1 Department of Clinical Microbiology, 5 Pharmacy Department, University College London Hospitals, Grafton Way, London WC1E 6DB; 2 Bloomsbury Institute of Intensive Care Medicine, Department of Medicine, UCL, London; 3 Department of Medical Microbiology, 4 Intensive Care Unit, Royal Free Hospital, London, UK
Received 8 May 2003; returned 3 October 2003; revised 3 November 2003; accepted 4 November 2003
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Abstract |
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Methods: Using a double-blind, double-dummy, prospective design, patients were randomized to (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy [one dose/12 h for three doses then every 24 h intravenously (iv)] or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv). Other antibiotics were used in combination with the trial agents in empirical treatment. Clinical and microbiological assessments were made daily in the first week, and at 8 and 21 days after treatment.
Results: One hundred patients received linezolid plus placeboteicoplanin, whereas 102 received teicoplanin plus placebolinezolid. Population baseline characteristics were similar in both groups. At end of treatment, clinical success [71 (78.9%) linezolid versus 67 (72.8%) teicoplanin] and microbiological success [49 (70.0%) versus 45 (66.2%)] rates were similar, as were adverse effects, intensive care unit mortality, and success rates at short- and long-term follow-up. Linezolid was superior at initial clearance of methicillin-resistant Staphylococcus aureus (MRSA) colonization (end of treatment, 51.1% versus 18.6%, P = 0.002). Two MRSA isolates showed reduced susceptibility to teicoplanin.
Conclusions: Linezolid has similar safety and efficacy to teicoplanin in treating Gram-positive infections in the critically ill. Short-term MRSA clearance achieved with linezolid suggests better skin and mucosal penetration.
Keywords: bloodstream infections, methicillin-resistant Staphylococcus aureus, MRSA, methicillin-susceptible Staphylococcus aureus, MSSA
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Introduction |
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Infections caused by Gram-positive organisms have increased steadily in the last decade and are now the commonest cause of hospital sepsis.5 Of concern is the increasing resistance of these Gram-positive organisms to first- and second-line antimicrobial agents.68 The proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolated from blood cultures taken in England and Wales increased from 1% in 1993 to 42% in 2001.9,10 This high rate of MRSA is reflected in many other countries: for example >50% in the USA and >70% in Japan.1113 Developing staphylococcal resistance to glycopeptides has also been reported.14 Enterococci are another common cause of nosocomial bloodstream infection and are also showing increasing resistance to vancomycin. In one study, vancomycin-resistant enterococci (VRE) accounted for 14.5% of all enterococcal bloodstream infections.15
Antibiotic resistance is thus an evolving problem with highly complex dynamics and is associated with appreciable effects on morbidity, mortality and hospital stay.16 With fewer effective therapeutic options available, intractable infection may soon become a commonplace finding with serious consequences.
Linezolid is the only commercially available oxazolidinone, the first new class of antibiotic to be developed in the last three decades. It binds to the 50S subunit on the bacterial ribosome producing an early inhibition of protein synthesis.17 Although it is predominantly bacteriostatic, linezolid has good in vitro and in vivo activity against a variety of Gram-positive organisms including methicillin-susceptible (MSSA) and -resistant (MRSA) S. aureus, coagulase-negative staphylococci (CoNS) and VRE.18,19
Several clinical trials of linezolid have been published;2022 however, its efficacy and safety in a critically ill patient population have been less well reported.23 Side effects such as thrombocytopenia24 and monoamine-oxidase inhibition (MAOI) interactions could be more likely in a sick population receiving numerous concomitant medications including sympathomimetics and dopaminergic drugs.
We thus conducted a randomized, double-blind, prospective study comparing linezolid with our standard glycopeptide (teicoplanin) in the treatment of suspected or proven Gram-positive infections in critically ill patients in two mixed medicalsurgical, tertiary referral ICUs. To our knowledge, the double-dummy design is the first such implementation in an ICU antibiotic study.
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Materials and methods |
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This randomized, double-blind, double-dummy trial was performed during June 2000December 2001 on the two intensive care units of the University College London Hospitals (UCLH) (18 and four beds) and the Royal Free Hospital (RFH) (10 beds) using separate randomization schedules generated by an independent statistician. There were 1378 admissions over the year of the study at UCLH, of whom 237 (17.1%) died, and 555 at RFH, of whom 153 (27.6%) died. The median length of stay was 2 days (0120 days) at UCLH and 3 days (392 days) at RFH.
