Therapeutic options for Gram-positive infections

@~rnol of Hospital Infection (200 I) 49 (Supplement A): S25-S32 doi: IO. I053/jhin.200 I. 1091, available online at http://www.idealibrary.com

Therapeutic infections

options

M

on 10 E %L@

for Gram-positive

Michael J. Rybak Anti-Infective Research Laboratory, Wayne State University and Detroit Receiving Hospital, Detroit, Ml, USA

Summary:

Gram-positive infections impose a major burden on patients and the healthcare systems globally. The need to treat these infections correctly in an empirical fashion is of paramount importance. Further complicating this changing aetiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus new agents such as linezolid have been developed to assist with initial empirical prescribing in infections where Gram-positive pathogens may be present. The characteristics of linezolid, including spectrum of activity, pharmacodynamic profile, tolerablility and overall efficacy should strengthen confidence when considering initial antimicrobial therapy in patients in risk areas. Future agents also being developed to fight multiresistant Gram-positive infections include oritavancin, daptomycin and the glycylcyclines; however, these are still in the development phase. 0 2001 The Hospital

Keywords:

Gram-positive

infections;

antimicrobial

Gram-positive infections pose enormous challenges for clinicians, particularly those pathogens showing growing antimicrobial resistance. im3 These pathogens cause both nosocomial and community infections of the blood, respiratory tract, and skin and soft tissues. In the USA there are 27 million surgical procedures annually with 3-4% becoming infected. The most prevalent pathogens are Gram-positive with Staphylococcus azueus accounting for 20% of infections. Other notable pathogens include coagulase-staphylococci and enterococci. The National Nososcomial Infection Survey (NNIS) has demonstrated growing antimicrobial resistance among these and other pathogens. Specifically, the bacteria of concern are S. aureus, namely

1475-9594/O

I /OSA0025

+8 $35.0010

Anti-Infective and Detroit

Society

therapy.

Introduction

Author for correspondence: Michael J. Rybak, Research Laboratory, Wayne State University, Receiving Hospital, Detroit, MI, USA. Tel.: +1 313-745-4554; Fax: +l 313-577-8915; E-mail: [email protected]

Infection

drugmethicillin-resistant S. aureus (MRSA), resistant Streptococcus pneumoniae (DRSP) and vancomycin-resistant enterococci (VRE). Each organism poses particular therapeutic problems as shown by a range of surveillance programmes which have highlighted varying levels of resistance to standard therapeutic options. Furthermore, different clinical settings have varying degrees of resistance due to a range of risk factors. These risks include age, immunosuppression, extended stay in intensive care or similar high-dependency unit, underlying disease or co-morbidities, recent surgery, mechanical ventilation, prior hospitalization or antimicrobial therapy. It is the appreciation of the importance of initiating empirical antimicrobial therapy in “at-risk” patients, irrespective of their origin, that has been shown by Kolleff and co-workers to be vital in preventing serious consequences including longer hospital stay or even death, in those who are treated inappropriately with antimicrobials. In many countries the traditional empirical options have lost their predictable activity and with this resistance

0 200 I The Hospital

Infection

Society

S26

emergence come therapy failures, use of more antimicrobials, extended hospitalization and increased morbidity and mortality.4 These traditional therapeutic options include anti-staphylcoccal penicillins (nafcillin, oxacillinor dicloxacillin) or first-generation cephalosporins, clindamycin, vancomycin, p-lactaml3 lactam-inhibitor combination, macrolides, fluoroquinolones, trimethoprim/sulphamethoxazole. In many countries vancomycin is often regarded as the first option against potential Gram-positive infections in the hospital setting as up to 30% of staphylococci are methicillin-resistant; however, emergence of glycopeptide resistance and the appreciation of other deficiencies of vancomycin (high levels of toxicity, intravenous (iv) only formulation, poor tissue concentrations, suboptimal pharmacodynamics, and poor clinical outcomes in the key patient populations) have led to the development of several new compounds, of which two have been approved - quinupristin/dalfopristin and linezolid. At least three other compounds are in various stages of development. This review examines these new antimicrobials as empirical treatment options for Gram-positive infections. Quinupristinldalfopristin Quinupristin/dalfopristin is available as a combination of 30% quinupristin: 70% dalfopristin (w/w) marketed as Synercid@. This combination is bactericidal against a range of Gram-positive pathogens5 However, it is important to note that quinupristin/ dalfopristin is not active against Enterococcus faecalis, yet is inhibitory against E. faecium. Resistance to the family of macrolides, lincosamides and streptogramins (MLS) is increasing, with resistance to quinupristin/dalfopristin in the range of 2-S% reported in the USA, Europe and Canada.6-8 Resistance occurs through one of three mechanisms;’ target site modification conferred by the erm gene; drug-inactivating enzymes, streptogramin A acetyltransferase and streptogramin B hydrolase or efflux. Quinupristin/dalfopristin is only administered parenterally via a “pit” or a central venous line, at a dose of 7.5 mg/kg every 8 to 12 hours, achieving peak serum concentrations of 2.9 and 7.2 mg/L respectively for the two components quinupristin and dalfopristin. The terminal half-lives of these two constituents are similar, 0.9 h and 0.7 h respectively. Tissue penetration of quinupristin/dalfopristin is modest with blister fluid concentrations achieving 40% of those

