Economic impact and formulary positioning of linezolid: a new anti-Gram-positive antimicrobial

journal of Hospital Infection (200 I) 49 (Supplement A): S33-S4 I doi: IO. l053/jhin.200 I. 1092, available online at http://wwv.idealibrary.com

on IDE

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bI”

Economic impact and formulary positioning of linezolid: a new anti-Gram-positive antimicrobial D. Nathwani Tayside University

Hospitals,

Dundee,

UK

Summary: Gram-positive bacteria have emerged as major causes of colonization and serious infection within the nosocomial and increasingly also within the community setting. These infections have significantly contributed to patient morbidity and mortality as well as prolongation of hospital stay, a key determinant of the cost of an episode of infection in hospital. In many countries globally, infections due to methicillin-resistant Staphylococcus ~UY~US (MRSA) are providing the greatest burden of clinical infection, settings. Combined with this scenario is often occurring in vulnerable patients or “high risk” therapeutic the increasing requirement for health care organizations to provide cost-effective health care as well as care that is delivered on evidence-based practice delivered through formularies or guidelines. This article aims to: 1) summarize the key economic considerations pertinent to these multiresistant infections but with an emphasis on MRSA, 2) discuss the current therapeutic options of managing MRSA infections, and 3) discuss the formulary positioning of linezolid by means of outlining its core strengths, weaknesses and the opportunity it provides to hospital infection management. 0 2001 The Hospital

Keywords:

MRSA;

economic;

cost-effectiveness;

linezolid;

. Introduction The last 15 years has seen the emergence of Grampositive bacteria as major causes of colonization and serious infection within the nosocomia11’2 and increasingly also within the community setting.3 This has resulted in considerable impact on clinical, microbiological and economic outcomes including the patiin many countries, ents quality of life.4’5 Globally infections due to methicillin-resistant Staphylococcus UUWZLS(MRSA) are providing the greatest burden of clinical infection, often occurring in vulnerable patients or “high risk” therapeutic settings.6 Combined

Author for correspondence: D. Nathwani, Infection Ward, (Ward 42) East Block, Tayside University Hospitals, Dundee, DDl 9SY, UK. Tel.: +44 (0)1382 660111; Fax: +44 (0)1382 816178; E-mail: [email protected]

1475-9594/O

I IOSAOO33 +9 $35.0010

formulary

Infection

Society

positioning.

with this scenario is the increasing requirement for health care organizations to provide cost-effective health care.7 For any episode of serious infection the length of hospital stay’ remains the key cost driver and its reduction an important stimulus for costeffectiveness.’ Not only is this desirable from an economic perspective” but patients and society also are increasingly demanding this.’ * The therapeutic options for managing these serious resistant infections remain the glycopeptides, either as monotherapy or in conjunction with an additional drug such as rifampicin.12 More recently intravenous streptogramins were approved for this purpose. i3 The recent recognition of glycopeptideresistant staphylococci14 combined with the lack of an oral formulation of a potent agent that is available against a range of multiresistant Grampositive infections has limited the therapeutic

0 2001 The Hospital

Infection

Society

D. Nathwani

s34

options available to the clinician. Presently the majority of these serious infections are managed by the setting, or to a intravenous route l2 in the inpatient lesser extent in the ambulatory setting.” Oral therapy with second-line agents such as trimethoprim, rifampicin or fusidic acid is currently confined to treating mild or chronic infections or as a means of switching to oral therapy from a glycopeptide The clinical evidence perdelivered parenterally.16 taining to the latter practice of switch therapy with a different class of drugs in managing serious infections is purely ad-hoc and not based on randomized studies but based, rather on in vitro susceptibility.17 The availability of linezolid, a new class of antibiotic, an oxazolidinone, which is effective against a broad range of resistant and sensitive Gram-positive infections, and which is available in the intravenous and oral form is a recent alternative to these options. It offers 100% bioavailability, is administered twicedaily and is safe with no significant drug interactions in complex patients often on polypharmacy. Linezolid presents clinicians with greater flexibility in managing a range of serious infections often in the absence of positive microbiology.18’19 The ability to manage serious infections with oral therapy or the ability to step down patients to oral therapy clearly offers significant opportunities in terms of facilitating hospital discharge.20 In addition, the other advantage of oral therapy relates to problems and costs associated with intravenous access which should not be underestimated.21 The overall decision-making process behind antibiotic availability and appropriate prescribing is increasingly being undertaken at an organizational level under the guidance of the “drug and

Table I

therapeutics” or “antibiotic” subcommittees. These decisions are made on grounds of evidence of clinical efficacy and effectiveness, safety and tolerability, 22 At an indiviconvenience and cost-effectiveness. dual prescriber level, the microbiology is not often available when initiating empiric therapy in unwell patients and the choice of therapy is an educated guess based on severity assessment and an appraisal of likely risk factors for acquisition of infection with a of early resistant infection. 23’24 The importance appropriate therapy cannot be overemphasized in 25,26 so as to achieve optimal outcome. sick patients All these factors must be considered when determining the appropriate positioning of a new antibiotic within a formulary or good clinical practice guideline. Of course, key measures of audit to evaluate this use also need to be developed at this time so as to ensure that clinicians receive feedback of good quality information related to their own and the organization’s prescribing practice. This article aims to: 1) summarize the key economic considerations pertinent to these multiresistant infections but with an emphasis on MRSA; 2) discuss the current therapeutic options of managing MRSA infections; 3) discuss the formulary positioning of linezolid by means of outlining its core strengths, weaknesses and the opportunities it provides.

Economic

considerations

of MRSA

infections

Recently the economic consequences of MRSA and other multiresistant infections to the patient or individual, the hospital and to the community or society have been reviewed.27 Table I summarizes

Possible impact of infection with a resistant infection on the patient, hospital and society

Index patient

Hospital

Increased morbidity and mortality from infection episode Slower response to therapy/risk of treatment failure Extra investigations and treatment e.g surgical drainage Longer length of hospital stay More absence from work and delay in return to normal functions Reduced quality of life

Increased

Society control

of

infection/isolation

costs

Increased laboratory use for screening/ surveillance Use of broader spectrum empiric therapy Longer length of hospital stay Reduced hospital throughput (efficiency) Possible impact on waiting times in certain countries Use of costly therapies Possible increased overall staphylococcal infection rate

Risk of spread of infection in the community through carriage Patient anxiety/reduced quality of life Increased potential with infection

risk of re-admission

Economic

impact

and formulary

position

of linezolid

the key generic issues related to the patient, the hospital and the community. In addition to considering from which perspective any economic evaluation is viewed, we need to emphasize the importance of taking into account all costs (direct, indirect and intangible) and the time-frame over which they are likely to be incurred.22 The clear economic impact of increasing the hospital cost of managing episodes of nosocomial infection such as MRSA compared with infection due to a susceptible organism (MSSA) have been quantified by Rubin et a1.28 and others.29 Rubin and colleagues estimated, using a hospital discharge model, that MRSA infections had a mortality rate 2.5 times higher than MSSA infections, and the cost of an MRSA infection was $2500 more than the cost of an MSSA infection. The main contributors to this increased cost were longer length of hospital stay, increased vancomycin use and the costs of isolation. Even though one may argue about the true impact on mortality of MRSA infections compared with MSSA infections, what is clear is the undoubted effect on costs. In any such analysis there are a number of, key drivers of cost for an episode of infection. These were quantified recently for an episode of hospitalacquired infection in England. These are highlighted in Figure 1. On closer examination of these cost components, it is clear that hospital overheads and costs associated with nursing care account for at least 64% of the total costs whilst antimicrobials constitute less than 2% of all costs.’ The main determinant of hospital overheads and nursing care costs is the length of hospital stay”’ thereby Other tests and investigations Paramedics and 3% \ Other drugs saecialist nurses 4% Onerations and 1

managemeht time and capital charges 32% Figure I Key cost drivers in hospital infections showing costs incurred by patients with hospital-acquired infections.