Ethical conduct of the study
Approval was obtained from the Ethics Committees of both hospitals, and the study was designed to be consistent with Good Clinical Practice guidelines. Before inclusion in the trial, comprehensive information regarding the trial objectives and procedures were provided to the patient or their next of kin. Agreement to participate was obtained from the patient (if mentally competent), otherwise it was sought from the family.
Patient selection
Patients with known or suspected Gram-positive infection were included. Infection caused by MSSA and MRSA, enterococci (including VRE) and CoNS were all eligible. Patients were enrolled if they met all of the following criteria: at least 16 years of age and 40 kg weight; expected survival with effective antibiotic therapy and supportive care; willingness to complete all study-related activities; and known or suspected Gram-positive infection for which treatment with a glycopeptide was clinically indicated.
Each patient required at least two of the following: fever (body temperature 38°C orally or
39.5°C rectally), or hypothermia (body temperature
35.5°C taken rectally); respiratory rate >30 breaths/min; systolic hypotension (systolic blood pressure <90 mmHg); heart rate >120 beats/min; PaO2 < 8 kPa (60 torr) on air or PaCO2 > 6.3 kPa (47 torr) on air; necessity for mechanical ventilation; elevated peripheral white cell count (WBC) >10 000/mm3; >15% immature neutrophils regardless of total peripheral WBC, or leukopenia with total WBC <4500 cells/mm3.
For the clinical syndromes below, the following enrolment criteria were required:
Nosocomial pneumonia. Symptoms starting after more than 48 h of hospitalization, with at least two of the following: purulent sputum or change in character; auscultatory findings consistent with pneumonia, dyspnoea, tachypnoea >30 breaths/min or hypoxaemia (PaO2 < 8 kPa [60 torr]); chest X-ray at baseline or within 48 h of initiation of treatment consistent with pneumonia.
Skin and soft tissue infection (SSTI). Severe skin infection involving deeper levels (fascia, muscle) or extensive skin areas. Signs and symptoms include at least two of the following: drainage/discharge; erythema; fluctuance; heat/localized warmth; pain/tenderness to palpation or swelling/induration. A skin infection was considered severe if the patient also had one or more of the following: fever; leukocytosis; extensive or deep soft tissue infection such as major abscess, ulcer, burn or cellulitis.
Gram-positive bloodstream infection. Patients with bloodstream infection plus the Sepsis Syndrome, as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee.25 Any central venous catheter in place at the onset of symptoms to be removed and replaced, if necessary.
Osteomyelitis or septic arthritis. Evidence from histological examination of surgical specimens of bone, synovium or synovial fluid, or a positive Gram stain, or positive culture of bone biopsy or synovial fluid.
Patients meeting any of the following criteria were excluded, as defined in the original protocol: pathogen resistant to either of the trial antibiotics before enrolment (if such a pathogen was isolated after treatment was commenced, the patient was continued in the trial unless clinical deterioration occurred); female patients either pregnant or breast feeding; central nervous system (CNS) infections; infected devices that could not be removed; known phaeochromocytoma, carcinoid syndrome, untreated hyperthyroidism or uncontrolled hypertension; previous enrolment in this study; known hypersensitivity to linezolid or teicoplanin; treatment for longer than 24 h with a potentially effective antibiotic within 48 h of study entry, unless this therapy failed; concurrent use of another investigational medication; patients with infections that could require more than 28 days of treatment; endocarditis; known or suspected pulmonary conditions likely to preclude evaluation of therapeutic response; if HIV infected, CD4 cell count <200 cells/mm3.
Randomization. On enrolment patients were randomized 1:1 in blocks of 10 to one of the two treatment arms according to a pre-prepared computer-generated randomization schedule.
Power calculations A difference of 20% in the microbiological efficacy of the two antibiotics would justify the use of one over the other. If 100 patients were recruited successfully into each group, there would be an 80% chance of detecting as significant (at the two-sided 5% level) a difference in efficacy of 61% versus 82% for eradication of an organism, assuming 20% would not be microbiologically evaluable. Given the high mortality and likelihood of complications from underlying disease in these critically ill patients, clinical evaluability was expected to be more difficult to establish, and less likely to provide a statistical endpoint.
