International Journal of Antimicrobial Agents 23 (2004) 315–324

An economic evaluation of a European cohort from a multinationaltrial of linezolid versus teicoplanin in serious Gram-positive

bacterial infections: the importance of treatment settingin evaluating treatment effects�

Dilip Nathwania,∗, Jim Z. Lib, Dan A. Balanc, Richard J. Willkeb, Brian E. Rittenhoused,Essy Mozaffarie, Manouche Tavakolif , Tom Tangg

a Infection and Immunodeficiency Unit, Ward 42, East Block, Ninewells Hospital and Medical School,Tayside University Hospitals, Dundee, Scotland DD1 9SY, UKb Global Outcomes Research, Pfizer Inc., Kalamazoo, MI, USA

c Department of Economics, Western Michigan University, Kalamazoo, MI, USAd Global Pricing, Reimbursement and Health Outcomes, Pfizer Inc., Peapack, NJ, USA

e Global Health Outcomes, Pfizer Inc., Peapack, NJ, USAf PharmacoEconomics Research Centre, University of St. Andrews, St. Andrews, Scotland, UK

g Global Medical Affairs, Pfizer Inc., Peapack, NJ, USA

Received 11 August 2003; accepted 2 September 2003

Abstract

In a recent multinational trial, hospital resource use and total cost of treatment were compared between linezolid and teicoplanin for severeGram-positive bacterial infections among 227 European hospitalised patients. The results show that the linezolid group had a 3.2-day (6.3 forlinezolid versus 9.5 for teicoplanin groups) shorter mean intravenous antibiotic treatment duration. Certain baseline variables, particularly theinpatient location at enrolment and the presence of outpatient/home parenteral antibiotic therapy (OHPAT), had substantial effects on length ofstay (LOS) and cost of treatment. After adjusting for the between-treatment difference in these two variables and other baseline variables, the re-sults showed non-significant shorter LOS and lower mean total cost of treatment for the linezolid group among patients with no access to OHPAT.© 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Keywords: Linezolid; Teicoplanin; Gram-positive bacterial infections; LOS; Cost of treatment; Intravenous to oral switch

1. Introduction

Gram-positive bacteria are important causes of a diverserange of nosocomial and community-acquired infections.Nosocomial infections have emerged as a particular sourceof concern[1,2]. In the US two million patients annuallyacquire these infections[3] and this pattern is emergingglobally. For example, in the UK at any one time approx-imately 10% of hospitalised patients develop an infection

� Some of the results in this paper were presented at the 12th EuropeanCongress of Clinical Microbiology and Infectious Diseases (ECCMID),Milan, Italy, 25 May 2002.

∗ Corresponding author. Tel.:+44-1382-660111;fax: +44-1382-816178.

E-mail address: dilip.nathwani@tuht.scot.nhs.uk (D. Nathwani).

after hospital admission[4]. Staphylococcus aureus andcoagulase-negative staphylococci represent important andcommon causes of nosocomial infections such as bacter-aemia, pneumonia and skin and soft tissue infections in Eu-rope[5]. Methicillin resistant staphylococcus (MRSA) ratesin Europe are generally high, around 26%, but are variableranging from<2% (Switzerland and The Netherlands) to54.4% (Portugal).

Glycopeptides have been the drug of choice for MRSAinfections. Vancomycin is the only glycopeptide availablein the US; but in Europe, Latin America and Asia te-icoplanin is a commonly used alternative glycopeptide formanaging serious MRSA infections either in hospitals[6]or in ambulatory settings[7]. The advantages offered byteicoplanin over the intravenous (IV) only vancomycin in-clude once daily administration due to its longer half-life,

0924-8579/$ – see front matter © 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.doi:10.1016/j.ijantimicag.2003.09.020

316 D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324

the possibility of intramuscular (IM) injection and lowernephrotoxicity [8]. However, the emergence of clinicallysignificant glycopeptide resistance amongst enterococci[9]and, more recently, glycopeptide insensitivity in staphy-lococci [10] has highlighted the need for new agents tocombat these serious infections.

Linezolid is the first of a new synthetic class of an-tibiotics, the oxazolidinones, which offers a wide spec-trum of activity against most methicillin susceptible andresistant Gram-positive organisms without displayingcross-resistance with other classes of antimicrobial agents.In clinical trials, linezolid was shown to be of equivalent ef-ficacy and to have excellent tolerability when compared withvancomycin and teicoplanin for a range of serious infec-tions and compared with�-lactams for community-acquiredpneumonia and skin/soft tissue infections[11–18].