additional

s35

highlighting the principal opportunity this provides in reducing overall cost of an episode of infection. These data highlight the fact that if hospitals, formulary committees and clinicians are to consider the true worth of new therapies, the potential for facilitating hospital discharge would be of primary importance providing that the clinical effectiveness and safety profile of the agent are at least equivalent to existing treatments. Furthermore, reduction in the length of hospital stay is clearly desirable not only from an economic perspective but also all the other attendant benefits of not being hospitalized.30 These include the costs related to intravenous (iv) adminreduction in line-associated phlebitis, istration3 bacteraemia, increased mobility and decreased dependency leading to less likelihood of problems such as pulmonary emboli. Moreover these considerations put into perspective the relatively minimal contribution of drug acquisition costs on the overall cost of managing an episode of infection. Despite the evangelical faith that many hospital administrators, pharmacists and clinicians have in this, it is important that at a formulary level, all the key issues pertinent to the cost-effectiveness of an agent are rationally and objectively assessed. Health economic analyses managing methicillin-resistant infection

of linezolid for staphylococcal

MRSA is a major pathogen both nosocomially and increasingly in the community. Its frequency is increasing in Europe, North America and the Far East. In the USA, the National Nosocomial Infections Surveillance demonstrated a H-fold increase in prevalence over 20 years (2.4% in 1975 to 35% in 1996).32 MRSA infections represent a significant clinical challenge as they are concurrently resistant to many other antimicrobials besides methicillin/oxacillin. These organisms have been implicated in a range of infections including nosocomial pneumonia and occasionally community-acquired pneumonia,34 skin and soft tissue (both complicated and uncomplicated), complicated urinary tract infections, and nosocomial bacteraemia.33 The fiscal and quality of life impact of these methicillin-resistant staphylococcal species (MRSS) infections are only now being evaluated. The economic dangers of suboptimal empiric therapy either by using inappropriate agents or delaying potentially optimal therapy is evident by the realization that treatment failure will lead to an increased length of hospitalization, further courses

S36

of multiple antimicrobials, and an increase in overall treatment costs 23,25,26including the cost of isolation6 and potential of transmission of infection to other patients or healthcare workers in the hospital or community after hospital discharge. It is therefore vital that these patients receive appropriate treatment from the outset and not wait until a poor response stimulates change in management. Unfortunately, the antimicrobial options for methicillin-resistant species of staphylococci are limited, with the glycopeptides (vancomycin and teicoplanin) being the conventional drugs of choice. The efficacy and safety of linezolid in managing these infections has been evaluated in a number of recent clinical trials.34,35 Additionally, the economic implications of managing these infections with linezolid compared with the traditional ‘gold standard’ vancomycin has been analysed pertaining to duration of iv therapy and their impact on length of stay. We have also hypothesized the potential value of an economic decision model for the empirical treatment of complicated skin and soft tissue (cellulitis) infections. 36 Such modelling exercises, clearly of interest to clinicians and formulary assessors, should form the basis for future comparative clinical effectiveness studies as they reflect real life practice. The data pertaining to the health economic impact of managing MRSS infections were derived from an open-label Phase III study. Li et aZ.37 compared linezolid (iv therapy followed by oral treatment) with iv vancomycin particularly for medical resource utilization in a multicentre setting: 460 hospitalized patients with a range of infections of known or suspected MRSS were included in the analysis. The main outcomes studied were length of hospital stay, weekly discharges, and days of antibiotic treatment. Clearly the ability of linezolid to switch from iv to oral medication was an important consideration in the overall evaluation. Normally one would use overall sample population results for an economic analysis. This is particularly appropriate when results are homogenous for different sites of infection. This is known as the “Intention to Treat” (ITT) population. This is less appropriate when different infective indications are associated with various treatment intensities and co-morbid conditions as was the case in this study population.37 Therefore, the data presented include two subsamples, those patients with complicated skin and soft tissue infections, representing the largest specific indication subgroup (230 patients).The other more heterogeneous group (230) consisted of