M. 1. Rybak

seen in plasma.5 Quinupristin/dalfopristin inhibits the biotransformation rate of cytochrome P450 3A4 (CYP P3A4) substrates such that plasma clearance of some drugs such as cyclosporin is decreased. Clinical use of quinupristin/dalfopristin has shown clinical success rates against MRSA in the range of 64-76% of cases,’ with similar bacteriological success rates of 68% and 71% of VRE infected patients. Emergence of E. faecium resistance to quinupristin/dalfopristin has occurred in 4% of patients globally, but US centres reported a 14% incidence.’ Moreover E. faecalis superinfections occurred with quinupristin/dalfopristin therapy. Indication-specific clinical trials of skin and skin structure infections (SSSI) yielded clinical success rates of 68.2% and 70.7% for quinupristin/dalfopristin and comparators (vancomycin, cefazolin or oxacillin) respectively in complicated Gram-positive SSS I .l” Clinical studies of nosocomial pneumonia compared quinupristin/dalfopristin with vancomytin yielding clinical success rates of 56% and 58% respectively. Intubated patients responded equally to both drug regimens, with a clinical success rate of 54%.i1 Quinupristin/dalfopristin therapy was associated with therapy discontinuation due to adverse events in 15.3-19.1%, mild to moderate or severe events, compared with 4.7-9.5% reported with comparator agents.’ Adverse events typically reported with quinupristinfdalfopristin include nausea 4.6%, vomiting 2.7%, diarrhoea 2.7%, rash 2.5%, myalgiaf arthralgia 1.3%. Increase in bilirubin parameters were observed with quinupristin/dalfopristin, conjugated bilirubin level 3.1% and total bilirubin five times the upper limit of normal in 0.9%. The respective comparator values were 1.3% and 0.2%. Quinupristin/dalfopristin is indicated for a limited range of infections, namely those due to vancomycinresistant E. faecium (VREF), in SSSI and nosocomial pneumonia in the UK,12 but only VREF bacteraemia and cSSS1 (MSSA and S. pyogenes) in the USA.13 The antibacterial spectrum of quinupristin/ dalfopristin, toxicological profile, administration issues and limited range of indications demonstrate the problems of treating todays’ serious infections, especially those in the hospital setting. The sequelae of using the inappropriate antimicrobial initially have been demonstrated to lead to increased morbidity and mortality. Thus one new agent has been developed and approved, linezolid, and at least three others are being developed.

