Pfizer Inc. ignored a 2005 FDA Warning Letter to stop promoting its antibiotic Zyvox(R) as clinically superior to the significantly less expensive, generic vancomycin when its own FDA-approved label indicated otherwise. The drug giant also defrauded federal and state taxpayers by marketing Zyvox off-label, according to a qui tam whistleblower complaint filed by Philadelphia law firm Sheller, P.C. and other documents unsealed with today’s $2.3 billion Pfizer settlement.
The $2.3 billion settlement included off-label marketing allegations for the withdrawn arthritis drug Bextra(R), which was included in the Sheller complaint. Zyvox (linezolid) is an antibacterial agent that is approved by the FDA to treat certain types of infections, including nosocomial pneumonia and complicated skin and skin structure infections (“CSSSIs”) due to Methicillin Resistant Staphylococcus Aureus (“MRSA”). Worldwide sales of Zyvox totaled $1.115 billion in 2008.
The largest pharmaceutical qui tam whistleblower settlement in history, the $2.3 billion settlement was announced today by the U.S. Department of Justice and the U.S. Attorney’s Office for the District of Massachusetts.
via Sheller, P.C. Law Firm Instrumental in Pfizer’s $2.3 Billion Settlement Today in Largest Pharmaceutical Whistleblower Case in History.
Primer extension experiments indicated that spr0333 methylates G2445 of the 23S rRNA and mutations in spr0333 abolished this methylation. Reintroduction of a nonmutated version of spr0333 in resistant bacteria reestablished G2445 methylation and led to cells being more sensitive to linezolid and other antibiotics. Interestingly, the spr0333 ortholog was also mutated in a linezolid-resistant clinical Staphylococcus aureus isolate. Whole-genome sequencing and comparative analyses of S. pneumoniae resistant isolates was useful for discovering novel resistance mutations.
via Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance — Genome Research.
Purpose. A case of elevated creatine phosphokinase (CPK) levels associated with linezolid therapy in a patient on chronic antihyperlipidemic therapy is presented.
Summary. A 79-year-old Caucasian man with a primary diagnosis of acute hemoptysis secondary to pneumonia was admitted to the medical–surgical intensive care unit. A chest radiograph showed a large, right, lower-lobe infiltrate with alveolar consolidation. The patient’s medical history included hyperlipidemia that was chronically treated with lovastatin and gemfibrozil. Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was suspected and confirmed. Vancomycin 1 g i.v. every 12 hours was administered for approximately 10 days into the admission and switched to linezolid 600 mg i.v. every 12 hours after a lack of response to vancomycin. On hospital day 11, the patient’s CPK concentration was 47 units/L. Seven days later, his CPK concentration was 2584 units/L and his lovastatin and gemfibrozil were discontinued on that day. The patient’s CPK concentration peaked at 5369 units/L on the following day, and linezolid was discontinued at that point. One week later, his CPK concentration was 28 units/L. Approximately two weeks after the patient’s CPK levels normalized, he developed numerous complications. The patient died as a result of respiratory failure 11 days after being extubated, which occurred about 38 days after his admission. Although concomitant use of statins and gemfibrozil is known to increase the risk for CPK elevations, the continued rise in CPK levels after discontinuation of antihyperlipidemic therapy and the rapid time course for normalization after linezolid discontinuation are more consistent with an event associated with linezolid initiation.
Conclusion. A patient on chronic antihyperlipidemic therapy developed elevated CPK levels after receiving linezolid for the treatment of MRSA pneumonia.
via Elevated creatine phosphokinase levels associated with linezolid therapy — Allison et al. 66 (12): 1097 — American Journal of Health-System Pharmacy.
Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of ventilator-associated pneumonia (VAP), especially in patients who develop VAP late in their hospital course. Clinical failure in MRSA VAP is unacceptably high. Linezolid is an oxazolidinone antimicrobial agent that demonstrates bacteriostatic activity against MRSA and has been demonstrated to be equivalent to vancomycin in the treatment of nosocomial pneumonia. Retrospective analysis of two randomized, double-blind, studies suggests that linezolid therapy may confer clinical benefit over vancomycin in patients with MRSA VAP. Linezolid demonstrates excellent penetration into the epithelial-lining fluid and this feature has been postulated to be integral to its therapeutic benefit in MRSA VAP. This article evaluates the findings of a recently published prospective, randomized, open-label, comparator-controlled, multicenter trial that aims to compare the early microbiological efficacy of linezolid with vancomycin in the treatment of VAP caused by MRSA.
via HighWire Press — Medline Abstract.