D. Nathwani

patients with pneumonia (99), bacteraemia (SO), urinary tract infections (27) and other non-specified sites (54). Analysis of the ITT population was undertaken for length of hospital stay, weekly hospital discharge rates and medical resource utilizations for all patients during the whole study period. The data were further analysed based upon the primary site of infection, i.e. skin and soft tissue as one set and the other group of heterogeneous infections which included pneumonias, urinary tract, blood and other miscellaneous infections. The overall pooled data are shown in Table II. The demographic and clinical characterisitics were similar with respect to race, sex, and geographic region between the two treatment groups. Moreover baseline physical findings were comparable with the exception that the linezolid-treated patients were significantly older than those who received vancomycin (63.9 years vs. 59.8 years, P= 0.0157). Comparison of linezolid with vancomycin showed a significantly earlier hospital discharge (discharge by week 1) in those treated with linezolid: 30% compared with 19% in the vancomycin group, P = 0.005, Figure 2. Analysis of the Clinically Evaluable group showed a similar, but smaller difference in earlier hospital discharge, Figure 3 (CE group clinical success 77.0% linezolid vs. 74.4% vancomyobservations occurred despite tin P = 0.63).These the linezolid-treated patient group having a poorer medical history and being sicker than the vancomytin cohort, 27.5% vs. 13.5% P=O.O2. Table II Selected health-economic overall pooled sample Intention LZD No. of patients Length Median Mean Patients Week I 2 Duration iv alone Mean Median iv and po Mean Median

discharged 30 48

P

220

of stay (days) I4 19.6

15 20.2

0.19

0.005 0.47

therapy

(days)

6.7 5

I I .3 IO

0.000 I 0.000 I

12.6 I3

I 1.3 IO

0.05 0.03

VAN = vancomycin

Clinically LZD

Evaluable

VAN

124

by (%) 19 45

of antibiotic

LZD = linezolid,

to Treat

VAN

240

analyses of MRSS infected patients in

P

130

I4 20.0

I6 21.3

0.08

49

I2 39

0.00 I 0.1 I

6.8 6

13.8 I3

0.0001 0.000 I

15.4 I5

13.8 I3

0.02 0.003

Economic

impact

and formulary

position

of linezolid

s37

s 100 m$8

80

2 *kc .t$z

60

Seleaed health-economic onolyses or subset of MRSS infected Table III patients with complicated skin and sofz tissue infections Intention

-2

,“v y,q

40

gj

20

No. of patients e .-

0

Week 1

Week 2

Week 3

Week 4

Week 8

Length Median Mean Patients Week I 2

Figure 2 group (9,

Hospital

discharge

in all patients

in the intent-to-treat

Duration iv alone Mean Median iv and po Mean Median

of stay

to Treat

LZD

VAN

122

108

(days) 9 17.2

discharged 36 54

I4 19.4

by (%) I7 46

of antibiotic

therapy

Clinically P

Evaluable

LZD

VAN

P

70

74

0.052

8 15.4

I6 20.3

0.0025

0.001 0.24

44 61

I2 39

0.00 I 0.008

5.4 4

14.8 I4

0.000 I 0.000 I

16.6 I5

14.8 I4

0.07 0.027

(days)

5.8 4

12.6 II

0.000 I 0.0001

14.2 I4

12.6 II

0.09 0.05

60 50 s 40 30 20

10 n Week l*

Week 2

Week 3

Week 4

Week 8

*P = 0.01 Figure 3 Percentage of MRSS patients clinically evaluable cohort.

discharged

by week

in a

One of the driving factors behind hospitalization is the need to continue iv antimicrobials in the hospital, although out-patient use of parenteral administration services should reduce this alleged need. Comparison of the use of iv in the two ITT populations showed a clear difference in favour of linezolid, with a mean of 5.8 days iv use followed by 6-7 days oral therapy. Vancomycin being an iv only compound was used for a mean of 12.6 days. This difference in route of administration was statistically significant (P= 0.0001). In the skin and soft tissue infection (SSTI) group, Table III also showed the significant difference in favour of linezolid in terms of reduced iv use (5.8 days vs. 12.6 days, P=O.OOOl), length of hospital stay was significantly shorter in the linezolid treated patients than the the vancomycin cohort, (9 days vs 14 days, P = 0.052). Interestingly this difference was also seen in the clinically evaluable groups as well, 8 days vs 16 days, P= 0.0025. No statistically significant differences were observed among patients with other infections.