Linezolid is available in the IV and 100% bioavailableoral forms. Conversion to oral therapy shortens the durationof IV therapy and thereby facilitates hospital discharge andshortens length of stay (LOS)[19,20], a significant advan-tage when compared with vancomycin and teicoplanin, par-ticularly as ambulatory parenteral therapy is limited outsidethe US[21]. The potential economic benefits and drug for-mulary evaluations of linezolid have been recently reviewed[22].

The widespread use of teicoplanin for managing seriousGram-positive infections in Europe and South Americaand the importance of evaluating the economic and healthresource utilisation of new therapies stimulated a recentmultinational (non-US) randomised trial comparing line-zolid with teicoplanin for the treatment of multiple sourcesof Gram-positive infections including pneumonia, com-plicated skin and soft tissue infections and bacteraemia.The primary objective of the trial was to evaluate theclinical efficacy and safety of linezolid compared withteicoplanin, but the trial was also designed to assess re-source utilisation and the cost of treatment as the secondaryendpoints.

Patients for this trial were enrolled from 13 countriesfrom Europe and South America/Mexico. Clinical and eco-nomic results for the entire trial-wide sample have beenreported elsewhere[18,23,24]. While it is a common beliefthat there are no major differences in the biological as-pects of the patients and/or the infections across countries(therefore, clinical trials are often conducted multination-ally to determine the efficacy and safety), major differencesoften exist between European and South American coun-tries in the treatment patterns, amounts of medical resourceconsumption and the cost of treatment (seeSection 4fordetails). Consequently, we judged it most appropriate toanalyse the resource use and cost data for the European andSouth American samples separately; results for the lattersample have been published elsewhere[25]. The primaryaim of this paper is to quantify and compare hospital re-source use and cost of treatment between linezolid andteicoplanin for the cohort of 227 European patients.

2. Materials and methods

This trial was conducted in accordance with the HelsinkiDeclaration. Institutional review board/independent ethicscommittee (IRB/IEC) approval was obtained from all in-vestigator sites prior to the start of the trial, and informedconsent was obtained from all participating patients.

2.1. Study design

Data were collected from a multinational, randomisedopen-label trial comparing linezolid with teicoplanin for thetreatment of serious Gram-positive bacterial infections inhospitalised patients. Patients were randomised in a 1:1 ra-tio to receive 7–28 days of (1) linezolid 600 mg every 12 h(initiated on IV with an option to be switched to oral) or (2)teicoplanin (initiated on IV with an option to be switchedto IM) as per approved prescribing information. Conversionfrom IV to oral (for linezolid) or IM (for teicoplanin) wasat the discretion of the investigators Concomitant antibi-otic treatment to cover Gram-negative co-infections waspermitted.

To be eligible, patients were required to satisfy all the in-clusion criteria, including: to be at least 13 years of age and40 kg in weight; to be expected to survive throughout thestudy with effective antibiotic treatment and support careand to have known or suspected Gram-positive infectionsfor which treatment with a glycopeptide was clinically in-dicated. The infections were limited to pneumonia (hospitalacquired or hospitalised after community acquired), severeskin/soft tissue infections including wound infections, bac-teraemia or right-sided endocarditis. Disease specific criteriafor each infection were per the Infectious Disease Society ofAmerica guidelines. Patients were excluded from study par-ticipation if they met any of the exclusion criteria, including:females of childbearing potential who were breastfeeding,had a positive pregnancy test at baseline, or could not prac-tice adequate methods of birth control to prevent pregnancyduring the study; having left-sided endocarditis, osteomyeli-tis, central nerve system infections or infective exacer-bations of chronic obstructed pulmonary disease; havingknown pheochromocytoma, carcinoid syndrome, untreatedhyperthyroidism, or uncontrolled hypertension; previousenrolment in this protocol or another linezolid protocol;hypersensitive to linezolid or teicoplanin or vancomycin;having baseline laboratory assay results showing absoluteneutrophil count<500/mm3 or known liver disease withtotal bilirubin >5.0 times of upper limits of normal; or HIVpositive patients requiring prophylaxis forPneumocystiscarinii.