Therapeutic

options

for

Gram-positive

infections

S27

Linezolid

Table

The first oxazolidinone, linezolid (PNU100766) was approved for clinical use in the USA in 2000 and early 2001 in the UK. This agent is the first truly novel synthetic antimicrobial to be introduced for almost 30 years. Furthermore it acts at a unique site in the protein synthesis process. Linezolid acts by disrupting the interaction of fMet-tRNA with the 50s ribosomal subunit during the creation of the pre-initiation 70s complex. This intervention effectively inhibits protein synthesis much earlier in the process, unlike other currently available agents such as aminoglycosides, macrolides, streptogramins and tetracyclines.i4 Linezolid has antibacterial activity against a wide range of Gram-positive pathogens, including MRSA, VRE and glycopeptide-intermediate S. aweus (GISA)? As linezolid has been developed to treat serious infections caused by Gram-positive pathogens including, both methicillin-susceptible and -resistant staphylococci and vancomycin-susceptible and resistant enterococcal strains. Studies into resistance selection and the mechanism of resistance have shown little evidence of spontaneous resistance development in S. aureus (mutation frequency <8 x 10-11).‘6 Recently Gonzalez et al. reported six cases of E. faecium which showed increases in MIC during prolonged linezolid therapy. These isolates were from complicated patients of whom four out of five were transplant cases.i7 These developments were not unexpected as all of the patients had received prolonged courses of linezolid therapy (over 4 weeks), moreover all of these patients had indwelling devices, and in addition, some received unapproved low doses of linezolid, i.e. 200 mg every 12 hours. This complex of circumstances may select for resistance to almost any antimicrobial. Genetic sequencing studies are in progress to ascertain the strains; interestclonality of these six E. faecium ingly all of the isolates have the same point mutation. The proposed breakpoints from the NCCLS, and other breakpoint committees are shown in 18,19,20 Table I. Laboratory studies of the antibacterial action have shown linezolid to be bacteriostatic in most species, although some studies16’20 have demonstrated bactericidal activity in a limited number of strains of S. pneumoniae. In addition to the basic antibacterial activity studies, investigations into the specific effects of

Source

I

Linezolid recommended

breakpoints

(mg/!-) Breakpoint

EUCAST”

Susceptible Resistant Susceptible Susceptible Intermediate Resistant Susceptible Susceptible Susceptible Resistant

94 >4

NCCLS”

Staphylococcus Enterococcus

S. pneumoniae Non-S. pneumonioe BSAC”

Table II Microbial tissue infections

eradication fir selected pothogens from skin and soft

Pathogen

Linezolid

S. aureus

85/93 91.4% 23129 79.3% 717 100% 126/143 88.1%

S. pyogenes S. agalactioe Overall

Oxacillin/dicloxacillin 871103 84.5% 27132 84.4% 416 66.7% 130/131 86.1%

95% Cl” -2.1,

16.0

- 24.4, 14.3 -4.4,

71.1

- 5.6, 9.7

P valueb 0.13 0.6 0.09 0.6

These are the results of Phase Ill clinical trials of linezolid vs comparators for treatment of skin and soft tissue infections. The drug columns indicate the success rates. ’ The 95% confidence intervals (Cl) give a sense of the variation that may be expected by chance differences from one random sample to another and also indicate 95% confidence that the range stated here for each study contains the true value found in the result. b P represents the statistical significance associated with this finding.

linezolid on virulence factor expression of two Gram-positive species (S. aweus and S. pyogenes) have shown marked reduction in the production of cl-haemolysin, SPEA exotoxin and coagulase by S. aureus and streptolysin 0 and DNAase by S. pyogenes at fractions of the MIC.21 Pharmacokinetic studies of linezolid have shown the drug to be rapidly and completely absorbed yielding peak serum levels of 18 mg/L around 2 hours after administration. A terminal half-life of 5-7 hours combined with a Gram-positive post-antibiotic effect (PAE) of 3.6-3.9 h permits linezolid to be administered every 12 hours. Such a regimen provides a trough concentration of >4.0mg/L after 625 mg 12-hourly. This regimen yielded an Area-Underthe-Curve (AUC) of 138.0; 89.7 mg/L for the oral and iv formulations respectively. Tissue penetration of linezolid is good, with marked accumulation occurring in sweat, saliva, and epithelial lining and

