Linezolid Treatment Research Articles

Successful Treatment of Chronic Bone and Joint Infections with Oral Linezolid

Linezolid is an attractive alternative for the treatment of chronic bone and joint infections because it is active against common pathogens including methicillin-resistant staphylococci and vancomycin-resistant enterococci and because its oral formulation is convenient for long-term administration. To evaluate the ability of linezolid to produce long-term remission, we prospectively monitored 11 consecutive adult patients who received linezolid for osteomyelitis (n = 9) or prosthetic joint infection (n = 2). Linezolid 600 mg was administered orally twice daily for a mean of 10 weeks (range, 6 to 19 weeks). Pathogens were methicillin-resistant Staphylococcus aureus (n = 5), methicillin-resistant coagulase-negative staphylococci (n = 4), vancomycin-resistant Enterococcus faecium (n = 1), and vancomycin-sensitive Enterococcus faecalis (n = 1). After a mean followup of 27 months (range, 17 to 41 months), all 11 patients had remission by clinical, laboratory, and radiographic criteria. During week 8 of linezolid treatment, one patient developed a gram-negative superinfection, which resolved with appropriate therapy. During week 6 of linezolid treatment, one patient developed mild thrombocytopenia and another patient developed mild anemia. Both episodes of myelosuppression were reversible within 10 days after completing the planned 6-week courses of linezolid. We recommend weekly complete blood counts to detect hematologic abnormalities. We conclude that oral linezolid seems to be a useful and convenient alternative for the treatment of bone and joint infections.

Capnocytophaga spp. Brain Abscess in an Immunocompetent Host: Problems in Antimicrobial Chemotherapy and Literature Review

The fourth case report of a brain abscess due to the fastidious Gram-negative organism Capnocytophaga spp. is described and discussed on the grounds of clinical, microbiological, and therapeutic evidence. A probable origin from a cat bite and/or an underlying severe mandibulary granuloma is suspected. Due to lack of clinical and neuroradiological response to neurosurgery and a combination of imipenem-amikacin-clindamycin-fluconazole, second-line empiric linezolid treatment proved rapidly successful, in the absence of further microbial isolations. In vitro antimicrobial susceptibility testing is often unpredictable for Capnocytophaga spp., and agents usually active on Gram-positive organisms may also be effective, both in vitro and in vivo. Due to its favorable brain penetration and its dual mode of administration, linezolid may be an alternative option for patients with multiple risk factors, brain abscess of suspected polymicrobial origin, and lack of response to empiric or culture-driven therapeutic attempts.