2.2. Trial sample

The total intent-to-treat (ITT) sample of the entire trialcontains 430 patients who received at least one dose ofstudy medication. These patients were enrolled between 22

D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324 317

November 1999 and 18 December 2000 from 50 investigatorsites in Europe (227 patients) and South America/Mexico(203 patients). Clinical and economic results for the totalITT sample have been reported elsewhere[18,23,24]whichshowed that the linezolid group had a significantly higherproportion of treatment success at the end of treatment asassessed by the investigators (95.5% for linezolid versus87.6% for teicoplanin,P = 0.005), especially among pa-tients with bacteraemia (88.5% versus 56.7%,P = 0.009)[18]. The economic results showed that the linezolid grouphad a 3.2-day shorter mean duration of IV antibiotic treat-ment (P < 0.0001) and a non-significant 1.4-day shortermean LOS (P = 0.20)[23], as well as a non-significant US$339 lower multivariate adjusted mean total cost of treatment(P = 0.63) [24]. Our analysis focuses on the European co-hort of 227 patients. Investigators’ assessment of efficacy forthis European cohort was similar to that for the total sample:treatment success rate for the European cohort was 92.4%for linezolid versus 81.7% for teicoplanin (P = 0.02) at endof treatment.

2.3. Measurements

2.3.1. Demographic and baseline clinical characteristicsAge, race, gender, country from which the patients were

recruited and primary site of infection were recorded atrandomisation. Historical and current medical conditions in10 anatomic systems were also recorded; the number ofanatomic systems with conditions was counted to derive thenumber of historical and current medical conditions. Dataregarding whether a patient had sepsis or systemic inflamma-tory response syndrome (SIRS) were also collected based onthe definition and classification recommended by the Amer-ican College of Chest Physicians and the American Societyof Critical Care Medicine[26]. In addition, the type of in-patient location (general ward, step down care/high depen-dency care unit or ICU) from which a patient was enrolledwas also recorded. Together with the numbers of historicaland current medical conditions and sepsis/SIRS, these fourvariables provide an approximate measure for a patient’sclinical severity.

In some European countries such as Sweden, Italy andUK, outpatient or home parenteral antibiotic therapy (OH-PAT) is present in some hospitals. Hospitalised patients inthese hospitals may be discharged while continuing their IVantibiotic treatment at outpatient settings, resulting in reduc-tion of their LOS. Because OHPAT is not widely availablein Europe[27] and the mix of patients with access to OH-PAT in this trial may not be typical of European practices,we included the presence of OHPAT as a control factor inour analysis to enhance the generalisability of our findings.

2.3.2. Resource useThe following categories of medical resource utilisation

were collected from patients enrolled in this trial: durationand doses of antibiotic uses (study medication), duration and

the type of inpatient location, co-medications, tests and pro-cedures, and outpatient service usage. The maximum periodfor resource use data collection was 49 days from the initi-ation of a study medication, based on the maximum treat-ment duration of 28 days plus the maximum period of 21days for a post-treatment test-of-cure visit, as required bystudy protocol. While all above categories of resource utili-sation data were included for the estimation of the total costof treatment, we singled out LOS and duration of antibiotictherapy for an in-depth analysis, because costs associatedwith these two types of resource utilisation constitute themajority of the total costs of treatment (seeSection 3). Du-ration of IV, IM or oral antibiotic treatment was determinedby counting the days in which a patient received either line-zolid or teicoplanin. LOS was determined by counting theinpatient days during the 49-day study period. For patientswho continued to stay in the hospital beyond the 49-day pe-riod, LOS was truncated at day 49. LOS for these patientsand for those with missing discharge dates within the 49-dayperiod is labelled as ’censored’ for statistical analysis.

2.3.3. Cost of treatmentUnit costs for the medical resources collected in the trial

were obtained from secondary sources (Study A2-1914,MEDTAP International, Bethesda, MD) from the hospitalperspective whenever possible. For the two study medi-cations (linezolid and teicoplanin), daily ex-manufacturerprices were used to reflect likely acquisition costs for hospi-tals. Because unit costs were not available in some countries,they are imputed using the methods developed by Schul-man et al.[28]. The cost of each resource was calculatedas the product of the quantity utilised during the 49-daystudy period multiplied by its unit cost. The costs weresummed to derive the total cost of each category as well asthe total cost of treatment for each patient. The individualpatient’s costs were converted into a common currency (i.e.US$ 2001) so that costs for patients enrolled from differentcountries could be pooled and statistically analysed.

2.4. Statistical analysis methods

2.4.1. Resource useFor duration of antibiotic treatment, means and standard

deviations were calculated and between-treatment differ-ences in the means were tested using the Student’st-test.For LOS, the Kaplan–Meier (KM) survival analysis methodwas used to account properly for the 11% of cases withcensored LOS data. Based on the KM functions, medi-ans (and inter-quartile ranges) and means were estimated.Between-group differences in the KM functions were testedusing the Wilcoxon test. LOS analysis was conducted insub-samples in addition to the total sample to identify base-line variables that might have an impact on the LOS. Tocontrol for the effects of these baseline variables, regres-sion analysis was also conducted using an accelerated failuretime model with a log-logistic distribution (the log-logistic

318 D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324

model)[20,29]. Results from the log-logistic models are re-ported as the odds ratio of being discharged early duringthe study period; in addition, LOS ratio at median was alsoreported for the treatment and OHPAT variables.