M. J. Rybak

S28

blister fluids. Many of these in excess of concurrent serum concentrations and to levels higher than those of comparable agents such as quinupristin/dalfopristin. Applications of these pharmacokinetic features to the pneumococcal mouse infection model showed that linezolid pharmacodynamics are best portrayed using the “Time above the MIC” parameter rather peak serum or AUC to MIC analyses. Figure 1 shows the steady-state serum profile of linezolid for both the oral and parenteral formulations against the MICaos of clinically significant Gram-positive species, including susceptible and resistant strains. Linezolid is not metabolized via the cytochrome P450 system, thus eliminating many potential drug interactions. However, linezolid is a weak reversible, oxidase non-selective inhibitor of monoamine (MAOI) so has the potential to interact with adrenergic and serotonergic agents. Current clinical evidence has not shown this to be important. Linezolid is metabolized by non-enzymatic chemical oxidation of the morpholine ring into two inactive metabolites. Linezolid is predominantly excreted renally, with 80-85% found in the urine (30% parent compound, 40% metabolite A, 10% metabolite B), 7-12% in faeces. However, in patients with mild to moderate renal impairment, dosing does not need to be modified. In haemodialysis patients, linezolid dosing may need to be supplemented as 30% of the drug is dialysed. Thus post-dialysis dosing is recommended. Mild to moderate hepatic impairment does not affect linezolid metabolism; severe liver disease and linezolid has not been studied. Linezolid has been investigated in infective indications where Gram-positive pathogens, both susceptible and resistant strains, pose an increasing threat to current empirical standards. Clinical trials

u

Enterococcus

rll

Figure

0

5

I

Linezolid

Linezolid 600 mg q12h steady state

sp MIC

10 15 Time after last dose (hours)

steady state plasma concentrations.

20

with linezolid used 600 mg 12-hourly, unless the patient weighed <40 kg in which case dosage was 1 mg/kg twice-daily. The route of administration of linezolid varied with the infection being studied, nosocomial pneumonia employed only iv therapy while the other indications used oral dosing alone. Nosocomial pneumonia was examined in a multicentre, randomized, double-blind comparison of linezolid (600 mg 12-hourly) plus aztreonam against iv vancomycin (2 g 12-hourly) with aztreonam. Patients were enrolled in the study if they had two of the following signs and symptoms; cough, purulent sputum, auscultatory findings of pneumonia, dyspnoea, tachypnoea or hypoxaemia; or identification of an organism consistent with a respiratory pathogen isolated from the respiratory tract, sputum or blood. In addition, eligible patients had to have at least two of the following; fever or hypothermia, respiratory rate >30 breaths/min, systolic blood pressure <90mm Hg, pulse rate 2120 beats/min. altered mental status, need for mechanical ventilation, raised total peripheral WBC count >lOOOO cells/mm3, >15% immature neutrophils, or leukopenia with total white blood cell (WBC) count <4500 cells/mm3. new or progresA chest radiograph showing sive infiltrates, consolidation or pleural effusion, Gram-stain and culture of respiratory or other relevant specimens, venous access for iv dosing and life expectancy of at least 1 week were also necessary for inclusion. Patients were excluded if they had an infection due to organisms known to be resistant to either study medication, known or suspected non-bacterial pulmonary disease, recent coagulopathy, CD4 cell count uncontrolled or untreated hyper<200 cells/mm3, tension, hypersensitivity to any study medication among a collection of other standard clinical trial exclusion criteria. The primary efficacy variables included outcomes in the clinically evaluable (CE) and microbiologically evaluable (ME) cohorts at the Test of Cure visit i.e. 12-28 days after the end of therapy. Criteria for clinical outcome assessment were: cure, resolution of baseline signs and symptoms of pneumonia with improvement or lack of progression of radiographic findings; failure, persistence or progression of signs and symptoms of pneumonia after at least 48 hours of therapy. Over 400 patients were enrolled in the two arms, yielding 108 and 96 clinically evaluable patients in the linezolid and vancomycin groups respectively. There were no significant demographic differences