Linezolid Therapy for Orthopedic Infections

OBJECTIVE To assess the clinical and bacteriological efficacy and the safety and tolerability profile of linezolid when used as the primary component of a combined surgical and antimicrobial treatment strategy for orthopedic infections. PATIENTS AND METHODS We retrospectively reviewed medical records to obtain clinical, bacteriological, and safety outcomes of 20 consecutive patients who took linezolid for the treatment of orthopedic infections between April 1, 2000, and November 30, 2002. RESULTS Twenty patients received linezolid therapy for microbiologically confirmed orthopedic infections due to gram-positive cocci during the 32-month study period. Fifteen patients (75%) had infections involving orthopedic hardware; in 10 of these patients, the hardware was removed. All 20 patients underwent surgical débridement. At a mean follow-up of 276 days, 11 patients (55%) achieved clinical cure, 7 (35%) had clinical improvement but received long-term antimicrobial suppressive therapy, 1 (5%) had clinical relapse after discontinuing linezolid treatment, and 1 (5%) died of a cause unrelated to linezolid treatment. Bacterial persistence was documented in 3 patients (15%), all of whom were infected with methicillin-resistant Staphylococcus aureus. Eight patients (40%) developed reversible myelosuppression, 1 (5%) had irreversible peripheral neuropathy, and 2 (10%) discontinued linezolid treatment because of pancytopenia or urticaria. CONCLUSION Oral linezolid may be an effective alternative therapy for orthopedic infections due to linezolid-susceptible gram-positive bacteria in patients who are unable to take other antimicrobial drugs because of drug allergy or intolerance or antimicrobial resistance. To assess the clinical and bacteriological efficacy and the safety and tolerability profile of linezolid when used as the primary component of a combined surgical and antimicrobial treatment strategy for orthopedic infections. We retrospectively reviewed medical records to obtain clinical, bacteriological, and safety outcomes of 20 consecutive patients who took linezolid for the treatment of orthopedic infections between April 1, 2000, and November 30, 2002. Twenty patients received linezolid therapy for microbiologically confirmed orthopedic infections due to gram-positive cocci during the 32-month study period. Fifteen patients (75%) had infections involving orthopedic hardware; in 10 of these patients, the hardware was removed. All 20 patients underwent surgical débridement. At a mean follow-up of 276 days, 11 patients (55%) achieved clinical cure, 7 (35%) had clinical improvement but received long-term antimicrobial suppressive therapy, 1 (5%) had clinical relapse after discontinuing linezolid treatment, and 1 (5%) died of a cause unrelated to linezolid treatment. Bacterial persistence was documented in 3 patients (15%), all of whom were infected with methicillin-resistant Staphylococcus aureus. Eight patients (40%) developed reversible myelosuppression, 1 (5%) had irreversible peripheral neuropathy, and 2 (10%) discontinued linezolid treatment because of pancytopenia or urticaria. Oral linezolid may be an effective alternative therapy for orthopedic infections due to linezolid-susceptible gram-positive bacteria in patients who are unable to take other antimicrobial drugs because of drug allergy or intolerance or antimicrobial resistance.

Linezolid Therapy for Orthopedic Infections

To assess the clinical and bacteriological efficacy and the safety and tolerability profile of linezolid when used as the primary component of a combined surgical and antimicrobial treatment strategy for orthopedic infections. We retrospectively reviewed medical records to obtain clinical, bacteriological, and safety outcomes of 20 consecutive patients who took linezolid for the treatment of orthopedic infections between April 1, 2000, and November 30, 2002. Twenty patients received linezolid therapy for microbiologically confirmed orthopedic infections due to gram-positive cocci during the 32-month study period. Fifteen patients (75%) had infections involving orthopedic hardware; in 10 of these patients, the hardware was removed. All 20 patients underwent surgical débridement. At a mean follow-up of 276 days, 11 patients (55%) achieved clinical cure, 7 (35%) had clinical improvement but received long-term antimicrobial suppressive therapy, 1 (5%) had clinical relapse after discontinuing linezolid treatment, and 1 (5%) died of a cause unrelated to linezolid treatment. Bacterial persistence was documented in 3 patients (15%), all of whom were Infected with methicillin-resistant Staphylococcus aureus. Eight patients (40%) developed reversible myelosuppression, 1 (5%) had irreversible peripheral neuropathy, and 2 (10%) discontinued linezolid treatment because of pancytopenia or urticaria. Oral linezolid may be an effective alternative therapy for orthopedic infections due to linezolid-susceptible gram-positive bacteria in patients who are unable to take other antimicrobial drugs because of drug allergy or Intolerance or antimicrobial resistance.

Real-time monitoring of bacterial infection in vivo: development of bioluminescent staphylococcal foreign-body and deep-thigh-wound mouse infection models.

Staphylococcal infections associated with catheter and prosthetic implants are difficult to eradicate and often lead to chronic infections. Development of novel antibacterial therapies requires simple, reliable, and relevant models for infection. Using bioluminescent Staphylococcus aureus, we have adapted the existing foreign-body and deep-wound mouse models of staphylococcal infection to allow real-time monitoring of the bacterial colonization of catheters or tissues. This approach also enables kinetic measurements of bacterial growth and clearance in each infected animal. Persistence of infection was observed throughout the course of the study until termination of the experiment at day 16 in a deep-wound model and day 21 in the foreign-body model, providing sufficient time to test the effects of antibacterial compounds. The usefulness of both animal models was assessed by using linezolid as a test compound and comparing bioluminescent measurements to bacterial counts. In the foreign-body model, a three-dose antibiotic regimen (2, 5, and 24 h after infection) resulted in a decrease in both luminescence and bacterial counts recovered from the implant compared to those of the mock-treated infected mice. In addition, linezolid treatment prevented the formation of subcutaneous abscesses, although it did not completely resolve the infection. In the thigh model, the same treatment regimen resulted in complete resolution of the luminescent signal, which correlated with clearance of the bacteria from the thighs.

