For common, nonsevere events such as low-grade grades 1 or 2 anaemia, linezolid would typically be temporarily interrupted and then restarted at half the dose. These clinical decisions were individualised and were made at the discretion of the routine treating clinician. At the time of the study, there was no dosing recommendation based on high-quality evidence for linezolid for TB treatment in children.
This was based on an approximation of the dose required to achieve similar exposure as in adults receiving mg once daily, based on existing pharmacokinetic data from children with non-TB infections [ 9 ]. Samples were drawn just prior to, and at 1, 4, and 10 hours after, the observed dose. For both studies, medications were administered identically, on an empty stomach after an overnight fast, and were given either as whole tablets if the child was able to swallow, as a suspension if available, or as crushed tablets mixed in a small amount of water if the child was unable to swallow and the suspension was unavailable due to occasional stockout , using identical formulations in both studies.
On occasion, all anti-TB medications were administered via nasogastric tube on pharmacokinetic sampling days, only if the child refused to swallow medications orally e. One hour after the anti-TB medication dose, antiretroviral medications were administered in HIV-infected children, and a standard breakfast was offered. A deuterated internal standard, Linezolid-d3, is used to monitor the method across a calibration range of 0.
The method performed well over the period of analysis, with an accuracy ranging from All children had regular clinical and laboratory safety assessments, including a full blood count monthly for the first 6 months, then every 2 months or as clinically indicated until completion of treatment. All adverse events were recorded and were assessed for attribution to linezolid based on the judgment of the investigator or subinvestigator, who was not blinded to the presence or duration of linezolid treatment, and graded for severity.
There were no differences between these versions for most of the adverse events that are relevant to linezolid, including low platelets, low white blood cell count, and peripheral neuropathy; the grading for these events is shown in S1 Table.
There were slight differences in the way low haemoglobins were graded, which are summarised separately in S2 Table. The analyses described here and in the following section are consistent with the general statistical approach in the protocol. Baseline characteristics were presented with descriptive statistics. Only children receiving linezolid as a component of their routine drug-resistant TB treatment regimen were included in safety analyses i.
Adverse events at least possibly related to linezolid were presented by grade, and the rate of events per person-time of observation were calculated. The development of a pharmacokinetic-pharmacodynamic model to assess the relationship between linezolid exposures and adverse events was planned after the study was fully enrolled and completed. At the time of the current analysis, this was explored using the analyses described below. The median interquartile range [IQR] linezolid area under the concentration time curve from 0 to 24 hours at steady state AUC 0—24ss was reported and compared by the presence of linezolid-related adverse effects using the Wilcoxon rank sum test.
Survival curves for time to any linezolid-related adverse effect and time to grade 3 or 4 linezolid-related adverse effects were displayed using Kaplan-Meier plots. Patients were censored at the time of the relevant linezolid-related event or when linezolid was discontinued. If the proportional hazards assumption was violated, log-rank test was reported along with a comparison of the restricted mean survival times RMSTs [ 29 , 30 ].
During the peer review process, these analyses were repeated to assess associations between the minimum linezolid concentrations C mins and linezolid-related adverse effects. Pharmacokinetic data were characterised based on a population nonlinear mixed-effects modelling approach using the software NONMEM 7.
Between-subject variability BSV was modelled exponentially, and the residual error was described using a combination of an additive and proportional error model.
Inter-occasion and inter-cohort variability were also evaluated to deal with the differences between both studies and pharmacokinetic occasions. Model building was performed in 2 stages, with the structural model developed first and the covariate analysis done subsequently. The main covariates evaluated in the analysis were weight, height, age, sex, race, HIV status, linezolid administration method oral versus nasogastric tube , formulation whole versus crushed versus suspension , linezolid given as single dose versus at steady state, and interactions with concomitant drugs.
Covariate identification was done using the stepwise covariate modelling SCM through the PsN software version 4. This method consists of the stepwise testing of linear and nonlinear covariate-parameter relationships with forward inclusion and backward exclusion approaches with significance levels of 0.
Given the modest sample size and the large number of covariates, the analysis was also done with a forward inclusion level of 0. The final inclusion of the identified significant covariates was done taking into account scientific plausibility, statistical significance, and clinical relevance.
Both stages of model building were evaluated by the likelihood ratio test, goodness of fit plots, and visual predictive checks VPCs.
R software version 3. Model-identified optimal doses were derived based on the following assumptions with respect to formulation availability: a independent of formulation, e.
Of the 48 children included, 5 participants contributed data from more than 1 pharmacokinetic sampling occasion. The pharmacokinetic profiles of these 5 children are displayed in S1 Fig , including the raw pharmacokinetic data, their individual prediction, and the dose and formulation received on each occasion. No concentrations were below the limit of quantitation. The final pharmacokinetic model consisted of a one-compartment disposition model characterised by clearance CL and volume V parameters.