Therapeutic

options

for

Gram-positive

infections

between the two groups. The clinical cure rates for the CE patients were 66.4% and 68.1% for the linezolid and vancomycin respectively, (95% CI, -14.9% to 11.3%). In the patients with protected specimen brush, BAL, TTA culture, similar clinical cure was observed, 70.6% (24/34) and 67.7% (21/31) for the linezolid and vancomycin, respectively. In the ME patients, there was no statistically signifiant difference between the two regimen, 67.9% vs. 71.8% (95% CI, -22.8% to 15.0%) for linezolid and vancomycin respectively. Pathogen-specific microbiological eradication rates for ME patients were all S. auveus 61%, 65.2%; MRSA 65.2%, 77.8%; S. pneumoniae 100% in both groups. Moreover, development of resistance among initially susceptible isolates was not observed during therapy or follow-up. The adverse events reported in this study showed no significant differences between the groups; however, mortality was higher in the vancomycin group, 25.4% (49) compared with 17.7% (36) in the linezolid group. Most of these deaths occurred during the follow-up period. Indeed mortality attributable to underlying diseases was higher in the vancomycin group (83.3%) compared with 73.4% of the linezolid patients. There were no deaths due to therapeutic failure in the linezolid arm and four (8.2%) in the vancomycin group. No deaths in either study group were attributed to study drug. Linezolid has been assessed in complicated skin and soft tissue infections (SST) in a multicentre, randomized, double-blind trial. Patients received 600 mg linezolid every 12 hours or iv oxacillin 2g every 6 hours, those who might have Gram-negative pathogens were given empiric iv aztreonam l-2 g three or four times per day until culture results excluded their presence. As the patients’ condition improved and they met the requirements for oral administration they might be switched to oral linezolid 600 mg 12-hourly or oral dicloxacillin 500 mg 6-hourly. Of the 826 patients originally enrolled, 819 received at least one dose of drug; of these 600 were clinically evaluable and 294 microbiologically valid (298, 302 clinical; 143, 151 microbiological for linezolid, iv to oral and oxacillin/dicloxacillin respectively). Both groups were treated for 13.4 days, with iv therapy being given for <5 days in each arm. The most common diagnosis was cellulitis >44%, with skin abscesses 1 5%, erysipelas 1 O%, with skin ulcers, infected surgical incisions, wounds and bites being less prevalent. In terms of clinical response in the CE groups 88.6% and 85.8% of patients were cured by linezolid

S29

and oxacillin/dicloxacillin respectively (95% CI-2.58.2; P= 0.3), thus the two groups were equivalent. In the ME group, microbiological success was reported as 88.1% and 86.1% respectively for linezolid and oxacillin/dicloxacillin (95% CI, -5.6 to 9.7, P= 0.6). Species analysis eradication showed a better, but not significant, response to linezolid with S. aweus, 91.4% vs. 84.5% (95% CI, -2.1-16.0; P=O.13), as shown in Table II. Overall, the regimen were equally well tolerated with drug-related adverse events being reported in 16.8% and 17.2% of linezolid and oxacillinf dicloxacillin groups respectively. Drug-related adverse reactions caused significantly more withdrawals in the oxacillin/dicloxacillin group (3.6%) than in the linezolid regimen (l.O%), P=O.O14. There were no drug-related deaths. Patients with community-acquired pneumonia (CAP) have been treated with linezolid in three clinical trials, one Phase II, and two Phase III. The two latter studies comprised both inpatients and outto stanpatients, by design linezolid was equivalent dard therapy in both trials. Over 900 patients were enrolled in the two studies, with 481 receiving linezolid and 470 a cephalosporin(ceftriaxone or cefpodoxime). Clinical evaluation at Test of Cure (15-21 days after end of therapy) showed linezolid to achieve 90.3% efficacy compared with 89.6% in the standard group. Microbiological assessment at this same time point showed 89.1% and 87.9% success rates for the two regimen. In a summary of the three studies linezolid compared with, ceftriaxone/cefpodoxime eradicated S.pneunzoniae, S. aweus and H. influenzae at rates of 92.0%, 90.0%, 88.5% and 90.0%, 82.8% and 88.5% respectively. Fifty-three patients had concurrent pneumococcal bactaeremia (<5%), linezolid had a significantly higher success rate than the comparator 93.3% vs. 69.9%, P=O.O22. The precise grows, reason for this marked difference is not immediately obvious as there were few drug-resistant strains in the studies. The tolerability and adverse event profile of linezolid from the clinical trial programme and subsequent post-marketing surveillance reports show it to be a well-tolerated antimicrobial. In eight studies, 2046 patients received linezolid, 2001 received a comparator such as vancomycin, oxacillin/dicloxacillin, ceftriaxone/cefpodoxime or clarithromycin. Overall the incidence of drug-related adverse events was 21.7% and 15.7% for linezolid and the