Safety and tolerability of linezolid.

Clinical trials have shown that linezolid (600 mg twice daily in adults) is safe and generally well tolerated for up to 28 days. Drug-related adverse events, which are typically mild to moderate in intensity and of limited duration, include diarrhoea, nausea and headache in adults, and diarrhoea, loose stools and vomiting in children. Clostridium difficile-related complications with linezolid are uncommon. Linezolid is a weak, reversible monoamine oxidase inhibitor: foods containing high concentrations of tyramine should be avoided, and linezolid should be used with caution in patients taking adrenergic or serotonergic agents or in those with uncontrolled hypertension. In the majority of patients, linezolid has minimal adverse effects on blood chemistry or haematology. There have been case reports of reversible thrombocytopenia, anaemia and neutropenia associated with linezolid therapy. In Phase III studies, 2.4% of patients treated with linezolid and 1.5% of patients treated with comparator drugs developed reversible thrombocytopenia (P = 0.066), but there was no evidence of an increased risk of agranulocytosis, aplastic anaemia or other irreversible blood dyscrasias. Reduced platelet counts were associated with linezolid treatment for >/=2 weeks; complete blood counts should be monitored weekly in patients receiving linezolid for more than 14 days and treatment should be discontinued if there is evidence of myelosuppression.

Pharmacology Review

Linezolid is an oxazolidinone antibiotic recently approved for treatment of infections due to antibiotic-resistant strains of Enterococcus faecium , Staphylococcus aureus, and Streptococcus pneumoniae. Because infections with these organisms, particularly vancomycin-resistant E faecium (VREF) and methicillin-resistant S aureus (MRSA), are becoming more common in critically ill neonates, linezolid is likely to play an increasingly important role in the antibiotic treatment of neonates who have antibiotic-resistant gram-positive infections. ### Mechanism of Action Oxazolidinone antibiotics, including linezolid, inhibit bacterial protein translation through a unique mechanism. Linezolid binds to the 23S subunit of the bacterial 50S ribosome. In doing so, the antibiotic blocks formation of the 70S translation initiation complex. Not surprisingly, nonclinical strains that have 23S rRNA mutations have shown linezolid resistance in vitro. ### Spectrum of Action Organisms against which linezolid has proven antibacterial efficacy include: E faecium (vancomycin-resistant strains only), S aureus (including methicillin-resistant strains), S agalactiae , S pneumoniae, and S pyogenes. Linezolid also shows in vitro activity against E faecalis (including vancomycin-resistant strains), E faecium (vancomycin-susceptible strains), S epidermidis (including methicillin-resistant strains), S haemolyticus , S pneumonia (penicillin-resistant strains), viridans-group streptococci, and Pasteurella multocida. In general, linezolid is bacteriostatic for staphylococci and enterococci, but is bactericidal for streptococci. Linezolid has activity against methicillin-sensitive and -resistant strains of S aureus and reportedly is active even against glycopeptide-intermediate and -resistant S aureus strains. ### Absorption Linezolid is administered either intravenously or orally. The intravenous preparation contains 2 mg/mL linezolid in an isotonic citrate buffer; the oral suspension contains 20 mg/mL linezolid. The oral bioavailability of linezolid suspension in older children and adults is 100% and is not altered by food. Neither preparation contains alcohol. No data on oral absorption in neonates are available. ### Distribution Linezolid distributes to well-perfused tissues and has low plasma protein binding (approximately 31%). Studies have shown that linezolid penetrates into osteoarticular tissues well, exceeding the minimum inhibitory …