2.4.2. Cost of treatmentUnadjusted median, means and standard deviations of

the total cost of treatment and sub-categorical costs werefirst calculated for the total ITT sample; between-treatmentdifferences were tested using the Student’st-test. In addi-tion, between-treatment comparisons were also conductedfor sub-samples grouped by baseline variables. Finally, anordinary least squares regression model was fit to determinethe treatment effect on the total cost of treatment, adjustingfor patients’ baseline demographic and clinical characteris-tics.

In the multivariate analyses of both LOS and cost, we in-teracted linezolid treatment and OHPAT presence becauseof its difference between the two treatments (though therewas also difference in inpatient location at enrolment, theproportion of patients enrolled from the ICU was too smallto allow interaction between treatment and this variable).By altering the reference group in the regressions, we es-timated the linezolid effects with and without the presenceof OHPAT, and the OHPAT effects separately on linezolidand teicoplanin groups. Both sets of estimates are shown inthe multivariate results tables (Tables 3 and 5), even thoughthey were estimated from two separate, but equivalent, re-gression models.

2.4.3. Sensitivity analysisWhile it is logical to expect more resource use for more

severe patients, patients who died (the worst clinical out-come), particularly those who died early during the studyperiod, might have used less hospital resources resulting inlower cost of treatment. Although the number of deaths wassmall and there was no significant difference in the numberof deaths between the two treatment groups (13.6% for line-zolid versus 10.1% for teicoplanin group;P = 0.42), weestimated the impact of deaths by excluding these patientsin a sensitivity analysis.

3. Results

3.1. Demographic and clinical characteristics

Our study cohort consisted of 227 hospitalised patients,the majority coming from the UK (54%) and Germany (22%,with the remainder from Italy, Sweden, Spain and Belgium)(Table 1). Almost all patients were Caucasian (97.4%) with ahigher proportion of males (60%). About 40% patients were65 and older. These demographic variables were relativelyevenly distributed into the two treatment arms.

For the primary site of infections, more than half of the pa-tients had complicated skin and soft tissue infections (53%),

the rest of the sample consisted mainly of bacteraemia (26%)and pneumonia (18.5%). They were distributed relativelyevenly between the two treatment groups. The two treatmentgroups also had similar numbers of historical and concurrentmedical conditions and proportions of patients with SIRS orsepsis diagnoses.

About 11% of the patients were enrolled from the inten-sive care unit (ICU), with more in the linezolid group thanin the teicoplanin group (13.6% versus 7.3%,P = 0.13).Furthermore, nearly half of the patients (48.5%) were inhospitals with OHPAT presence, with more in the linezolidgroup than in the teicoplanin group (53.4% versus 43.1%,P = 0.12).

3.2. Resource use

For the total sample, linezolid patients had a 3.2-dayshorter mean duration of IV antibiotic treatment (6.3 daysversus 9.5 days,P < 0.0001), while the mean total durationof antibiotic treatment was 2.4 days longer for the linezolidgroup (12.9 days versus 10.5 days,P = 0.003). UnadjustedLOS was similar between the two treatments for the totalsample (Table 2). In a sensitivity analysis in which the 27patients who died were excluded, the above findings remainqualitatively the same.

To explore the effect of baseline variables on LOS, wealso compared LOS across selected sub-samples by base-line variables. The most notable difference was observed be-tween the ICU and non-ICU patients: mean LOS was 24.8versus 15.9,P = 0.004). LOS was also different betweenthe elderly (age 65 and over) patients and the younger ones(20.5 versus 14.5,P = 0.02), across sites of primary infec-tions (13.5 for pneumonia, 15.2 for complicated skin andsoft tissue infection, 22.4 for bacteraemia,P = 0.003), be-tween patients with more (>1) and patients with less (0–1)current co-morbidities (18.2 versus 15.0,P = 0.003) andacross the SIRS/sepsis diagnoses (12.5 for patients with noSIRS/sepsis diagnosis, 17.6 for SIRS, 19.4 for sepsis and21.7 for severe sepsis or septic shock,P = 0.003). In ad-dition, there was a significant difference in LOS betweenpatients in hospitals with OHPAT presence and patients inhospitals without it (13.8 versus 19.8,P < 0.0001).