s30

comparators respectively. The most frequent drugrelated adverse events reported were diarrhoea, 4.2%, 3.2%; nausea 3.4%, 2.3%; and headache 2.2%, 1.3% respectively. All other events occurred at <2%. Discontinuations due to drug-related adverse events occurred in 2.4% and 1.9% patients. Deaths occurred in 4.8% and 4.9% of patients respectively. There were no clinically relevant differences between linezolid and the various comparators examined. Laboratory analysis of various parameters revealed few significant shifts during treatment on either linezolid or standard treatment. Haematological variations were observed in the phase III studies, with thrombocytopenia occurring at a rate of 2.4% vs. 1.5% and haemoglobin decrease 0.7% vs. 0.2% for linezolid and the comparators respectively. In the year since FDA approval linezolid has been prescribed to >55 000 US patients with 72 spontaneous reports of haematological abnormality, an overall incidence of 1 in 750. These observations are similar to antimicrobials such as co-amoxicillin-clavulanate or ceftriaxone. Almost all of these reports occurred in patients who had received continuous linezolid for over 28 days in addition to receiving a range of concomitant medications for underlying diseases. The changes in platelet counts or anaemia appear to be time-related events and are uncommon. The sponsor has issued recommendations to monitor haematological parameters in patients who receive linezolid for more than 14 days and to be particularly aware of possible thrombocytopenia >14 days or anaemia after 21 days linezolid administration. These mild-moderate haematological changes are reversible on drug discontinuation. Due to the route of metabolism and excretion, linezolid has few interactions with other drugs; indeed MAO-inhibition appears to be of little clinical significance following comparison of both linezolid patients receiving concurrent MAO interacting drugs with a similar group in the comparator arm. No differences in lower body temperature or heart rates were observed between the groups. Linezolid is given as a 600 mg dose either orally or intravenously twice-daily for lo-28 days depending on the infection and the causative pathogen. It is recommended that VRE infections be treated for longer than MRSA, i.e. 28 consecutive days rather than 14 days. However, physician discretion should guide duration of treatment, but for periods longer than 14 days monitoring of haematological parameters is recommended.

M. J. Rybak

The place of linezolid on formulary is discussed by Nathwani (pp. S33-S41 in this Supplement); however, data currently available suggest that linezolid is a safe, well-tolerated effective agent for the initial or empirical treatment of both susceptible or resistant Gram-positive infections. Indeed pharmacoeconomic analyses of the current studies highlight the value of empirical use of linezolid from the outset in “high-resistant risk” areas or patients who have risk factors which predispose them to resistant pathogens, which in turn may be led to poor outcomes. Furthermore the value of continuation therapy, i.e. from iv to oral of the same agent, can confer benefits beyond those of efficacy and safety. Linezolid was approved in the USA in early 2000 with the UK and Canada also approving this novel agent in 2000/2001, and wider European approval is anticipated in 2001. As the first approved oxazolidinone effective for the empirical treatment of a range of Gram-positive organisms, including susceptible and resistant isolates, linezolid provides a safe, convenient and appropriate option for these increasingly problematic infections. Since the introduction of linezolid, one still has to be prepared to combat the next phase of potential microbial mutation; thus there are three other antimicrobials in various stages of clinical development which are specifically targeted at treating multiresistant Gram-positive infections; daptomycin, oritavancin, with the glycylcycline, tiglicycline (GAR 936), also under investigation. Daptomycin (Cubist Pharmaceuticals) is a lipopeptide which kills bacteria by disrupting the cell membrane in a concentration-dependent manner. It has broad spectrum anti-Gram-positive activity, see Table III. Phase III clinical trials are in progress. Oritavancin is a glycopeptide, similar to vancomycin except that it is active against bacteria that possess each or all of the resistance genes ztan A, van B or van C. The activity of oritavancin is significantly better than vancomycin with MICs of 2.0, 1.5 and 0.8 mg/L and >1024, >256 and >8mg/L respectively for these three genotypes of enterococci. For most other species the activity is broadly similar to that of vancomycin. Clinical studies are in progress examining its efficacy in multiresistant Gram-positive SSSI and bacteraemia. Tiglicycline,GAR 936 is a glycylcycline being developed by Wyeth-Ayerst. It is a tetracycline derivative with in-vitro activity against multiresistant Gram-positive species, a range of atypical

Therapeutic

options

for

Table III

Gram-positive

infections

s3 I

In vitro activity of current and developmental

Species

5. aoreus MRSA Enterococci(VS) Van A> Van B Van C 5. pneumoniae (penicilin-resistant)

Oritavancin3’