Treatment schedule. Treatment was planned to be at least 3 days and at most 28 days. Resolution of symptoms and signs for at least 24 h was the expected minimum indication to stop treatment after 3 days. Patients were randomized to receive either: (i) intravenous linezolid (600 mg/12 h) plus teicoplanin dummy (one dose/12 h for three doses then every 24 h iv) or (ii) teicoplanin (400 mg/12 h for three doses then 400 mg/24 h iv) plus linezolid dummy (one dose/12 h iv).
Teicoplanin (or teicoplanin dummy) dosage was modified in renal failure as per manufacturers guidance; for obese patients (>100 kg), the dose of teicoplanin (or placebo) was given at 6 mg/kg, and for septic arthritis or deep-seated sepsis each dose was increased to 800 mg (or 12 mg/kg). The placebo dummies were prepared by the local pharmacies of both hospitals and were identical in appearance to the active antibiotic. The two hospitals operated on separate schedules, and the codes were maintained on a password-secure database. Investigators and patients were blinded to the active agent used.
Concomitant antibiotic therapy was allowed to cover suspected or proven Gram-negative organisms (gentamicin, amikacin, ciprofloxacin, ceftazidime, imipenem or meropenem), atypical pathogens (erythromycin or clarithromycin) or anaerobes (metronidazole). Trimethoprim/sulfamethoxazole was only allowed for long-term prophylaxis or treatment of Pneumocystis pneumonia. Antifungals and anthelmintics were prescribed as necessary.
Clinical assessment. After obtaining agreement to participate and before initiation of any of the trial antibiotics, a baseline history and physical examination were performed and laboratory tests taken as required. The Acute Physiology and Chronic Health Evaluation score (APACHE II)26 was recorded on entry to the study. The Sequential Organ Failure Assessment (SOFA)27 and Therapeutic Intervention Scoring System (TISS) scores28 were calculated daily during days 15, then every 6 days thereafter while on therapy, and at the time of follow-up.
Microbiological assessment. Before starting antibiotic therapy, relevant specimens e.g. blood, wound discharge, sputum, bronchial aspirates, pleural or ascitic fluid were collected for Gram stain and susceptibility testing. If a culture result was available within 2 days of the time of enrolment, this was used as the defining Gram-positive infection. Screening for carriage of MRSA and MSSA was conducted using pooled swabs from nose and groin. Screening swabs were all inoculated onto one plate containing mannitol salt agar (with oxacillin) (Oxoid) and into nutrient broth with salt (2.5% with aztreonam 75 mg/L, and 7.5%). After overnight incubation at 37°C, the salt broths were subcultured onto mannitol salt agar (without oxacillin). Suspect colonies on the original plate were identified at 24 and 48 h, subcultured to a blood agar plate with an oxacillin disc and incubated at 30°C overnight. The salt broth subculture was incubated for a further 24 h and re-examined on day 4. Intermediate oxacillin results were confirmed with an oxacillin Etest (AB Biodisk, Solna, Sweden).
Fine-needle aspiration or biopsy of the closed lesions of cellulitis was employed to obtain specimens for culture, if clinically required. Repeat cultures (e.g. sputum, blood) were obtained 4872 h after initiation of therapy, at the end of treatment, and on days 8 and 21 if a specimen was available. If intravenous catheters were removed as a possible source of infection, the tip of the catheter was cultured using the semi-quantitative culture method of Maki et al.29 Isolates were tested for susceptibility to linezolid and teicoplanin by disc (BSAC method) and Etest (AB Biodisk, Solna, Sweden). Breakpoints used for Etest were 4 mg/L for linezolid and 8 mg/L for teicoplanin, as recommended by the manufacturer. All isolates with a provisional identity of MRSA or MSSA were phage typed at the Laboratory of Hospital Infection, CPHL, Colindale, UK (Drs B. Cookson and T. Pitt).
Efficacy assessments. Clinical assessments were recorded on days 15, then every 6 days up to and including the end of treatment, with additional assessments at days 8 (range 714, short-term) and 21 (range 2030, long-term) after completion of treatment. The primary efficacy variable was microbiological outcome. Secondary efficacy variables included clinical outcome, clearance of MRSA carriage and individual pathogen results.
