Addition of PNU-100480 to First-Line Drugs Shortens the Time Needed to Cure Murine Tuberculosis

Williams, Kathy; Brickner, Steven J.; Stover, C. Kendall; Zhu, Tong; Ogden, Adam; Tasneen, Rokeya; Tyagi, Sandeep; Grosset, J; Nuermberger, Eric L.

doi:10.1164/rccm.200904-0611oc

Cited by 115 publications

(84 citation statements)

References 30 publications

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“…Linezolid is the only currently licensed oxazolidinone. Sutezolid (PNU-100480 [U-480]) is a thiomorpholinyl analog of linezolid with superior efficacy against M. tuberculosis in the hollow-fiber, mouse, and whole-blood models (2)(3)(4). Timedependent killing of M. tuberculosis by sutezolid has been reported in whole blood and hollow fibers (2,3).…”

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confidence: 99%

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Zhu

Friedrich

Diacon

et al. 2014

Antimicrob Agents Chemother

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Mycobacterium tuberculosis resistance to standard first-line drugs (drug-resistant tuberculosis [DR-TB]) is a serious and growing global health threat, causing at least 444,000 new tuberculosis (TB) cases and 150,000 deaths annually (1). Oxazolidinone antimicrobials are increasingly viewed as candidates for inclusion in new regimens for DR-TB, as they have a distinct mechanism of action (binding to the 23S ribosome) without cross-resistance to current drugs. Linezolid is the only currently licensed oxazolidinone. Sutezolid (PNU-100480 [U-480]) is a thiomorpholinyl analog of linezolid with superior efficacy against M. tuberculosis in the hollow-fiber, mouse, and whole-blood models (2-4). Timedependent killing of M. tuberculosis by sutezolid has been reported in whole blood and hollow fibers (2, 3).Orally administered sutezolid is rapidly oxidized in vivo to an active sulfoxide metabolite (PNU-101603 [U-603]), which then undergoes renal excretion. The concentrations of U-603 achieved in human plasma are severalfold greater than those of the parent. Some studies have reported similar MICs for both U-480 and U-603 (0.25 g/ml) for reference strains and clinical isolates, regardless of the method of testing (5, 6); however, others have reported lower median MIC values (Յ0.062 g/ml) for the parent when clinical isolates are tested in liquid culture (6).The relative contributions of the parent and metabolite to killing of mycobacteria appear to differ according to cellular location. Studies in the hollow-fiber model using concentrations of parent and metabolite that are achieved in human plasma have indicated that killing of extracellular mycobacteria by sutezolid is mainly due to the metabolite (2). In contrast, studies in which sutezolid or its metabolite were added separately to cultures of M. tuberculosisinfected mammalian cells have found the parent to be at least 10-fold more potent than the metabolite (7). However, these studies have not examined the activity of sutezolid as it would occur in the cells of patients with tuberculosis, which may differ in immune function and drug metabolism.The present study used mathematical modeling to examine the relative contributions of U-480 and U-603 to the killing of intracellular M. tuberculosis in ex vivo cultures measuring whole-blood bactericidal activity (WBA) that were conducted in clinical trial B1171003, the first study of sutezolid in patients with pulmonary tuberculosis. MATERIALS AND METHODS Subjects.As previously reported (8), subjects consisted of men and women aged 18 to 65 years with chest radiographs with findings consistent

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confidence: 99%

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Zhu

Friedrich

Diacon

et al. 2014

Antimicrob Agents Chemother

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“…When added to a first-line regimen in a murine model, PNU-100480 had a synergistic bactericidal effect, while linezolid had an antagonistic effect (26). However, these data for PNU-100480 were obtained from testing drugsusceptible isolates.…”

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confidence: 99%

Susceptibility of Clinical Mycobacterium tuberculosis Isolates to a Potentially Less Toxic Derivate of Linezolid, PNU-100480

Alffenaar

Laan

Simons

et al. 2011

Antimicrob Agents Chemother

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Susceptibility of clinical Mycobacterium tuberculosis isolates to PNU-100480 and linezolid was evaluated by the MGIT 960 system. The isolates had various susceptibilities to isoniazid (INH), rifampin, ethambutol, and streptomycin. The mean MIC for PNU-100480 was 3.2 times lower than that for linezolid. Therefore, PNU-100480 is a promising candidate to be developed further as an adjunct in the treatment of multidrug-and extensively drug-resistant tuberculosis (MDR/XDR-TB).

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“…In a murine model of TB, it was more effective than linezolid with an efficacy similar to H and R [Alffenaar et al 2011]. It increased the bactericidal activity when added to standard therapy in a murine model, confirming its sterilizing activity [Williams et al 2009a]. In combination with moxifloxacin and Z, it was more active than standard first-line therapy in a murine TB model, suggesting that it has the potential to reduce the required treatment period for both DS-and DR-TB [Williams et al 2009b].…”

Section: Oxazolidinonesmentioning

confidence: 81%

New treatment options for multidrug-resistant tuberculosis

Field¹,

Fisher

Jarand

et al. 2012

Ther Adv Respir Dis

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Despite the development of effective treatments, tuberculosis (TB) remains a major health problem. TB continues to infect new victims and kills nearly 2 million people annually. The problem is much greater in resource-limited countries but is present worldwide. Inadequate public health resources, cost, the obligatory long treatment period, and adverse drug effects contribute to treatment failures and relapses. Drug-resistant Mycobacterium tuberculosis (MTB) strains arise spontaneously and are propagated by inadequate treatment. According to World Health Organization global data, 17% of MTB strains in new, previously untreated cases are resistant to at least one drug. Approximately, 3.3% of new MTB cases are resistant to both isoniazid and rifampin, also called multidrug resistant (MDR), and rates of MDR-TB are greater than 60% in previously treated patients in some countries. Approximately 5% of cases of MDR-TB are also resistant to fluoroquinolones and to injectable drugs, and are called extensively drug resistant (XDR). Recently, XDR strains have been isolated that are also resistant to all standard second-line anti-TB medications. Successful drug treatment of TB with complex resistance profiles is virtually impossible with currently available drugs. There is a desperate need for new compounds that cure strains resistant to currently available drugs and for drugs that are better tolerated and will shorten treatment regimens. In the short term, new strategies for the management of drug-resistant TB with currently available drugs are being explored. These include the use of high-dose isoniazid, substitution of rifabutin in a small proportion of rifampin-resistant cases, linezolid, fluoroquinolones, and phenothiazines. A number of novel drugs are undergoing clinical testing and will hopefully be available in the near future. These include the newer oxazolidinones, diarylquinolines, nitroimidazopyrans, ethenylenediamines, pyrroles, and benzothiazinones.

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Addition of PNU-100480 to First-Line Drugs Shortens the Time Needed to Cure Murine Tuberculosis

Cited by 115 publications

References 30 publications

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Population Pharmacokinetic/Pharmacodynamic Analysis of the Bactericidal Activities of Sutezolid (PNU-100480) and Its Major Metabolite against Intracellular Mycobacterium tuberculosis in Ex Vivo Whole-Blood Cultures of Patients with Pulmonary Tuberculosis

Susceptibility of Clinical Mycobacterium tuberculosis Isolates to a Potentially Less Toxic Derivate of Linezolid, PNU-100480

New treatment options for multidrug-resistant tuberculosis

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