Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression

Drusano, George L.; Rogers, Stephanie; Brown, David; Peloquin, Charles A; Neely, Michael; Yamada, Walter M.; Kim, Sarah; Almoslem, Mohammed; Schmidt, Stephan; Louie, Arnold

doi:10.1128/aac.02533-20

Cited by 5 publications

(16 citation statements)

References 21 publications

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“…Preclinical animal models of infection are employed to develop new agents, but also to screen among molecules to rank them. 78,79 Limitations include variable natural susceptibility to TB, different immune responses, different lesion pathology, and so forth. Also, animal models of infection may have very different pharmacokinetics compared to humans, leading to substantial differences in efficacy.…”

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

“…We may look at the combination of these citations 78–81 and recognize that, taken together, they lay out an algorithm to identify potential high value multi‐drug combinations. As more and more agents are discovered or repurposed, this algorithm will be increasingly useful.…”

Section: Problems and Solutionsmentioning

confidence: 99%

“…The HFIM can be used to evaluate the impact of different pharmacokinetic profiles on bacterial cell kill, as well as resistance suppression. 78,79 Then, the in vitro results are examined with mathematical modeling, allowing one to establish links between HFIM reproductions of plasma and bronchoaveolar lavage (BAL) concentrations from animals or humans, and the pharmacodynamics of test drugs. 78,79 This information allows one to select the dose and frequency needed to optimize therapy.…”

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

“…81 This model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations to take forward in human trials. 81 We may look at the combination of these citations [78][79][80][81] and recognize that, taken together, they lay out an algorithm to identify potential high value multi-drug combinations. As more and more agents are discovered or repurposed, this algorithm will be increasingly useful.…”

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

“…Also, animal models of infection may have very different pharmacokinetics compared to humans, leading to substantial differences in efficacy. 78,79 Otherwise useful drugs could be discarded if a particular model does not look favorable. The HFIM can be used to evaluate the impact of different pharmacokinetic profiles on bacterial cell kill, as well as resistance suppression.…”

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

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The Treatment of Tuberculosis

Peloquin

Davies

2021

Clin Pharma and Therapeutics

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Tuberculosis (TB) remains a leading cause of infectious death worldwide, and poverty is a major driver. Clinically, TB presents as “latent” TB and active TB disease, and the treatment for each is different. TB drugs can display “early bactericidal activity (EBA)” and / or “sterilizing activity” (clearing persisters). Isoniazid is excellent at the former, and rifampin is excellent at the latter. Pyrazinamide and ethambutol complete the first‐line regimen for drug‐susceptible TB, each playing a specific role. Drug‐resistant TB is an increasing concern, being met, in part, with repurposed drugs (including moxifloxacin, levofloxacin, linezolid, clofazimine, and beta‐lactams) and new drugs (including bedaquiline, pretomanid, and delamanid). One challenge is to select drugs without overlapping adverse drug reaction profiles. QTc interval prolongation is one such concern, but to date, it has been manageable. Drug penetration into organism sanctuaries, such as the central nervous system, bone, and pulmonary TB cavities remain important challenges. The pharmacodynamics of most TB drugs can be described by the area under the curve (AUC) divided by the minimal inhibitory concentration (MIC). The hollow fiber infection model (HFIM) and various animal models (especially mouse and macaque) allow for sophisticated pharmacokinetic/pharmacodynamic experiments. These experiments may hasten the selection of the most potent, shortest possible regimens to treat even extremely drug resistant TB. These findings can be translated to humans by optimizing drug exposure in each patient, using therapeutic drug monitoring and dose individualization.

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Section: Understanding Drugs and Dosesmentioning

confidence: 99%

Section: Problems and Solutionsmentioning

confidence: 99%

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

Section: Understanding Drugs and Dosesmentioning

confidence: 99%

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The Treatment of Tuberculosis

Peloquin

Davies

2021

Clin Pharma and Therapeutics

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Evaluation of critical parameters in the hollow‐fibre system for tuberculosis: A case study of moxifloxacin

Aguilar‐Ayala,

Sanz‐García,

Rabodoarivelo

et al. 2024

Brit J Clinical Pharma

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AimsThe hollow‐fibre system for tuberculosis (HFS‐TB) is a preclinical model qualified by the European Medicines Agency to underpin the anti‐TB drug development process. It can mimic in vivo pharmacokinetic (PK)–pharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFS‐TB operational procedures.MethodsFirst, we characterized bacterial growth dynamics with different types of hollow‐fibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a moxifloxacin PK profile within hollow‐fibre cartridges, in order to check drug–fibres compatibility. Lastly, we mimicked the moxifloxacin total plasma PK profile in human after once daily oral dose of 400 mg to assess PK–PD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system.ResultsWe found that final bacterial load inside the HFS‐TB was contingent on the studied variables. Besides, we demonstrated that drug–fibres compatibility tests are critical preliminary HFS‐TB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions.ConclusionOur data contribute to the necessary standardization of HFS‐TB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFS‐TB currently overlooked.

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Time-dependent pharmacodynamics of amikacin on Mycobacterium abscessus growth and resistance emergence

Gibson,

Nandanwar,

Neely

2024

Microbiol Spectr

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Mycobacterium abscessus pulmonary disease is increasing in prevalence globally, particularly for individuals with cystic fibrosis. These infections are challenging to treat due to a high rate of resistance. Amikacin is critical to treatment, but the development of toxicity, amikacin resistance, and treatment failure are significant challenges. Amikacin has been characterized previously as peak-dependent and extended-interval dosing is commonly used. In our hollow fiber infection model of M. abscessus , amikacin exhibited time-dependent rather than the expected peak-dependent pharmacodynamics. Humanized amikacin exposures with more frequent, short-interval dosing (continuous infusion or every 12 hours) yielded improved microbiological response compared to extended-interval dosing (every 24 hours or 1–3 times per week). Short-interval dosing inhibited growth with a mean (SD) maximum Δlog 10 colony forming units of −4.06 (0.52), significantly more than extended-interval dosing ( P = 0.0013) every 24 hours, −2.40 (0.58), or 1–3 times per week, −2.39 (0.38). Growth recovery, an indicator of resistance emergence, occurred at 6.56 (0.70) days with short-interval dosing but was significantly earlier with extended-interval dosing ( P = 0.0032) every 24 hours, 3.88 (0.85) days, and 1–3 times per week, 3.27 (1.72) days. Microbiological response correlated best with the pharmacodynamic index of %T > minimum inhibitory concentration (MIC), with an EC 80 for growth inhibition of ~40%T > MIC. We used a previously published population model of amikacin to determine the probability of achieving 40%T > MIC and show that current dosing strategies are far below this target, which may partially explain why treatment failure remains so high for these infections. These data support a cautious approach to infrequent amikacin dosing for the treatment of M. abscessus . IMPORTANCE Pulmonary disease caused by Mycobacterium abscessus complex (MABSC) is increasing worldwide, particularly in patients with cystic fibrosis. MABSC is challenging to treat due to high levels of antibiotic resistance. Treatment requires 2–4 antibiotics over more than 12 months and has a significant risk of toxicity but still fails to eradicate infection in over 50% of patients with cystic fibrosis. Antibiotic dosing strategies have been largely informed by common bacteria such as Pseudomonas aeruginosa . The “pharmacodynamic” effects of amikacin, a backbone of MABSC treatment, were thought to be related to maximum “peak” drug concentration, leading to daily or three times weekly dosing. However, we found that amikacin MABSC kill and growth recovery, an indicator of antibiotic resistance, are dependent on how long amikacin concentrations are above the minimum inhibitory concentration, not how high the peak concentration is. Therefore, we recommend a re-evaluation of amikacin dosing to determine if increased frequency can improve efficacy.

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Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression

Cited by 5 publications

References 21 publications

The Treatment of Tuberculosis

The Treatment of Tuberculosis

Evaluation of critical parameters in the hollow‐fibre system for tuberculosis: A case study of moxifloxacin

Time-dependent pharmacodynamics of amikacin on Mycobacterium abscessus growth and resistance emergence

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