Definitions of clinical and microbiological outcomes are shown in the Appendix.
Adverse events. An adverse event was defined as an event not present before beginning study medication (or, if present before study onset, an event which increases in intensity), which was considered related to the study medication, or became serious during the follow-up phase of the study. Biochemical and haematological data were scrutinized regularly during and after the treatment for new or worsening abnormalities.
Statistical analysis
All data analysis of primary and secondary outcome measures was carried out according to a pre-established analysis plan. Primary efficacy variables were analysed for an intent-to-treat (ITT) group of patients. Analyses of primary and secondary efficacy variables were also performed for a modified intent-to-treat (MITT) group of patients. The ITT population was defined in the original protocol as all randomized patients who received at least one dose of study medication, whereas the MITT population was defined as the subset of the ITT population who had a pathogen isolated at baseline. Subgroup analyses of the primary efficacy variables were performed for selected diagnostic groups and for patients who received an adjunctive antibiotic. Analyses of safety variables were performed on all patients who received at least one dose of study medication. In addition to the pre-specified analysis, exploratory analysis of other variables was performed (fall in temperature during treatment, rate of change in SOFA score, length of stay in ICU).
For the primary and categorical secondary efficacy variables, confidence intervals (CI) for the differences in success rates between the linezolid and teicoplanin groups for each diagnosis were calculated based on a normal approximation to the binomial distribution.
Hypothesis tests used Students t-test for normally distributed variables; the two-sample Wilcoxon rank-sum (MannWhitney) test for skewed distributions; and Fishers exact test for homogeneity of proportions for categorical data.
In addition to comparing changes in temperatures and SOFA scores between baseline and end of treatment across treatment groups, changes in both variables during the first 5 days of treatment were analysed with a repeated measure model. Gaussian and overdispersed Poisson models were used, with a first order autoregressive correlation structure. Models were estimated using the generalized estimating equation approach.30 Patients undergoing haemofiltration were excluded from the analysis of temperature data for which the maximum daily temperature was used in the analysis. Mortality in the two groups was assessed with KaplanMeier survival estimates, using the log rank test for equality of survivor functions.
All statistical tests used were two-sided. P values < 0.05 were considered statistically significant. All statistical analyses were performed using Stata 7.0 (Stata Corporation, College Station, Texas, USA).
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Results |
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Baseline characteristics. Baseline demographic characteristics were similar in the two groups. There were fewer known and more suspected Gram-positive infections in the teicoplanin group (see Tables 1 and 2).
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Concomitant antibiotic therapy (Table 4)
In 49 (49.0%) linezolid and 59 (57.8%) teicoplanin patients, Gram-negative antibiotic cover was started during the pre-treatment period (±24 h of administration of the first dose of trial antibiotic) (P = 0.26). In six linezolid and five teicoplanin patients, Gram-negative antibiotic cover was added after 48 h (P = 0.77). Ceftazidime, ciprofloxacin and meropenem were the three most frequently used antibiotics. The choice of antibiotics in each group was similar. Two patients in the linezolid group had gentamicin introduced after the trial antibiotic was commenced in view of the severity of Gram-positive infection.
A total of nine (9.0%) patients in the linezolid group and 13 (12.7%) in the teicoplanin group were treated for known or suspected fungal infection. Liposomal amphotericin (n = 8), conventional amphotericin (n = 1) and fluconazole (n = 16) were used, three patients having two agents.
Duration of treatment. Length of treatment in the ITT population was similar for both groups with a median (range) of 8 (124) versus 7.5 (121) days for linezolid and teicoplanin, respectively (P = 0.36).
Efficacy rates. Efficacy was assessed clinically and microbiologically for both groups according to the above definitions of success/failure (see Figures 2 and 3).
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Clinical success at the end of treatment was achieved in 71/90 (78.9%) linezolid and 67/92 (72.8%) teicoplanin patients [P = 0.39, with 95% CI for difference in efficacy 0.063, 0.185]. For 10 patients in each group the clinical outcome could not be determined and thus cannot be included under the original protocol, but would result in overall rates of clinical success of 67.8% versus 62.0%.