CL and V included allometric scaling, using the exponents 0. Inter-occasion and inter-cohort variability were assessed and were not included in the final model due to the lack of significance. This lack of significance may be explained by the small number of pharmacokinetic measurements available at second and third occasions only 5 out of 48 children.
Similarly, the lack of significance when using inter-cohort variability suggests that the populations between cohorts were similar and comparable. No other covariates tested—including age, HIV status, formulation whole tablets versus crushed tablets versus suspension , WAZ, HAZ, body mass index, administration by nasogastric tube—significantly improved the model fit for any of the pharmacokinetic parameters after accounting for the effect of weight.
Table 2 describes the final model parameters. The final model fit the observed data well, as shown in the VPC Fig 1. Calculated AUC and maximum plasma concentrations from our study population are described in Table 3. Dots represent the observed linezolid concentrations; the solid lines correspond to the 5th, 50th, and 95th percentiles of these observations. VPC, visual predictive check.
The proposed weight-banded doses across weights that approximated the emerging AUC targets reported in adults with MDR-TB receiving a mg once-daily dose are shown in Table 4. The expected linezolid exposures AUC 0—24ss across weights from simulations using the final model and this weight-banded dosing strategy are shown in Fig 2.
Seventeen children were included in the safety analysis median age 4. The linezolid dose was adjusted after 4 For the single episode of peripheral neuropathy, which occurred in a year-old female, linezolid was temporarily interrupted, and the patient was treated with gabapentin, resulting in symptomatic improvement.
The linezolid was restarted at a lower dose after symptoms resolved with no sequelae, and symptoms did not recur at the lower dose. We did not identify any events of optic neuropathy. For children with an adverse event, the median IQR time to any linezolid-related adverse event was 3. The Kaplan-Meier survival curves for time to linezolid-related adverse events are displayed in Fig 3. Kaplan-Meier survival curves for time to linezolid-related adverse events by C mins are shown in S2 Fig.
MDR-TB, multidrug-resistant tuberculosis. This study provides data on linezolid pharmacokinetics in children with TB to inform evidence-based dosing. Linezolid-related adverse events were frequent and occasionally of high grade grade 3 or 4 in children treated long term for MDR-TB. The previously published paediatric data reported on single intravenous doses only, so direct comparison to our data is challenging.
In certain age groups, exposures in our paediatric cohort were even higher than expected target exposure in adults. These differences could be related to previously unidentified drug-drug interactions with other anti-TB drugs. No association was found between any pharmacokinetic parameters and concomitant drugs in our study; however, the study may have been underpowered to detect these.
Linezolid has complex metabolism, and as previously noted, there is substantial variability in linezolid pharmacokinetics between individuals and by disease state [ 17 , 18 , 33 , 34 ]. Differences in bioavailability, including formulation effects, should also be considered.
The formulations used in our study were all nongeneric, as used in most adult studies to date, and no differences were observed in pharmacokinetic parameters by formulation administration whole versus crushed versus suspension in our cohort. Our study combined linezolid pharmacokinetic data after both single and multiple doses.
Usually, pharmacokinetic parameters CL, V of distribution, and absorption rate constant derived based on single-dose pharmacokinetic data can predict well multiple-dose pharmacokinetics, if the pharmacokinetics are linear and there are no time-dependent trends, such as autoinduction or nonlinear elimination.
This was the case for linezolid. Additional data on linezolid pharmacokinetics in children treated for MDR-TB are important to confirm all of these findings. At the linezolid doses used in this study, 10 of 17 children treated long term experienced a linezolid-related adverse event, all of whom had anaemia in addition to some other, less frequent events.
This is similar to adult data and to a previous summary of published case series and case reports in which 9 of 18 children had a linezolid-related event [ 9 ]. In our study, regular monitoring was able to identify anaemia at mild grades in most children.
The approach of temporarily interrupting the linezolid until the haemoglobin had improved, followed by re-introduction at a lower dose usually half the previous dose , was generally well tolerated. Five children experienced a grade 3 or 4 anaemia, 4 of whom permanently discontinued linezolid.
Although all patients recovered from their anaemia without sequelae, the frequency and severity of these events highlights the importance of careful monitoring of haematological parameters during long-term linezolid treatment.
In our study, once haemoglobin values began to drop, they often fell rapidly, so the first signs of a falling haemoglobin should prompt more frequent testing, and there should be a low threshold for temporarily interrupting doses, depending on the importance of linezolid to the efficacy of the regimen.
The cumulative incidence of adverse events increased with longer duration of treatment; however, there were events detected even in the first 60 days, including grade 3 and 4 events. Reducing the duration of linezolid treatment would likely reduce, but not eliminate, the risk of adverse events, and careful safety monitoring will be necessary in future clinical trials and in routine care, regardless of the duration of linezolid therapy.