Background: TR-700 is the active moiety of TR-701 (DA-7157), a new oral/intravenous oxazolidinone prodrug. We examined its activity against linezolid-susceptible and -resistant staphylococci and enterococci. Methods: MICs were determined by the CLSI agar dilution method. Results: MICs of TR-700 were tightly clustered around 0.5 mg/L for linezolid-susceptible staphylococci and enterococci compared with 2 mg/L for linezolid. MICs for 52 linezolid-resistant isolates were raised, but only exceeded 4 mg/L for two Enterococcus faecium isolates homozygous for the G2576T 23S rRNA mutation and for one with an unknown mechanism of linezolid resistance.
Conclusions: TR-700 is 4- to 16-fold more active than linezolid and overcame most linezolid resistance in vitro.
via Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci — Livermore et al. 63 (4): 713 — Journal of Antimicrobial Chemotherapy.
To evaluate the cost-effectiveness of vancomycin vs. linezolid in complicated skin and soft tissue infections (cSSTIs) with methicillin-resistant Staphylococcus aureus (MRSA) using a decision analytic (DA) model. METHODS: A DA model was created to evaluate the cost-effectiveness of four treatment strategies in the treatment of MRSA cSSTIs: linezolid intravenous (i.v.) to oral (LIN), vancomycin i.v. inpatient treatment (VAN-1), vancomycin i.v. switch to oral linezolid (VAN-2) and vancomycin i.v. switch to outpatient vancomycin i.v. (VAN-3). Probabilities were determined from published clinical trials. Incremental cost-effectiveness ratios for the various strategies were the primary outcome. Univariate (one-way) sensitivity analysis and second-order Monte Carlo simulation (using 10,000 trials) were conducted for all parameters used in the model. RESULTS: The DA model predicted that VAN-3 was the most cost-effective strategy from the base-case analysis. Average cost-effectiveness ratio for this strategy was $26,831.42/cure. Univariate sensitivity analysis revealed that the model was sensitive to linezolid duration of inpatient stay and duration of i.v. vancomycin before switching to an oral agent or discharged with outpatient i.v. administration with vancomycin. Probabilistic sensitivity analysis showed that VAN-1 was dominated by LIN, but LIN was only 30% cost-effective compared with VAN-3. Acceptability curve showed that the probability of choosing LIN as a cost-effective strategy compared with VAN-1, VAN-2 and VAN-3 increased as the willingness-to-pay (WTP) increased. CONCLUSION: Alternative vancomycin strategies (VAN-2 and VAN-3) that take advantage of early discharge opportunities were cost-effective compared with LIN. However, LIN’s higher efficacy would make it cost-effective for payers with a high WTP threshold.
via HighWire Press — Medline Abstract.
A 58-year-old woman presented with signs of systemic infection. Her medical history included bladder resection for transitional cell carcinoma, bilateral total hip arthroplasty (THA), and depression, for which she was on venlafaxine. Serological and imaging investigations revealed MRSA infection of the bilateral THA. The patient was started on vancomycin and rifampicin intravenously. As intravenous access was becoming problematic and long-term antibiotics were needed, treatment was changed to oral linezolid and oral rifampicin. Four days after the commencement of linezolid, the patient was acutely disorientated with generalized cerebellar signs and no autonomic dysfunction. A computed tomography scan of the head and lumbar puncture revealed no abnormal findings. A diagnosis of serotonin toxicity was made. The patient recovered when linezolid and venlafaxine were discontinued and supportive measures were provided. Linezolid is a popular choice of antibiotic, especially for the treatment of orthopedic–related MRSA infections. Patients who commonly require linezolid as an antimicrobial are those with complex infections where other antibiotic treatment has failed. It is therefore important to be vigilant with linezolid use. Physicians should be aware of the nonspecific presentation of serotonin symptoms and the treatment.
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via HighWire Press — Medline Abstract.
Results: Cmax concentrations and the volume of distribution at steady state (Vss) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (kel), t1/2 and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC0–{infty} from 98.1 mg·h/L (volunteers) to 42.5 mg·h/L (patients). Although renal clearance was similar in the two groups (24.7 ± 23 versus 30.6 ± 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 ± 191 versus 80.4 ± 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063).
Conclusions: The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.
via Pharmacokinetic evaluation of linezolid in patients with major thermal injuries — Lovering et al. 63 (3): 553 — Journal of Antimicrobial Chemotherapy.