In 91 patients either the trial drug alone was used, or concomitant antibiotics were unlikely to have had any activity against the pathogen implicated (e.g. ceftazidime, metronidazole). In these patients, there was no significant difference in efficacy between linezolid and teicoplanin [34/51 (67%) versus 24/40 (60%), P = 0.52, 95% CI 0.133, 0.266]. Likewise, there was no significant difference in outcome in the remaining patients in whom concomitant antibiotics potentially may have had some Gram-positive activity, e.g. carbapenems, ciprofloxacin, gentamicin [32/49 (65%) versus 39/64 (61%), P = 0.70, 95% CI 0.135, 0.223]. Outcome was also similar when individual antibiotic combinations and pathogens were examined.
Documented or presumed microbiological eradication of the baseline pathogen was achieved in 49/70 (70.0%) linezolid and 45/68 (66.2%) teicoplanin recipients (P = 0.72, 95% CI 0.117, 0.194) (Figure 3).
Eighty-one linezolid and 73 teicoplanin patients had known baseline pathogens. Clinical outcomes were indeterminate in six and four of these patients, respectively. Clinical success was achieved in 61/75 (81.3%) linezolid and 54/69 (78.3%) teicoplanin patients (P = 0.68, 95% CI 0.101, 0.162). The microbiological outcome of this culture-positive group was success in 44/61 (72.1%) microbiologically evaluable linezolid patients and 38/55 (69.1%) teicoplanin patients (P = 0.84, 95% CI 0.136, 0.196). Clinical and microbiological outcomes were similar in both groups at follow-up assessment days 8 and 21. There was no significant difference in clinical or microbiological outcomes in those patients treated for microbiologically confirmed MRSA infections. Superinfection with Gram-negative organisms occurred in two linezolid and four teicoplanin patients.
Patients with clinical failure in the linezolid (n = 19) and teicoplanin (n = 24) groups were similar with respect to age (median 67 years, range 2084 versus 56 years, 1780), and sex (males:females, 16:3 versus 18:6) and had high (>15) entry APACHE scores [15 (79%) versus 17 (71%)]. The most common infections treated were lower respiratory tract infection (nine versus 15) and wound infection (four versus two). The causative organisms were MRSA (eight versus seven), MSSA (two versus three), CoNS (two versus three) and enterococci (two versus one).
There was no significant difference in medical resource use between the groups in terms of outcome, length of hospital stay or interventions related to infection.
Efficacy rates for bloodstream infection. Twenty-four linezolid and 35 teicoplanin patients had bacteraemia at the time of enrolment. Clinical success was achieved in 18/22 (81.8%) clinically evaluable linezolid patients, and 26/32 (81.3%) evaluable teicoplanin patients (P = 1.00, 95% CI 0.205, 0.216). Clinical outcome was indeterminate in two and three cases, respectively, because the patient died within 72 h of starting treatment (n = 2) or was removed from the study (n= 3) due to rash (n = 1) or withdrawal of family or clinician agreement (n = 2). Microbiological efficacy was also similar, i.e. in 15/19 (78.9%) linezolid and 17/27 (63.0%) teicoplanin (P = 0.34, 95% CI 0.986, 0.418) patients. Five linezolid and eight teicoplanin patients were not microbiologically evaluable due to death (2, 3), withdrawal from the study (2, 2), pathogen resistance (teicoplanin, 1 VRE) or superinfection (1, 2) (see Table 5).
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Other efficacy variables. In the ITT population, length of stay in the ICU after trial entry [median (range)] was 9 (054) days for the linezolid group and 9 (0105) days for the teicoplanin patients (P = 0.30). The mean (S.E.M.) drop in temperature between baseline and end of treatment amongst patients with fever was 1.24°C (0.15) for linezolid versus 1.08°C (0.14) for teicoplanin [95% CI for difference in change of temperature between treatment groups 0.570, 0.260, P = 0.46 (fever defined by baseline temperature 38°C, linezolid n = 43, teicoplanin n = 44)]. Changes in SOFA score [median (range) of end of treatmentbaseline] were also similar: 0 (8/+8) for linezolid versus 1 (12/+9) for teicoplanin (P = 0.36). Repeated measures analysis found equivalent rates of decline in temperatures in both groups. Similarly, repeated measures analysis found no evidence that treatment influenced SOFA scores, whether for all patients with at least three equally spaced SOFA scores, for the subgroup of patients alive at end of treatment or for patients not alive at end of treatment.