Clearly even within the confines of a Phase III clinical trial, which can often negate such real-world findings, this ability to convert to oral therapy contributed to a shorter length of hospital stay in favour of linezolid treated patients. Although not statistically significant, it is still evidence of the benefits of the ability to convert to oral therapy beyond simply being able to use a less expensive regimen. In summary, compared with vancomycin, linezolid treatment of hospitalized patients with known or suspected MRSS infections reduces duration of iv treatment and increases the likelihood of being discharged in the first week of hospitalization. The effect was greatest in the large group of patients with SSTIs. Vinken et al. 36 used a decision-modelling approach to compare the direct medical cost of linezolid with standard treatment of cellulitis among hospitalized patients. For analytical purposes, standard care was defined along two main pathways: 1) initiating care with iv flucloxacillin, switching to vancomycin if the pathogen is found to be resistant to flucloxacillin, or maintaining flucloxacillin if the pathogen is found susceptible or when culture and sensitivity analysis is inconclusive; or 2) initiating care with vancomycin, switching to iv flucloxacillin if the pathogen is found susceptible to flucloxacillin, maintaining vancomycin if the infection is found resistant or when culture and sensitivity are inconclusive. For those patients on iv flucloxacillin, a switch to oral dicloxacillin was permitted when clinically appropriate. The authors proposed that the

D. Nathwani

S38

cost of care of initiating treatment with linezolid would be less than that for both vancomycin and flucloxacillin in resistance risk ranges typically encountered in UK hospitals. It was also suggested that empiric first-line effectiveness may be superior with linezolid. Efficacy data were obtained from recent clinical trials with linezolid and standard treatment, and medical resource utilization was obtained from an expert panel of clinicians. Base case analyses assumed an unknown pathogen rate of 80% based on both physician experience and the literature. It was shown that initiating treatment of cellulitis with linezolid is (1) more efficacious as first-line treatment and (2) less costly than initiating treatment with flucloxacillin when there is a possibility of a resistant pathogen being greater than 20.6%. Moreover, initiating treatment with linezolid, although equally effective, is less costly than vancomycin across the entire spectrum of the patients’ risk of being infected by a resistant pathogen. The data from these two studies involving SSTIs are clearly significant and important to all concerned, including formulary committees, and worthy of attention and action. Guidelines

and formulary

positioning

The expansion of managed healthcare systems in Europe since 1990 has highlighted the move from pure cost-containment to appropriateness and quality of care. This is based on the rationale that reductions in ineffective or poor quality treatment may be a valuable strategy in reducing overall healthcare costs without reducing health benefits. This has stimulated an evidence-based approach to considering the various properties of any new therapy to determine its ultimate place in the hospital therapeutic arsenal. Accordingly, a new agent like linezolid will be carefully scrutinized by drug and therapeutics committees when being considered for use in clinical practice. In most hospitals such apparently “expensive” agents will be subject to detailed assessment for appropriateness of clinical use. Although one accepts that introduction of new drugs into clinical practice should compliment the many effective non-drug measures in controlling these infections (e.g. infection control), the main question to be addressed when a new agent is available is “What does linezolid offer us compared with what we have already”? The corollary to this is “Why should we not continue to manage the problem with our current drugs”?