Because of the difference of inpatient location at enrol-ment (ICU versus non-ICU) and OHPAT presence, we com-pared LOS between the treatments within strata by thesetwo variables to determine their influence on the treatmenteffect; the results are presented inTable 2. None of thebetween-treatment differences in these subsamples was sig-nificant. However, the 3.5-day shorter LOS for the linezolidgroup among the non-ICU no-OHPAT-presence subsamplewas worthy of note.

Finally, we used the log-logistic model to determine howthe baseline variables collectively affect the treatment effecton LOS. Results are reported as the odds ratio of being dis-charged early for all variables and the LOS ratio at medianfor treatment and OHPAT (Table 3). The adjusted odds for

D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324 319

Table 1Demographic and clinical characteristics at baseline

Linezolid Teicoplanin P-valuea

n Percentageb n Percentageb

Total 118 52.0 109 48.0

Country 0.36Belgium 1 0.8 0 0Germany 22 18.6 28 25.7Italy 12 10.2 10 9.2Spain 6 5.1 3 2.8Sweden 15 12.7 7 6.4UK 62 52.5 61 60.0

Age (years) 0.4614–64 68 57.6 68 62.4≥65 50 42.4 41 37.6

Mean± S.D. 59.3± 19.9 58.0± 16.8 0.57

Race 0.99White 115 97.5 106 97.3Black/Asian/Pacific Islander 3 2.5 3 2.7

Gender 0.93Male 71 60.2 65 59.6Female 47 39.8 44 40.4

Primary infection 0.41Pneumonia 21 17.8 21 19.3Skin and soft tissue infection 67 56.8 54 49.5Bacteraemia 29 24.6 30 27.5Otherc 1 0.8 4 3.7

Inpatient location at enrolment 0.13Non-ICU 102 86.4 101 92.7ICU 16 13.6 8 7.3

No. of historical medical conditions 0.940–1 60 50.8 56 51.4≥2 58 49.2 53 48.6

Mean± S.D. 1.9± 1.9 2.0± 1.8 0.84

No. of current medical conditions 0.410–1 53 44.9 43 39.5≥2 65 55.1 66 60.5

Mean± S.D. 2.3± 2.0 2.3± 1.9 0.80

SIRS/sepsis diagnosis 0.87None 32 27.1 28 25.7SIRS 59 50.0 51 46.8Sepsis 21 17.8 24 22.0Severe sepsis or septic shock 6 5.1 6 5.5

OHPAT 0.12Yes 63 53.4 47 43.1No 55 46.6 62 56.9

a Between-treatment differences were tested using chi-square test for categorical variables and Student’st-test for interval variables. There are nostatistically significant differences at 0.05 level for all the variables.

b Denominator for the percentage is the total number of patients in each treatment group.c Including liver abscess, septic arthritis, urinary tract infection or appendix abscess.

patients in the linezolid group to be discharged early were7% lower when OHPAT was present (OR= 0.93) and 42%greater when OHPAT was not present (OR= 1.42); neitherone was significant. When measured as the LOS ratio at me-dian, LOS at median for the linezolid group was 4% longer

(LOS ratio = 1.04) when OHPAT was present, but 16%shorter (LOS ratio= 0.84) when OHPAT was not present.The presence of OHPAT, in turn, had relatively greater ef-fects on LOS for teicoplanin patients than for linezolid pa-tients. The results also show that age, being enrolled from

320 D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324

Table 2Between-treatment comparison of antibiotic treatment duration and LOS: total sample and selected subsamples

Variable Linezolid Teicoplanin P-valuea

Total sampleSample size 118 109Intravenous antibiotic treatment duration 6.3 9.5 0.0001Total antibiotic treatment duration (IV+ PO/IM) 12.9 10.5 0.003LOS: median (Q1–Q3) 11 (5–23) 10 (6–28) 0.79LOS: mean 16.3 17.5

LOS by subsamplesEnrolled from the ICU

Sample size 16 8Median LOS (Q1–Q3) 22.5 (12.5–35) 24.5 (13–39.5) 0.81Mean LOS 24.3 26.0

Enrolled from the non-ICU wardsSample size 102 101Median LOS (Q1–Q3) 9 (5–20) 9 (5–25) 0.59Mean LOS 15.0 16.8

OHPAT presenceb

Sample size 61 47Median LOS (Q1–Q3) 8 (4–20) 7 (4–15) 0.52Mean LOS 14.0 13.0

No-OHPAT presenceb

Sample size 41 54Median LOS (Q1–Q3) 13 (6–20) 15 (8–29) 0.32Mean LOS 16.6 20.1

a LOS estimated using Kaplan–Meier function;P-value based on Wilcoxon test.b Excluding patients who were hospitalised in the ICU when treatment started.