Vancomycin6

2 I 2 1.5

2 2 2

antimicrobials

0.8 0.0 I

Summary Gram-positive bacteria including staphylococci and streptococci are continuing to cause serious infections in both the community and hospital patient. The consequences of poorly selected initial antimicrobial treatment have been highlighted with all their morbidity, mortality and financial issues. As resistance also rises then the therapeutic options are few. One of empirical options includes linezolid as a flexible, efficacious, safe antimicrobial with potential pharmacoeconomic advantages. Older agents including oxacillin/dicloxacillin and derivatives are losing their predictable potency in the face of growing methicillin resistance furthermore as glycopeptide resistance emerges in Europe then agents such as teicoplanin and vancomycin will be less predictably effective. Thus a compound such as linezolid may provide an appropriate solution to many of the growing Gram-positive infectious issues,irrespective of pathogen resistance, and as confidence grows this agent can be used empirically as an initial therapeutic option. References 1. Cohn ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992; 257:

>8 0.5

(MI&o

Linezolid6

Dapto6

4 4 4

0.13 0.13 I.0 -

>I024 >256

organisms, some Gram-negative aerobes and selected anaerobes. It is currently in Phase II clinical development intended for use against multiresistant Gram-positive species. It is too soon to determine whether these three new developmental agents will be efficacious and safe enough to reach the clinical setting. However, the advent of linezolid provides a new standard for serious infections where risk factors significantly impact the choice of initial therapy.

1050-1055.

anti-Gram-positive

0.5

mgllj GAR9362y

I

-

0. I25 0.5 IO

NT

0.25

2. Wood MJ. Chemotherapy for Gram-positive nosocmial sepsis. J Chemother 1999; 11: lo-16 3. McGowan JE, Jr. The impact of changing pathogens of serious infections in hospitalized patients. Clin Inj Dis 2000; 3l(suppl. 4) ~124-130. 4. McGowan JE, Jr Economic impact of antimicrobial resistance. Emerg If Dis 2001; 7: 286-292. 5. Lamb HM, Figgilt DP, Faulds D. Quinupristin/ dalfopristin: a review of its use in the management of serious Gram-positive infections. DrzLgs 1999; 58: 1061-1097. E, MoldovanT, Grucz RG. 6. Rybak MJ, Herscberger In-vitro activities of daptomycin, vancomycin, linezolid and quinupristin-dalfopristin against staphyloenterococci, including vancomycincocci and intermedaite and -resistant strains. Antimicrob.Ag Chemother 2000; 44: 1062-1066. 7. Low DE, Keller N, Barth A, Jones RN. Clinical prevalence, antimicrobial susceptibility and geographic resistance patterns of enterococci: results from the SENTRY antimicrobial surveillance program, 19971999. Clin Inf Dis 2001; 32(suppl. 2): s133-~145. 8. Ballow CH, Jones RN, Biedenbach DJ, Bolmstrom A. Multicenter evaluation of linezolid antimicrobial activity in Europe. 11 th Fur Cong Clin Micro Inf Dis Istanbul, Turkey, April 2001, Abst. #1272. SM, Zervos M J. Emergence of 9. Chow JW, Donahedian increased resistance to quinupristin-dalfopristin during therapy for Enterococcus faecium bacteremia. Clin If Dis 1997; 24: 90-91. RL, Graham DR, Barriere SL et al. Treat10. Nichols ment of hospitalized patients with complicated Grampositive skin and skin structure infections: two randomized, multicenter of quinupristin-dalfopristinversus cefazolin, oxacillin or vancomycin. J Antimicrob Chemother 1999; 44: 263-273. of 11. Fagon J-Y, Patrick H, Haas DW et al. Treatment Gram-positive nosocomial pneumonia: prospective randomized comparison of quinupristin-dalfopristin versus vancomycin. Am J Respir Crit Care Med 2000,

161: 753-762. 12. Product Licence, quinupristin-dalfopristin(Synercid); Aventis, Slough, Berks UK, 2000. Insert, Synercid, quinupristin-dalfpristin. 13. Package Aventis, Collegeville, PA 1999. 14. Swaney SM, Aoki H, Gunoza MC et al. The oxazolidinone linezolid inhibits initiation of protein synthesis

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15.

16.

17.

18. 19. 20. 21. 22.

23.

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