are occasionally found to be resistant (MIC=8-16 μg/mL) [114]. CLINICAL EFFECTIVENESS In a retrospective pooled analysis linezolid was compared to vancomycin for the treatment of S. aureus bacteremia [115]. Although there are reports of suboptimal results after vancomycin therapy in these patients, the pooled analysis simply revealed a noninferiority of the linezolid arm [116,117]. Another meta-analysis showed that linezolid was superior to vancomycin or -lactams for patients with primary or secondary bacteremia, but data regarding different species were not reported [13]. Finally, linezolid administration was associated with higher mortality in patients with catheter-associated blood-stream infections, a finding that was mainly attributed to patients with gram-negative bacteremia [118]. When linezolid was compared to vancomycin, it was significantly better in both survival and clinical cure rates, according to a

Vardakas et al.

sub-analysis of two double-blind studies of patients with MRSA nosocomial pneumonia [119], raising the question about the potential replacement of glycopeptides as first-line therapeutic agents against this high-mortality infection [7,120]. Since subgroup analyses may be associated with biases and while awaiting more definite results from an ongoing randomized controlled trial studying the comparative effectiveness of linezolid and vancomycin for MRSA nosocomial pneumonia, no recommendation can be made. It should be pointed out that linezolid should not be considered as a first-line choice for community-acquired pneumonia as it lacks good activity against H. influenzae and atypical pathogens. In an experimental model of pneumococcal pneumonia, linezolid was as effective as ceftriaxone, being able to resolve bacteremia, and to prevent mortality from fatal infection [121]. Data from randomized controlled trials also show that linezolid is as effective as ceftriaxone and cefpodoxime for pneumococcal pneumonia [122]. Nevertheless, in a meningitis model linezolid was clearly less effective than ceftriaxone against penicillin-sensitive pneumococci and slightly less effective against a penicillin-resistant strain, despite the fact that this drug displays good penetration into the meninges [123]. In a rather small clinical study linezolid was combined to ceftriaxone as an alternative to vancomycin or rifampicin, for the treatment of pneumococcal meningitis, with positive results [124]. There are few, albeit encouraging data, regarding the use of linezolid in the treatment of MRSA meningitis [125]. There is convincing evidence that linezolid represents a good candidate drug for the treatment of complicated skin and soft tissue infections. Again, this new antimicrobial was shown to be superior to vancomycin for the treatment of complicated skin and soft tissue infections due to MRSA [126]. In one of the early studies comparing the new drug with oxacillin-dicloxacillin, linezolid achieved similar cure and microbiological success rates (88.6% vs. 85.8% and 88.1% vs. 86.1% respectively) [127]. Another study, published 3 years latter suggested that treatment with linezolid was not only superior to comparators but actually was an independent predictor of cure [128]. Similarly, it was shown that linezolid when compared to vancomycin, could significantly reduce the length of hospital stay (LOS) [129]. These results are confirmed by numerous studies [126,130,131]. Because of these findings, and despite its higher acquisition cost, cost-effectiveness of the new compound in the treatment of SSTIs was suggested [132]. Chronic implant-related osteomyelitis due to multi-resistant Gram-positive cocci may respond to therapy with linezolid, according to a recent retrospective study [133]. Similarly, due to the excellent bioavailability the drug was successfully used for the treatment of osteoarticular multi-resistant infections in children [134], and adults [135]. In a study prospectively evaluating the efficacy and tolerability of prolonged linezolid therapy in the treatment of orthopedic implant infections, linezolid was efficacious in 100 and 92.3% for acute and chronic infections when the implant was removed and 72.2 and 42.8% respectively when it was not [136]. The most common adverse events after long-term suppression therapy were thrombocytopenia and anemia. Although linezolid is not yet recognized as a standard therapy for infective endocarditis it was used in a limited number of cases where the causative factor was resistant to other antibiotics with a success rate between 63.6 % and 79% [14,137]. Early switch from vancomycin to the oral form of the drug has been used in combination with surgical procedure in 14 cases with absolute success [138]. Nevertheless linezolid has failed in a case of vancomycinresistant E. faecalis endocarditis [139]. It is evident that further data from randomized controlled clinical trials are needed to determine the efficacy and safety of this new compound for treating endocarditis. As linezolid appears to be in vitro active against Gram-positive uropathogens there is a warrant for evaluation in clinical studies