Table 3Results from the multivariate log-logistic model on LOS

Variable OR: early discharge (95% CI)a LOS ratio at median (95% CI)b P-value

Treatment and OHPAT combined effectLinezolid treatment effectc

For patients with access to OHPAT 0.93 (0.51–1.99) 1.04 (0.73–1.47) 0.8349For patients with no access to OHPAT 1.42 (0.78–3.01) 0.84 (0.61–1.16) 0.2806

OHPAT effectc

For linezolid treated patients 1.54 (0.79–3.55) 0.80 (0.56–1.14) 0.2198For teicoplanin treated patients 2.35 (1.12–5.92) 0.65 (0.45–0.94) 0.0212

DemographicsAge (year) 0.97 (0.97–0.99) 0.0003Race (nonwhite) 1.09 (0.25–7.06) 0.9220Gender (female) 0.71 (0.48–1.16) 0.1542

Site of infectiond

Pneumonia 1.72 (0.90–3.85) 0.1100Bacteraemia 0.66 (0.39–1.30) 0.2068Other 0.89 (0.23–4.93) 0.8864

Disease severity factorsEnrolled from the ICU 0.34 (0.16–0.86) 0.0247Number of historical medical conditions 1.04 (0.91–1.21) 0.6180Number of current medical conditions 0.86 (0.77–0.98) 0.0236Having SIRS 0.47 (0.29–0.87) 0.0196Having sepsis 0.41 (0.23–0.85) 0.0191Having severe sepsis or septic shock 1.71 (0.45–9.09) 0.4640

a For a categorical variable, it is the ratio of the odds for the variable’s characteristic (e.g. linezolid treatment) over the odds of the implied comparator’scharacteristic (e.g. teicoplanin treatment); for an interval variable, it is the ratio of the odds for one additional unit increase of the variable characteristic(e.g. 1 year older in age) over the odds of the baseline value.

b Calculated for treatment variables only.c P-value was 0.74 for the total linezolid effect and 0.22 for the total OHPAT effect.d The comparison group is complicated skin and soft tissue infections.

D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324 321

Table 4Between-treatment comparison of costs: total sample and selected subsamples

Linezolid Teicoplanin Difference (L− T) P-valuea

n Total cost n Total cost

Total sampleTotal cost of treatment 118 10097 109 9406 691 0.67Study medication 1189 599 590 <0.0001Comedications 133 238 −105 0.14Tests and procedures 264 245 20 0.64Hospitalisation 8415 8182 233 0.88Outpatient cost 96 143 −47 0.19

Subsample analysis of total cost of treatmentInpatient location at enrolment

ICU 16 29090 8 37646 −8556 0.40Non-ICU 102 7118 101 7169 −51 0.95

OHPAT presence?b

Yes 61 6668 47 6228 440 0.70No 41 7788 54 7989 −201 0.88

a P-values are based on the Student’st-test.b Excluding patients hospitalised in the ICU when treatment started.

the ICU, having more current medical conditions, havingSIRS or sepsis all had significant effects on LOS.

3.3. Cost of treatment

Table 4shows the unadjusted mean total cost of treat-ment for the total sample and selected subsamples, as wellas the cost components for the total sample. The unadjustedmean total cost was US$ 691 higher for the linezolid group;the difference was not statistically significant (P = 0.67).This unadjusted difference was likely to be biased againstthe linezolid group because the group’s higher proportionof patients enrolled from the ICU whose mean total costof treatment was about 4.5 times as high as that for pa-tients enrolled from non-ICU wards (US$ 31,942 versusUS$ 7144,P < 0.0001). Furthermore, the linezolid groupalso had a higher proportion of patients in hospitals withOHPAT presence who, on the other hand, had lower meantotal cost of treatment than patients in hospitals withoutit (US$ 6477 versus US$ 7902,P = 0.096). These majordifferences make it necessary to adjust for the effects ofthese two variables. Subsample analysis by inpatient loca-tion at enrolment shows that between-treatment differencesfavoured linezolid (US$ 8556 lower in the ICU subsampleand US$ 51 lower in the non-ICU subsample, respectively).Subsample analysis by OHPAT shows that patients treatedwith linezolid had lower mean total cost when OHPAT wasnot present (US$−201) but higher mean cost when OHPATwas present (US$ 440). None of the between-treatment dif-ferences was statistically significant, due partially to limitedsample sizes. Examination of the cost components (Table 4)indicated that the majority of the mean total cost was ac-counted for by the hospitalisation cost (85%), followed bystudy medication cost (9%).