The three main criteria are:

that should

be considered

the current (not historical) clinical effectiveness of the drug, particularly in key areas of clinical practice where there is evidence of suboptimal clinical performance of existing drugs; the safety of the drug compared with existing practice and flexibility of route of administration; the pharmacoeconomic advantages of the new product compared with existing ones. Pharmacoeconomic evaluation is now a fact of life although a combination of poor quality of study designs and analyses, poor training of clinicians and others in this area, and the perception that an economic analysis can be manipulated to “fix it” for whatever the requirement of a new agent has led many to be suspicious of their true worth. The ability of many formulary committees to have some expertise in this area is helping to overcome this inherent suspicion. Pharmacoeconomic decisions formulary committees

for

There are several aspects which are important in the decision process made by a hospital guideline or formulary committee. These decisions are subject to many perspectives but primarily those of the hospital. What then are the pharmacoeconomic data required to assess the position of linezolid compared with existing drugs? The main driver of these costs is the occupation of a hospital bed (this is often the most expensive aspect of hospitalization) and to a lesser extent the drug acquisition cost. These costs need to be identified, measured and evaluated in “real life” clinical studies which preferably have prospectively included pharmacoeconomic primary or secondary endpoints.38 Most of these studies are primarily cost-minimization studies which compare direct costs associated with treatments. Very few studies of this nature compare the cost benefits of reducing the cost of hospitalization by facilitating discharge. Such benefits have been calculated for outpatient or home parenteral therapy programmes.39 The advantages of ambulatory oral antibiotic therapy would clearly be even greater. The addition of quality of life assessment is topical but is usually more relevant to chronic disease rather than acute infection. This may be of importance should linezolid be used in managing chronic infections such as osteomyelitis or endocarditis.

Economic

impact

Table

Strengths, weaknesses, opportunities

IV

and

formulary

position

of linezolid

s39

and threats offinezolid

Strengths Microbiology Unique mode of action No cross-resistance (e.g with lincosamides, macrolides, streptogramins) No natural compound in the environment Broad spectrum of activity (MSSS, MRSS, VRE, GISA etc) Low incidence of GISA (VISA) or VRE

Weaknesses Microbiology Bacteriostatic (but does not appear to behave this way in vivo by virtue of superior pharmacokinetic profile). No current indications or data for endocarditis, bone and joint sepsis Or with immunosuppressed patients (e.g febrile neutropenics)

Clinical eficaq Proven value in nosocomial pneumonia, CAP, SSTI and bacteraemia due to resistant Gram-positive cocci (all studies showed equivalent efficacy to comparators e.g vancomycin, oxacillinldicloxacillin).

cost

Pharmacology Good pharmacokinetic profile: Good tissue penetration (especially skin structure and lung) Administered twice-daily 100% oral bioavailable iv and oral formulation leading to increased flexibility of treatment route options No induction of CYP P450 enzymes Only minor interaction with MAOI and some foods Low renal clearance, can use in renal failure*

f67 per day compared with vancomycin f IO /day and teicoplanin f30/day (not counting loading dose). However, this may be offset by advantages of oral preparation and potential for earlier home discharge. Prospective pharmacoeconomic data will be available form linezolid vs. teicoplanin study. Inadequate data on long-term use (beyond 6 weeks). Some occurrence of resistance in VRE and occasional 5. aureus when used for long periods for infections with devices in situ.

Safety Well tolerated

(mainly gastrointestinal

Economics Significantly higher rates of hospital for SSTls) than vancomycin

adverse discharge

events) (most marked

Opportunity Major advancement in the therapeutic arsenal for serious Gram-positive infections. High patient and clinician expectations. Adopt cautious and controlled use from onset No marketing in community. (Price also higher f 89 if primary care wish to purchase it.) Opportunity to regulate through Primary Care Prescribing and Area Therapeutics Group Monitor use through antibiotic outcomes registry (a clinical database that can evaluate the clinical and microbiological impact of antimicrobials that can only be prescribed in limited conditions and is under specialist control) Would be major advance for endocarditislboneljoint, once further data is available Useful option to outpatient and home parenteral therapy VRE: GISA: VISA: *Note