[140]. Moreover, the bactericidal titers in urine (UBT) and the area under the UBT-time curve are at least comparable to ciprofloxacin [62]. Clinical data are limited but promising [5,19]. Linezolid has been used for the therapy for peritonitis and intra-abdominal abscesses, when the presence of VRE is considered of clinical significance. The vast majority of the published data concerning the efficacy of linezolid in intra-abdominal infections is coming from cases of peritonitis in dialysis patients. Concentrations of the drug >4μg/mL in dialysate were achieved after the first dose and maintained after repeated doses [141]. There is very limited experience with linezolid in the treatment of ocular infections. Oral administration of the drug results in rapid achievement of therapeutic levels in the aqueous of non-inflamed eyes [61]. In a study comparing the pharmacodynamic indices and MICs of 3 antistaphylococcal antimicrobials (vancomycin, quinupristin/ dalfopristin and linezolid) with 2 quinolones (gatifloxacin and moxifloxacin) for CoNS endophthalmitis, the antistaphylococcal drugs were more effective in vitro but, contrary to the previous study, all the antibiotics failed to provide adequate coverage for the 90% of the CoNS endophthalmitis isolates [142]. Linezolid is active against strains of Mycobacterium tuberculosis resistant to conventional antimycobacterial drugs and therefore several investigators reported their experience. Actually, concentrations 1μg/mL of this new antimicrobial compound effectively inhibited all tested strains, independently of the resistance status [143]. A possible synergy between fluoroquinolones, rifampicin and linezolid has been reported, although the clinical significance of these observations remains unclear [144]. However, an alarming report from Taiwan announces a significant increase in MIC90 of linezolid in multi-resistant M. tuberculosis strains over a 10 years period [145]. A more detailed review on this topic has been recently published [21]. Finally, despite the “bacteriostatic” mode of action, linezolid is proved to be safe and effective in treating resistant Gram-positive infections in neutropenic cancer patients with clinical and microbiological cure rates of 79% and 86%, respectively [79]. These results, equivalent to those of vancomycin, have been confirmed by others [80]. Linezolid has been investigated as a candidate drug for the prevention of central catheters related infection and sepsis [146,147]. Linezolid-heparin lock solution is stable and appears to be able to achieve eradication of S. epidermidis biofilms. However, very high concentrations (e.g. 4096 μg/mL) of linezolid are required to inhibit enterococcal biofilms in vitro [148]. Limited and occasionally conflicting data exists about the efficacy of linezolid in prophylaxis against hematogenous infections such as endocarditis [149,150]. Yet, there are reports of efficacious use of linezolid, either alone or in combination, for the prevention of experimental vascular prosthetic graft infection [151,152]. SAFETY It has already been mentioned that linezolid is not metabolised in the CYP450 complex and thus it can be safely administered with drugs metabolised by these enzymes. On the other hand, since linezolid is a nonselective, reversible monoamine oxidase inhibitor, concerns have been raised about its potential interactions with adrenergic and serotonergic agents. Transient increases in blood pressure of patients consuming tyramine containing foods and beverages or receiving pseudoephedrine and phenylpropanolamine, but not dextromethorphane, have been reported [153,154]. In addition, in a study of patients receiving both linezolid and selective serotonin re-uptake inhibitors the authors concluded that the combination could be tolerated if cautious monitoring for signs and symptoms of serotonin syndrome (confusion, delirium, restlessness, tremors, blushing, diaphoresis and hyperpyrexia) was employed [155].