Reducing the linezolid dose would be expected to reduce its activity and may increase the risk of acquired resistance. The risk to children, who tend to have paucibacillary disease, would likely be low, especially when the child has already been on treatment for weeks or more with effective companion drugs in the regimen, and the bacillary burden would have been substantially reduced. However, there is still uncertainty about the risk of acquired resistance and the efficacy of these lower doses of linezolid, and an improved understanding of how to weigh up this risk versus benefit is an area for future research.
Grade 3 or 4 events were strongly associated with higher linezolid exposures. The lower doses we have proposed may reduce this risk. Therapeutic drug monitoring may also be a consideration to explore further to reduce the risk of these more severe events. Peripheral neuropathy was detected in only one child, a year-old female, and improved with temporary discontinuation of linezolid and gabapentin treatment, and it ultimately resolved without sequelae after recommencing a reduced linezolid dose.
To our knowledge, there is no reason to believe that children do not develop linezolid-related peripheral neuropathy, although the risk may be lower than in adults.
Peripheral neuropathy presents with symptoms of pain, numbness, and tingling in a stocking-glove distribution, and signs of weakness, reduced deep-tendon reflexes, and loss of sensation of vibration, proprioception, and temperature.
All of these signs and symptoms can be challenging to elicit in young children. To our knowledge, there are no validated clinical approaches for screening for peripheral neuropathy that can be used in young children. The gold standard for diagnosis is nerve conduction studies, which are invasive and specialised tests not widely available in high—TB-burden settings.
The implication is that peripheral neuropathy may be difficult to identify in young children, and thus there is a risk of underdiagnosis. This is an important consideration when weighing the risk to benefit for the use of linezolid in children with MDR-TB. We did not identify any other serious, more rare events such as optic neuropathy or lactic acidosis.
This is reassuring but should be interpreted cautiously, as the number of children included here is modest, and formal ophthalmologic examinations were not done.
Lactate levels and pancreatic enzymes were not monitored, which is also a limitation. However, in no children were clinical symptoms or signs suggestive of optic neuropathy, lactic acidosis, or pancreatitis reported or suspected.
Add to cart. AcipHex rabeprazole Tablet Slow-release AcipHex Sprinkle rabeprazole Capsule Slow-release; Note: contents are intended to be sprinkled on food or liquid but should not be chewed or crushed. Acticlate doxycycline hyclate Capsule; Tablet Film-coated; tablet is scored and may be split; Note: mg tablets can be broken into two-thirds or one-third to provide a mg and 50 mg strength, respectively Actiq fenta NYL Lozenge Slow-release; Note: this lollipop delivery system requires the patient to slowly allow dissolution.
Actonel risedronate Tablet Irritant; Note: chewed, crushed, or sucked tablets may cause oropharyngeal ulceration. Copiktra develisib Capsule Antineoplastic Coreg CR carvedilol Capsule Slow-release a Note: may add contents of capsule to chilled, not warm, applesauce and consume immediately Cotempla XR-ODT methylphenidate Tablet Slow-release; oral disintegrating tablet designed to disintegrate on the tongue.
Creon 5, 10, 20 pancrelipase Capsule Slow-release a Cresemba isavuconazium Capsule - Crixivan indinavir Capsule Taste; Note: capsule may be opened and mixed with fruit puree e. List of Confused Drug Names. Medications requiring special safeguards to reduce the risk of errors and minimize harm. View all Recommendations. Irritant; Note: chewed, crushed, or sucked tablets may cause oropharyngeal ulceration. Slow-release; Note: chewed, cut, or crushed tablets may cause oropharyngeal irritation.
Sublingual form g ; Note: chewing or swallowing may result in lower bioavailability. Note: chewing or swallowing may result in lower peak concentrations and bioavailability.
Note: tablet should be swallowed whole and not crushed; tablet may be dispersed in water. Note: breaking, chewing, or emptying contents of the capsule can result in increased exposure. Can linezolid tablets be crushed. Premium Questions. Is there interaction between Linezolid, Paracetamol, Montelukast and Levocetirizine? Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.
Injection should be administered by intravenous infusion over a …. Zyvox Antibiotic Co's comment stream; Description. Connect with Zyvox Antibiotic Co. Zyvox Antibiotic Co has not added any external profiles yet. Circadin MR tablets melatonin.
Prepare the tablet as follows1: 1. Crush the tablet with a tablet crusher, or between two metal spoons. Add the powder to mL of water and Mistakes can occur when people have trouble swallowing a tablet or capsule and they try to chew, crush, break or mix the tablet or capsule in food or drink.
The reason is certain medications have a special release mechanism designed to slowly release a …. You can! Just serve it up with some sugar on the spoon! Some of them have a Coating on the outside so it may taste a little worse, but it will go down fast.
0コメント