Vancomycin-resistant enterococci. Glycopeptide-intermediate Staphylococcus BUYBUS. Vancomycin-intermediate Staphylococcus ~LWUS. these indications require further clinical and laboratory

Threats Misuse, particularly due to oral availability care Escalating drug costs

in primary

and secondary

data

Currently available data indicate that linezolid has a number of characteristics that would potentially afford it a favourable pharmacoeconomic profile. The key is the flexibility of oral and i.v. route which will facilitate hospital discharge by 1. allowing iv to oral switch in hospital; 3 allow the patient to continue on iv therapy in the d. outpatient and home setting should the clinical need so desire;

3. initiate

or continue

therapy

with

the oral route.

These properties will reduce hospital stay, the main determinant of overall cost. The question of drug acquisition cost and the cost of consumables (with the iv preparation) is likely to be of secondary importance. The availability of the oral route is perceived as a major advantage as presently there are relatively sparse, unproven therapeutic options for treating serious MRSA infections that allow iv to oral

D. Nathwani

s40

Table

V

Formulory positioning of linezolid;

Suggested positioning

JaysideUniversity Hospitals

of linezolid

I. Proven GISA, VRE efficacy 2. Patients with deteriorating or severely impaired renal function or where glycopeptides are not possible (e.g. poor or no iv access) 3. Glycopeptides not tolerated or have clinically failed 4. Infections where outpatient therapy of resistant Gram-positive infections is required e.g. for complicated skin and soft tissue structure infections 5. Change from iv to oral glycopeptide where rifampicinkrimethoprim is deemed less desirable

transition. The attendant benefits of oral therapy are many and have been previously described.40 The equivalent pricing of oral and iv linezolid should deter irrational use of oral therapy on traditional low cost grounds. As part of the new drug evaluation proposal to our hospital antibiotic subcommittee for linezolid, we adopted a SWOT (Strengths, Weaknesses, Opportunities and Threats) analytical style for presenting the data with availability of all appropriate supporting references if required (Table IV). This allowed members of the committee a ‘snapshot’ of the key properties and issues related to this agent so that its case could be appraised more efficiently and effectively. In addition, some supporting audit data on current antibiotic management of MRSS infections was also helpful. This approach appeared to be appreciated and helped to condense all the core information in an easy to read format and provided a valuable synthesis of the key issues so as to allow the committee more time for a broader debate and discussion related to this agent. A proposal of how linezolid may be best placed in the hospital formulary, based not only on the available data, but on existing audit and analysis of our current practice in managing serious resistant Gram-positive infections in our hospital is shown in Table V. This is our current positioning of this agent and does not appear to differ in principle from UK practice elsewhere (personal observation). Although we believe the positioning of this agent is likely to change with time and may differ by hospital, as each one may have unique problems related to a particular area(s), we commend the methodology of data presentation and overall principles guiding the current use of this agent. Conclusion This review is intended physician and pharmacist

to enable the prescribing to amalgamate the complex

issues of managing the empiric and targeted treatment of serious infections, the increasing role antimicrobial resistance has in clinical practice, and increasing the awareness of cost factors in the current healthcare environment. Linezolid has proven efficacy against GISA and VRE, as well as a range of methicillin-resistant staphlyoccoccal infections. It is a useful drug in patients with renal impairment or deteriorating renal function as dose alteration is not an issue. It provides an alternative agent in patients who cannot tolerate glycopeptides for whatever reason. Additionally linezolid should find a role as an oral antimicrobial for the outpatient management of a range of serious or complicated Gram-positive infections by facilitating iv to oral switch and earlier hospital discharge. Economic evaluation of any new drug necessitates an overall review of all the relevant cost data including convenience issues and the opportunity it may afford in terms of flexibility of site of care of the patient. In summary, this paper attempts to provide information for key decision makers involved in the formulary positioning of linezolid but with the emphasis on cost issues. Many of the questions raised in this paper will need to be addressed in forthcoming clinical trials and an analysis of the growing experience of this drug in a variety of clinical settings.

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Economic

9. 10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

impact

and formulary

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