Mortality. At the end of treatment in the ITT population, there were 18 (18.0%) deaths in the linezolid group and 25 (24.5%) in the teicoplanin group (P = 0.3). Cause of death was usually multifactorial, but Gram-positive sepsis clearly contributed in five and eight deaths, respectively. Short- and long-term follow-up mortality rates were also similar, with 34/99 (34.3%) versus 35/101 (34.7%) deaths, and 42/94 (44.7%) versus 41/97 (42.3%) for linezolid and teicoplanin, respectively. One patient from each group was lost to short-term follow-up, and six and five were lost to long-term follow-up in the linezolid and teicoplanin groups, respectively. No significant differences were seen in the KaplanMeier survival estimates (P = 0.92).
MRSA eradication rates. In the linezolid and teicoplanin groups, 45 and 43 patients were colonized with MRSA at the time of enrolment. MRSA clearance at the end of treatment occurred in 23 (51.1%) linezolid versus eight (18.6%) teicoplanin (P = 0.002, 95% CI 0.138, 0.512). Eleven of these patients had no subsequent samples. At follow-up this difference was less marked [at 7 days: 12/34 (35.3%) versus 4/29 (13.8%) were cleared, (P= 0.08, 95% CI 0.011, 0.419), and at 21 days 3/16 (19%) versus 5/15 (33%), (P= 0.43, 95% CI 0.452, 0.160)]. In eight patients who were apparently clear at the end of treatment, colonization was again detected by day 7; on only one occasion was a different MRSA phage type found. Two patients who were clear at 7 days were re-colonized by 21 days (one similar phage type, one different). Colonization status was unknown (lack or loss of sample) in 16 linezolid and 19 teicoplanin patients at the end of treatment.
Drug-related adverse events and laboratory abnormalities
Both antibiotics were well tolerated. No significant differences were seen between groups. Two clusters of cases of Clostridium difficile and viral diarrhoea were attributed to small outbreaks rather than trial-related events. C difficile was sporadic except for two instances of possible cross infection in pairs of patients. All but one patient in the linezolid group received other antibiotics. There were no cases of thrombocytopenia that could be attributed to either drug. Hypertension associated with administration of linezolid was not seen, either in patients with or without concurrent inotrope support therapy (see Table 6).
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Discussion |
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Previous trials have evaluated linezolid in the treatment of nosocomial pneumonia; the reported clinical success rates were 66.4% and 67.9%, with microbiological eradication rates of 68.1% and 61.8%, respectively.31,32 A study of hospital-acquired Gram-positive infections reported an overall cure rate of 95.5% (linezolid), significantly better than the comparator drug 87.6% (teicoplanin). In this study, success rates for SSTI, pneumonia and bloodstream infection were 96.6%, 96.2% and 88.5%, respectively.33
The use of other antibiotics in our study was restricted to patients with suspected or confirmed Gram-negative infections. Although these agents had some activity against Gram-positive organisms, they were evenly distributed in both treatment groups and are ineffective in the treatment of MRSA. Analysis by antibiotic combination did not alter the findings. Overall mortality was similar for both ITT groups at the end of treatment and at subsequent follow-up evaluations. The high mortality rates (42%) encountered at long-term follow-up reflect the characteristics of this severely ill, long-term ICU population. The subset of patients with known pathogens showed no difference in mortality between treatment groups. Adverse events were reported in 62% of patients, most being minor and short lived. The nature of the population dictated a high frequency of adverse events, although only a minority was felt to be potentially attributable to either drug.
Transient myelosuppression is a recognized adverse effect of linezolid, affecting 5% of patients on prolonged exposure (>14 days).24 We detected no cases of sustained thrombocytopenia (lasting more than 1 week), although this may reflect the relatively short courses of treatment used. Likewise, there is the potential for increased MAOI interactions with linezolid,34 especially as ICU patients are on multiple medications including catecholamines and sedative agents. However, no effects such as unexplained hypertension were observed in the 100 patients given linezolid, of whom 37 were receiving inotropes concurrently.