When the 27 patients who died during study period wereexcluded in the sensitivity analysis, the general trend re-mained the same but the mean total cost was reduced byabout 15%, indicating the deaths did not adversely reducethe cost of treatments.

Finally, we fitted regression models to examine the treat-ment effect on total cost of treatment adjusting for the base-line variables simultaneously. Results are reported as themultivariate adjusted cost estimates (Table 5). Again, thetreatment effect was evaluated together with the OHPATeffect. After adjusting for baseline variables, the linezolidgroup’s mean total cost of treatment was US$ 555 lower(P = 0.76) when OHPAT was present and US$ 1286 lower(P = 0.47) when OHPAT was not present. The presence ofOHPAT had relatively greater effect on costs for teicoplaninpatients than for linezolid patients. Of all the variables, onlyage and inpatient location at enrolment had significant ef-fects on total cost of treatment.

4. Discussion

Randomised clinical trials have been well established asgold standards for evaluating clinical efficacy and safetyof new pharmaceuticals. However, their suitability for eco-nomic evaluation has often been considered far from a goldstandard[30–34]. For example, patient selection criteria andthe limited sample size, optimised for clinical assessment,may not be sufficient to increase patients’ homogeneity foreconomic evaluation. In this study, we observed a differ-ence between the two treatment groups in the proportionof patients enrolled from the ICU and from hospitals withOHPAT presence. Given the effect of these two variableson LOS and total cost of treatment, such difference can

322 D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324

Table 5Multiple regression analysis of total cost of treatment

Explanatory variable Incrementalcosta

P-value

Treatment and OHPAT combined effectLinezolid treatment effectb

For patients with access to OHPAT −555 0.7617For patients with no access to OHPAT −1286 0.4682

OHPAT effectb

For linezolid treated patients −628 0.7468For teicoplanin treated patients −1359 0.4879

DemographicsAge (year) 76 0.0484Race (nonwhite) 192 0.9612Gender (female) 740 0.5730

Site of infectionsc

Pneumonia −1565 0.4060Bacteraemia 1128 0.5081Other −1172 0.7891

Disease severity factorsEnrolled from the ICU 25318 <0.0001Number of historical medical conditions −44 0.9051Number of current medical conditions 291 0.4247Having SIRS 1567 0.3608Having sepsis 1189 0.5529Having severe sepsis or septic shock −3667 0.3065

Intercept of the model 2115 0.4816

ANOVA test for the overall model fitF-value 10.95P-value for the model fit <0.0001Variance of the total cost explained

by the model (adjustedR2)39.8%

a As the parameter estimate of an explanatory variable. For a categor-ical variable, the incremental cost is for the variable’s characteristic (e.g.female for the gender variable); for an interval variable, the incremen-tal cost is for one additional unit increase of the variable’s characteristic(e.g. 1 year increase in age).

b The P-value was 0.73 for the total multivariate-adjusted linezolideffect and 0.77 for the total multivariate-adjusted OHPAT effect.

c The comparison group is complicated skin and soft tissue infections.

certainly bias the treatment effect, as shown by the unad-justed mean LOS and total cost of treatment for the twotreatment groups. Results from subsample and multivariateanalysis adjusting for this difference more appropriatelyreflect the true effect of treatment.

The analysis also showed that linezolid had potential forreducing LOS and cost when patients did not have access toOHPAT, but the potential was non evident when OHPAT wasavailable. It is worth pointing out that treatment in OHPATcould still incur substantial cost that was underestimated inthis trial [35,36]. These results support the findings fromearlier studies comparing linezolid with vancomycin, whichshow that the oral formulation of linezolid can facilitateearly hospital discharge[17,19,22]and shorten LOS[20].The results on the OHPAT effect are also consistent with thefindings from earlier studies[7,21].

The potential linezolid effect on reducing LOS and costof treatment was likely due to its 100% bioavailable oral for-

mulation, which allows patients to be discharged while con-tinuing treatment on the same drug. This is supported by thelinezolid group’s shorter IV duration and potentially shorterLOS and lower cost in this trial, especially for patients withno access to OHPAT. Studies have documented the benefitsof IV to oral sequential antibiotic therapy, which includesthe reduction in IV-line related secondary infections, LOSand total cost of treatment[20,37–43]. Such an oral optionwas not available in the teicoplanin arm although we recog-nise that in clinical practice an oral alternative such as fu-sidic acid or trimethoprim or minocycline with or withoutrifampicin could be used for this purpose. However, someclinicians would not deem these agents appropriate for oraltherapy of serious infections[22].