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In both children and adults, the most commonly reported adverse effects were gastrointestinal disturbances (nausea, vomiting, diarrhea and abdominal pain) and headache [13,156,157]. The rates of C. difficile related diarrhea were similar to that reported for other antibiotics [156]. In addition to these common adverse effects linezolid administration has been associated with a series of serious adverse effects like anemia, leucopenia, thrombocytopenia, lactic acidosis, optic and peripheral neuropathy and convulsions. Analyses showed essentially no difference between linezolid and comparator antibiotics in the cumulative percentage of patients with outlying hemoglobin, neutrophil, or platelet counts over the first 14 days of therapy [13,156]. However, with longer treatment durations, there appeared to be a small increased risk for decreased platelet counts in linezolid-treated patients compared with the risk for the comparator group, but the difference was not statistically significant. Peripheral and optic neuropathy have been reported in patients treated with linezolid, primarily those treated for longer than the maximum recommended duration of 28 days; in many of these patients treatment durations of 3-6 months were employed [158160]. Lactic acidosis has also been reported with the use of linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting [161,162]. Finally, convulsions have been also reported in patients treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures were present [8]. More gastrointestinal adverse events may be seen after oral administration (compared to intravenous administration). The major haematologic adverse events as well as peripheral neuropathy, lactic acidosis, and serotonin-like syndrome do not seem to be associated with the formulation of the antibiotic, i.e., oral or intravenous administration. Data regarding safety of linezolid in pregnant or nursing women are lacking. Based on data from studies on rats and mice linezolid was listed in category C; this means that it has no teratogenic effects at dosages equivalent to those administered in humans. However, non-teratogenic effects (postimplantational embryo death, including total litter loss, decreased fetal body weight and an increased incidence of costal cartilage fusion) increased in mice when maternal toxicity was observed. Finally, experiments on rats showed that when mothers were treated with linezolid during pregnancy or lactation newborn rat’s mortality increased during days 1-4 post delivery. In addition, if these rats were allowed to mature and mate they had a higher probability of preimplantation loss. Finally, linezolid was excreted in rat milk [8]. CONCLUSION Linezolid has a favorable pharmacokinetic profile. It is 100% bioavailable when administered orally thus allowing early switch from intravenous to oral therapy when needed. It penetrates readily to most tissues of the human body at concentrations well above the MICs of the targeted pathogens for the majority of the dosing intervals. Surveillance programs showed that resistance is still rare, despite the increasing reports of resistant pathogens. Clinical trials showed that it is an effective and safe –if carefully given- agent for the therapy of Gram-positive infections, including these due to multidrug-resistant isolates. A judicious use of this valuable antimicrobial drug gives a reasonable warrant for a long living clinical use. However, the use of linezolid seems to increase and will probably increase further in the forthcoming years. Several reasons such as the emergence of vancomycin intermediate S. aureus strains and the increasing incidence of vancomycin resistant enterococci, the need for monitoring of vancomycin serum levels, the reports that linezolid may be more effective and even cost-effective than vancomycin for given infections and the lack of an oral alternative have contributed to this phenomenon. In addition, several other treatment alternatives are already available in the market or have been proven

8 Current Drug Metabolism, 2009, Vol. 10, No. 1

at least as effective as vancomycin and will be commercially available in the future. Among these, teicoplanin is still not approved in the USA. Daptomycin has been proven effective for the treatment of patients with SSTIs, right sided endocarditis and bacteremia, but cannot be administered to patients with pneumonia. The same is true for quinupristin-dalfopristin. Telavancin, ceftaroline and ceftobiprole were as effective as vancomycin for patients with SSTIs and nosocomial pneumonia (ceftobiprole and telavavcin). The question is whether physicians could be persuaded to use a -lactam for the treatment of patients with MRSA infections or trust another glycopeptide if RCTs comparing it with linezolid won’t be available in the near future. Finally, although other agents (like iclaprim, eperezolid and other investigational oxazolidinones and -lactams) are also under development, it will probably take several years before they are eventually available in the market. ABREVIATIONS CoNS = Coagulase negative staphylococci IF = Initiation factors MRSA = Methicillin-resistant S. aureus MSSA = Methicillin-sensitive S. aureus Cmax = Maximum plasma concentration MIC90 = Minimal inhibitory concentration AUC = Area under the curve Tmax = Time to Cmax ELF = Epithelial lining fluid BAL = Broncho-alveolar lavage AC = Alveolar cells LRTIs = Lower respiratory tract infections SSTIs = Skin and soft tissue infections PAE = Post antibiotic effect VRE = Vancomycin-resistant enterococci LOS = Length of hospital stay UBT = Urine bactericidal titers REFERENCES [1]

[2]

[3]

[4]

[5]

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Received: June 01, 2008

Revised: August 10, 2008

Accepted: September 15, 2008

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