Cost-effectiveness of Linezolid for Treatment of Ventilator-Associated Pneumoni

Cost-effectiveness of Linezolid for Treatment of Ventilator-Associated Pneumoni

Hematologic Effects of Linezolid: Summary of Clinical Experience

Linezolid has been associated with reversible myelosuppression. Clinical trial data were evaluated for anemia, thrombocytopenia, and neutropenia. Thrombocytopenia and a slight increased risk for anemia were evident at > or =2 weeks of linezolid treatment. Hematologic abnormalities were consistent with mild, reversible, duration-dependent myelosuppression. Appropriate monitoring is warranted with linezolid use.

Linezolid treatment of vancomycin-resistant enterococcus faecium ventriculitis

The successful treatment of a 7-month-old infant with shunt-associated ventriculitis caused by vancomycin-resistant Enterococcus faecium is presented. Linezolid was administered intravenously every 8 h; children have a greater volume of distribution and total body clearance than adults and therefore require more frequent dosing. The patient tolerated the therapy without adverse effects.

Economic evaluation of linezolid, flucloxacillin and vancomycin in the empirical treatment of cellulitis in UK hospitals: a decision analytical model

Standard antibiotic treatment of infections has become more difficult and costly due to treatment failure associated with the rise in bacterial resistance. New antibiotics that can overcome such resistant pathogens have the potential for great clinical and economic impact. Linezolid is a new antibiotic that is effective in the treatment of both antibiotic-susceptible and antibiotic-resistant Gram-positive bacterial infections, including those resistant to other available antibiotics. This breadth of activity is unique in existing antibiotics for Gram-positive bacteria and serves as the rationale for exploring the hypothesis that linezolid is an appropriate choice when considering empirical treatment of cellulitis in complicated or compromised patients in the nosocomial setting. A decision-modelling approach was used to compare the predicted first-line treatment efficacy and direct medical costs of linezolid with standard treatment of cellulitis among hospitalized patients. For the purposes of this analysis, standard care is defined along two main pathways: (1) initiating care with intravenous (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 taking iv flucloxacillin, a switch to oral flucloxacillin was allowed when clinically appropriate. We hypothesized that the 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. In addition, while the registration trials showed equivalence of linezolid with the comparators in known or suspected methicillin-resistant Staphylococcus aureus (MRSA) and in known or suspected methicillin-susceptible Staphylococcus aureus (MSSA) (vancomycin and oxacillin) respectively, we hypothesized that first-line success rates would be higher in empiric treatment 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 who were questioned regarding resistant and susceptible infections separately. UK hospital direct medical costs of treatment were determined using standard costing techniques. Base case analyses assumed a residual 80% unknown pathogen rate after culture and susceptibility based on a physician survey and supported in the literature. The analysis in this model predicts that initiating empirical treatment of cellulitis with linezolid will (1) result in higher overall success rates than flucloxacillin for first-line treatment, regardless of resistance risk and (2) be less costly than initiating treatment with flucloxacillin when the likelihood of a patient being infected by a resistant pathogen is greater than 24.1%. Furthermore, initiating treatment with linezolid is predicted to result in higher overall success rates and be less costly than vancomycin across the entire spectrum of the patients' risk of being infected by a resistant pathogen.

PID10: EFFECTS OF LINEZOLID ON HOSPITAL LENGTH OF STAY IN METHICILLIN-RESISTANT STAPHYLOCOCCUS INFECTIONS ESTIMATED FROM MULTIVARIATE SURVIVAL ANALYSIS