Traditionally, economic consideration of antibiotic ther-apy has been focused on the acquisition cost of antibiotics.While this may be more appropriate for outpatient infec-tions, as antibiotic cost accounts for a majority of the totalcost of treatment, economic considerations for the treatmentof more serious infections, which is often initiated in hospi-tal settings, must take into account the cost of more expen-sive hospital resource use in addition to the cost of antibioticdrug acquisition, preparation and administration[44]. Eco-nomic analysis results from this trial, and in another trial inthe UK[45], demonstrated that the total cost of treatment ofa less expensive antibiotic might not always be lower whenall cost elements are taken into account.

The lack of statistical significance in key components ofthe analysis reflects some limitations of this study. The firstlimitation is the fact that we are using randomised clinicaltrial data for an economic analysis. Similar to most clin-ical trials, the sample size of the trial was optimised forclinical outcome assessment; the analysis of economic out-comes was inherently underpowered. Furthermore, restric-tions in clinical trial protocols also introduce the ’lack ofreality’ bias into the assessment of economic endpoints. Forexample, patients in such trials are more likely to remain inhospital longer, receive treatment for longer and patient se-lection may not be typical of the everyday setting. Anotherreason might have been the reluctance of clinicians to dis-charge patients out of hospital after they were switched tooral therapy, either to allow a period of observation for clini-cal stability or for non-infection (e.g. social) related reasons[41,46]. The second limitation is that retrospective analy-sis of subgroups makes clear statistical conclusions difficultand suggests the need for further confirmation. Another lim-itation was introduced by the need to incorporate resourcedata from many countries with diverse healthcare fiscal sys-tems. The significant differences in cost reported betweenthe two continents are a clear indication of this variance.Additionally, the study period of up to 49 days may not havepicked up the small number of patients who failed initialantibiotic treatment and who needed to be treated for longerthan this period. As we were unable to identify a specificresource for infection treatment such differences were notpossible to detect. On the other hand, one may argue that a

D. Nathwani et al. / International Journal of Antimicrobial Agents 23 (2004) 315–324 323

49-day study period is probably a reasonable time frame toexamine the main impact these few patients had on the to-tal cost of treatment for a particular treatment arm. Lastly,the greater than usual proportion of patients who had ac-cess to OHPAT may have made the between-treatment dif-ferences in resource utilisation and cost of treatment evensmaller.

Finally, as indicated in the introduction, we here providesome justifications to support the separation of the Euro-pean sample from the South American one in this analysis;results from the latter have been published elsewhere[25].Early exploration of the data suggested some major differ-ences between the two samples. These differences were notexpected to alter efficacy and safety comparisons materi-ally; however, the same cannot be said for LOS and costresults. For example, in this trial, we found that mean LOSwas 16.9 days for patients enrolled from European countriesbut it was only 11.0 days for the South American patients(P = 0.008). Furthermore, we found that the mean total costof treatment was about three times as high for the Europeanpatients as that for the South American patients (US$ 9766versus US$ 3336,P < 0.0001). In addition, we also foundthat there were differences in many of the baseline variablesbetween European and South American patients, includingage (40% versus 23% of age 65 and over), gender (40% ver-sus 52% of females), race (97% versus 35% being white),sites of primary infection (less pneumonia [19% versus 36%]but more bacteraemia [26% versus 3%] among Europeanpatients), inpatient location at enrolment (11% versus 6%from the ICU) and number of co-morbidities (58% versus44% with 2 or more). Given all the above differences, therewas a clear need to analyse the resource use and cost dataseparately for the two regions. While it is possible to do amore rigorous economic analysis on the whole sample, inwhich the cross-continent differences can be taken into ac-count, such analysis is much more complex and thereforebeyond the scope of the paper.

In this study of linezolid versus teicoplanin for thetreatment of serious Gram-positive infections among anEuropean cohort of 227 hospitalised patients, we foundthat patients treated with linezolid had shorter IV antibiotictreatment duration than patients treated with teicoplanin.Certain baseline patient demographic and clinical character-istics, particularly the inpatient location at enrolment, hadsubstantial effects on LOS and cost of treatment. Presenceof OHPAT also appeared to reduce LOS and cost. Therewas also a difference between the two treatment groups inthe proportion of patients enrolled from the ICU and fromhospitals with OHPAT presence, which biased the simple re-source use and cost comparisons between treatments. Afteradjusting for these and other baseline variables, the resultsshowed a trend towards higher likelihood of early hospitaldischarges and lower total costs of treatment for the linezolidgroup. The potential of linezolid’s cost-saving in this trialsetting appears to be greater among patients with no access toOHPAT.

Acknowledgements

This study was funded by Pharmacia Corp., now part ofPfizer Inc.

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