MRSA colonization frequently complicates the management of critically ill patients. It is the source for endogenous infection, environmental spread and cross-infection.35,36 In some cases, it will delay patient discharge, and increase costs,16,37 morbidity and mortality.38 Successful antibiotic treatment of systemic MRSA infections seldom leads to eradication of MRSA from carrier sites.39 Glycopeptides, the most common antibiotic type used to treat Gram-positive organisms in the ICU setting have poor soft tissue penetration,40 with a low clearance rate of carrier sites. All patients were screened systematically for MRSA carriage on ICU entry, once weekly during their ICU stay, and when clinically indicated. There was a significant reduction in MRSA carriage at the end of treatment in patients administered linezolid, but at short-term follow-up, colonization was again detected in some patients, usually with the same or similar strain. However, reduction of skin carriage of MRSA, even if temporary, might be expected to reduce the risk of transmission to other patients in the ICU and would perhaps allow earlier discharge to the general ward.41 This warrants further investigation.
There was no significant difference in ICU stay between the two groups in this study. The main advantage of linezolid in pharmacoeconomic terms is to allow earlier patient discharge on oral medication.33 However, this is not generally pertinent to a critically ill population. The earlier clearance of MRSA offers a potential cost saving in allowing earlier discharge to other wards, but was not demonstrated in a study of this size. Linezolid by intravenous or oral route costs £67/day (data provided by the manufacturer) compared with £38.30 for teicoplanin 400 mg/day.
The median course of treatment for both groups was 78 days. This, in our experience, is usually more than adequate for the majority of infections treated in the ICU, with minimal relapse or long-term complications such as endocarditis. There are no data available to guide optimal duration of therapy. A recent global study we conducted on bacteraemia management reflected this confusion, with a highly significant indirect correlation between microbiologist input and treatment duration.42
In conclusion, we found no evidence to suggest that linezolid differs from teicoplanin in safety or effectiveness in the treatment of Gram-positive infections in ICU. It is associated with greater short-term clearance of MRSA from colonization sites.
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Acknowledgements |
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Appendix |
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At the end of treatment, at short-term and long-term follow-up, all patients were assessed using the following criteria:
Cured. Resolution of clinical signs and symptoms of Gram-positive infection; improvement or lack of progression of infection-related radiographic abnormalities.
Improved. (Only evaluated at end of treatment.) Improvement in two or more, but not all, clinical signs and symptoms of Gram-positive infection, as compared with entry; improvement or lack of progression of infection-related radiographic abnormalities.
Failed. Persistence or progression of baseline clinical signs and symptoms of Gram-positive infection; progression of infection-related radiographic abnormalities; development of new clinical findings consistent with active infection.
Indeterminate. Circumstances precluding classification to one of the above (e.g. death, hospital discharge).
Clinical success was taken as cured or clinically improved. Patients classified as failures were carried forward from the end-of-treatment to short-term follow-up if no short-term follow-up data were available. Before a clinical assessment of success or failure was made, patients must have been treated for at least 2 or 3 days, respectively.
Microbiological outcomes
These were assessed using the following definitions:
Documented microbiological eradication. Absence of the original pathogen or pathogen(s) from culture of the original site of infection at the end of treatment.
Presumed microbiological eradication. Patient clinically cured at the end of treatment, but no appropriate material is available for culture from the original site of infection at the end of treatment.
Documented microbiological persistence. Presence of at least one of the original pathogens from the culture of the original site of infection at the end of treatment.
Presumed microbiological persistence. Patient deemed a clinical failure at the end of treatment but no appropriate material is available for culture from the original site of infection.
Recurrence. Isolation at (or before) the long-term follow-up visit from the original site of infection of at least one original pathogen that had been eradicated (documented or presumed) at the end of treatment.
Breakthrough infection. If a pathogen continues to be isolated from culture of the original site of infection while on trial therapy.
Superinfection. Pathogen isolated during therapy that differs from the original pathogen with concurrent signs of infection.
Colonization. Isolation of an organism other than that isolated at baseline in a patient classified as a clinical cure.
Indeterminate. Any patient not classified into one of the above categories.
Microbiological success was documented, or presumed eradication and failure was documented or presumed persistence.
Secondary outcome: clearance of MRSA carriage. Isolation of MRSA from screening cultures, sputum or wound on entry to the trial but absence at end of treatment and/or short-term follow-up.
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Footnotes |
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References |
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