OBJECTIVES: To estimate differences in adjusted hospital length of stay (LOS) between linezolid and vancomycin using multivariate survival analysis. Linezolid's bioequivalent IV and oral formulations may enable earlier hospital discharge compared to vancomycin treatment. METHODS: 460 hospitalized patients with suspected/confirmed methicillin-resistant Staphylococcus infections were treated with either linezolid (LZD) or vancomycin (VAN) in a randomized controlled trial. Covariate imbalances between treatment groups were tested using t-tests and chi-square tests. Multivariate Cox proportional hazards and several parametric models for LOS were tested for best fit using the Akaike Information Criteria and log-likelihood ratio statistics. The Cox proportional hazards assumption was rejected (p < .05); log-logistic survival models fit best. The log-logistic estimates are used to create two alternative adjusted survivorship functions, one based on individual corrections to LOS (Individual correction), and the other based on means of the predicted survivorship function for each individual (Mean survivorship). Adjusted LOS at quartiles of % discharged for each function was compared with unadjusted LOS using Kaplan-Meier method. RESULTS: Hospital unit type at randomization and number of comorbidities both differed significantly between groups and significantly affected LOS. With covariate controls in the log-logistic model, linezolid treatment significantly reduced LOS (p = .04). Adjusted/unadjusted LOS at quartiles of % discharged were: CONCLUSIONS: When adjusted for covariate differences, median LOS for linezolid patients was at least 2 days shorter than for vancomycin patients. Other differences in the LOS distribution are evident and may be important to decision-makers but off-median estimates may be sensitive to the adjustment method used. Methodologic considerations are explored further. % discharged Adjusted LOS (days) Unadjusted LOS Individual correction Mean survivorship Kaplan-Meier LZD VAN LZD VAN LZD VAN 25 6 10 6 9 6 8 50 (median) 14 16 13 16 14 15 75 26 28 28 29 29 29

Linezolid therapy of vancomycin-resistant Enterococcus faecium experimental endocarditis.

We compared the activities of linezolid (25 mg/kg of body weight, administered intraperitoneally every 8 h) and of vancomycin (25 mg/kg of body weight, administered intraperitoneally every 8 h) in a rat model of vanA vancomycin-resistant Enterococcus faecium experimental endocarditis. Results were expressed as median log(10) CFU per gram of vegetation after 3 days of treatment. The median log(10) CFU per gram of vegetation was 10.1 among 7 untreated control animals, 10.2 among 9 vancomycin-treated animals, and 7.9 among 10 linezolid-treated animals. Linezolid treatment was more active (P < 0.05) than vancomycin treatment or no treatment.

Linezolid therapy of Staphylococcus aureus experimental osteomyelitis.

The in vivo activity of linezolid or cefazolin against a clinical isolate of methicillin-susceptible Staphylococcus aureus (linezolid MIC, 2 microg/ml) was studied in a rat model of experimental osteomyelitis. Sixty rats with experimental S. aureus osteomyelitis were treated for 21 days with no antimicrobial, with 25 microg of linezolid per kg of body weight administered intraperitoneally twice or three times a day, or with 50 microg of cefazolin per kg administered intramuscularly three times a day. After treatment, the animals were sacrificed and the infected tibiae were processed for quantitative bacterial cultures. The results of treatment were expressed as log(10) CFU/gram of bone and analyzed by rank sum analysis. The results of linezolid treatment were not significantly different from those of untreated controls, while cefazolin treatment was significantly more active than no treatment or linezolid treatment.

Activities of the oxazolidinones linezolid and eperezolid in experimental intra-abdominal abscess due to Enterococcus faecalis or vancomycin-resistant Enterococcus faecium.

The in vivo effectiveness of oxazolidinones eperezolid (U-100592) and linezolid (U-100766) against one strain each of Enterococcus faecalis and vancomycin-resistant Enterococcus faecium was examined in a rat model of intra-abdominal abscess. MICs of both drugs were 2 microg/ml for each strain. At doses of 25 mg/kg of body weight twice daily intravenously or orally, linezolid produced small but statistically significant reductions in abscess bacterial density for E. faecalis. The reduction in viable cells observed would not likely be clinically relevant. Eperezolid was ineffective at this dose. At a dosage of 100 mg/kg/day, linezolid treatment led to an approximately 100-fold reduction in viable cells per gram of abscess. Against E. faecium infections, intravenous eperezolid and oral linezolid were effective, reducing densities approximately 2 log(10) CFU/g. Both oxazolidinones demonstrated activity against enterococci in this model. However, results were modest with the dosing regimens employed.