In vitro susceptibility of Gram-positive pathogens to linezolid and teicoplanin and effect on outcome in critically ill patients.

OBJECTIVES: To determine the prevalence of teicoplanin and linezolid resistance amongst Gram-positive pathogens isolated in the intensive care unit (ICU) and the impact of any resistance on clinical outcome. METHODS: Gram-positive isolates were collected from two critical care units over 1 year. All patients were screened weekly for methicillin-resistant Staphylococcus aureus (MRSA). Susceptibility to teicoplanin and linezolid was tested by Etest. The length of hospital and critical care unit stay and the use of antibiotics in each patient were recorded. RESULTS: Reduced susceptibility to teicoplanin (MIC>or=16 mg/L) was found in 21 [3.3% (95% CI 2.0-5.0%) 6 patients] of 643 strains of MRSA versus none of 374 methicillin-susceptible S. aureus (MSSA) [<0.3% (95% CI 0-0.9%)]. Of 49 enterococci 3 were teicoplanin-resistant. All Gram-positive isolates were susceptible to linezolid. The length of treatment with teicoplanin and outcome of patients infected with these strains were similar to that of susceptible strains. MRSA was a more common cause of infection than MSSA but a less frequent colonizer. CONCLUSIONS: Resistance to teicoplanin remains at a comparatively low level and there was no clear relationship between susceptibility and outcome in this critically ill population. There was no resistance in Gram-positives to linezolid but this should be kept as a reserve antibiotic to maintain its activity.

Pharmacokinetic studies of linezolid and teicoplanin in the critically ill.

OBJECTIVES: To determine the pharmacokinetic characteristics of linezolid and teicoplanin in critically ill patients. PATIENTS AND METHODS: Serum was collected frequently during day 0 and then pre- and 1 h post-dose on days 1, 2, 3, 5, 7 and every third day thereafter during treatment. Serum linezolid concentrations were analysed using HPLC. Serum teicoplanin levels were analysed by fluorescence polarization immunoassay. RESULTS: A two-compartment model was required to characterize linezolid pharmacokinetics (n=28) and account for the accumulation seen after multiple dosing. The estimated clearance was 0.049 +/-0.016 L/h/kg (+/-s.e.m. of estimate). At steady state (dosing interval 12 h), linezolid serum concentrations exceeded the breakpoint of 4 mg/L for 10.88 h (95% CI 10.09-11.66) after a 600 mg dose with an AUC/MIC of 92.4 (95% CI 57.2-127.7). Teicoplanin was best described by a two-compartment model (n=26). The clearance was 4.97+/-1.58 L/h. Serum levels exceeded the breakpoint of 4 mg/L for the entire dosing interval in all subjects (400 mg dose every 12 h) with an AUC/MIC of 399.3 (95% CI 329.6-469.0). However, only four of 14 exceeded trough serum concentrations of 10 mg/L. For both agents, trough levels were similar in those who survived and those who died. CONCLUSIONS: Linezolid dosage at 600 mg every 12 h was adequate in the critically ill without need for adjustment for renal function. For teicoplanin, further study is needed to confirm if a trough of 10 mg/L is associated with a higher rate of cure than 5 mg/L. If so, serum drug assays would be needed to ensure a therapeutic level.

Isolation of patients in single rooms or cohorts to reduce spread of MRSA in intensive-care units: prospective two-centre study.

BACKGROUND: Hospital-acquired infection due to meticillin-resistant Staphylococcus aureus (MRSA) is common within intensive-care units. Single room or cohort isolation of infected or colonised patients is used to reduce spread, but its benefit over and above other contact precautions is not known. We aimed to assess the effectiveness of moving versus not moving infected or colonised patients in intensive-care units to prevent transmission of MRSA. METHODS: We undertook a prospective 1-year study in the intensive-care units of two teaching hospitals. Admission and weekly screens were used to ascertain the incidence of MRSA colonisation. In the middle 6 months, MRSA-positive patients were not moved to a single room or cohort nursed unless they were carrying other multiresistant or notifiable pathogens. Standard precautions were practised throughout. Hand hygiene was encouraged and compliance audited. FINDINGS: Patients' characteristics and MRSA acquisition rates were similar in the periods when patients were moved and not moved. The crude (unadjusted) Cox proportional-hazards model showed no evidence of increased transmission during the non-move phase (0.73 [95% CI 0.49-1.10], p=0.94 one-sided). There were no changes in transmission of any particular strain of MRSA nor in handwashing frequency between management phases. INTERPRETATION: Moving MRSA-positive patients into single rooms or cohorted bays does not reduce crossinfection. Because transfer and isolation of critically ill patients in single rooms carries potential risks, our findings suggest that re-evaluation of isolation policies is required in intensive-care units where MRSA is endemic, and that more effective means of preventing spread of MRSA in such settings need to be found.

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study.

OBJECTIVES: Linezolid, the only commercially available oxazolidinone, is indicated for the treatment of Gram-positive infections, although little has been published specifically on its use in the critically ill. A randomized, prospective study was therefore performed to compare linezolid with the glycopeptide antibiotic, teicoplanin, for the treatment of suspected or proven Gram-positive infections in an intensive care population. 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 placebo-teicoplanin, whereas 102 received teicoplanin plus placebo-linezolid. 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.