Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

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Quantitative modeling of combination therapy can describe the effects of each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and modeling strategy that evaluates different synergy mechanisms using a rapidly killing peptide antibiotic (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments with all three antibiotics in monotherapy against a methicillin-resistant Staphylococcus aureus USA300 strain (inoculum, 10 8 CFU/ml). A sequential design (initial dosing of 8 or 32 mg/liter nisin, switched to amikacin or linezolid at 1.5 h) assessed the rate of killing by amikacin and linezolid against nisin-intermediate and nisin-resistant populations. Simultaneous combinations were additionally studied and all viable count profiles comodeled in S-ADAPT and NONMEM. A mechanism-based model with six populations (three for nisin times two for amikacin) yielded unbiased and precise (r ‫؍‬ 0.99, slope ‫؍‬ 1.00; S-ADAPT) individual fits. The second-order killing rate constants for nisin against the three populations were 5.67, 0.0664, and 0.00691 liter/(mg · h). For amikacin, the maximum killing rate constants were 10.1 h ؊1 against its susceptible and 0.771 h ؊1 against its less-susceptible populations, with 14.7 mg/liter amikacin causing half-maximal killing. After incorporating the effects of nisin and amikacin against each population, no additional synergy function was needed. Linezolid inhibited successful bacterial replication but did not efficiently kill populations less susceptible to nisin. Nisin plus amikacin achieved subpopulation synergy. The proposed sequential and simultaneous dosing design offers an efficient approach to quantitatively characterize antibiotic synergy over time and prospectively evaluate antibiotic combination dosing strategies.

Section: Discussionsupporting

confidence: 68%

“…An MRSA USA300 strain obtained from the Network on Antimicrobial Resistance was utilized for all experiments (18). Static time-kill studies and MIC tests were performed in Luria-Bertani broth (Difco Laboratories, Detroit, MI) supplemented with 12.5 mg/liter Mg 2ϩ and 25 mg/liter Ca 2ϩ .…”

Section: Methodsmentioning

confidence: 99%

Quantifying Subpopulation Synergy for Antibiotic Combinations via Mechanism-Based Modeling and a Sequential Dosing Design

Landersdorfer

et al. 2013

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“…Therefore, high-dose linezolid regimens seem not warranted for patients with low baseline platelet counts. Front-loaded linezolid regimens have recently demonstrated promising bactericidal activity (43,44). Based on the predicted toxicity for patients with normal to high baseline platelet counts (Fig.…”

Section: Discussionmentioning

confidence: 99%

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Boak

Rayner

Grayson

et al. 2014

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h Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10-to 28-day therapy for platelet nadirs of <100 ؋10 9 / liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

“…Therefore, increasing the daily dose for colistin for a short duration seems a promising and clinically viable strategy to decrease the potential for nephrotoxicity while enhancing the antimicrobial killing activity. This strategy has been applied for other antimicrobials (42)(43)(44) and may be particularly promising for colistin, which can achieve rapid and concentration-dependent bactericidal activity (7). However, these findings should also be balanced with toxicodynamic evaluations of these new regimens, as it has been shown that the fAUC is the driver for nephrotoxicity for colistin (41,45).…”

Section: Discussionmentioning

confidence: 99%

New Dosing Strategies for an Old Antibiotic: Pharmacodynamics of Front-Loaded Regimens of Colistin at Simulated Pharmacokinetics in Patients with Kidney or Liver Disease

Rao

Haas

et al. 2014

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e Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10 8 CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic