Evaluation of Pharmacokinetic Pharmacodynamic Target Attainment and Hematological Toxicity of Linezolid in Pediatric Patients

doi:10.21203/rs.3.rs-4526965/v1

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Research Article

Evaluation of Pharmacokinetic Pharmacodynamic Target Attainment and Hematological Toxicity of Linezolid in Pediatric Patients

https://doi.org/10.21203/rs.3.rs-4526965/v1

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published 25 Aug, 2024

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Background

Linezolid is commonly used to treat severe and/or resistant Gram-positive infections. Few studies have assessed its pharmacokinetics/pharmacodynamics (PK/PD) in pediatrics.

Objective

to evaluate the percentage of pediatric patients achieving the PK/PD target of linezolid using standard dosing regimens and to assess the incidence and risk factors associated with its hematologic toxicity.

Methods

This prospective observational study included pediatric patients aged 0–14 years who received linezolid for suspected or proven Gram-positive infections. Linezolid trough concentrations were measured, and hematologic toxicity was assessed.

Results

In total, 17 pediatric patients (5 neonates and 12 older pediatrics) were included in the analysis. The median trough concentration in neonates was significantly higher than that of the older pediatrics (7.1 [6.2–11.0] vs. 3.9 [1.95–6.5] mg/L, respectively, P = 0.04). Out of all patients, 53% achieved the therapeutic trough level of 2–7 mg/L, 18% had subtherapeutic levels, and 23% had higher-than-optimal troughs. Linezolid-associated hematological toxicity was documented in 53% of cases. Identified significant risk factors include treatment duration of more than 7 days, baseline platelet counts of less than 150 x 10⁹/L, sepsis/septic shock, and concomitant use of meropenem.

Conclusions

Linezolid's standard dosing failed to achieve its PK/PD target in approximately half of our pediatric cohort. Our findings underscore the complex interplay between the risk factors of linezolid-associated hematological toxicity and highlight the importance of its vigilant use and monitoring if it is to be initiated in pediatrics with concomitant multiple risk factors.

Pharmacokinetics

pharmacodynamics

linezolid

pediatrics

hematologic toxicity

Linezolid is a synthetic oxazolidinone antibiotic commonly used to treat serious Gram-positive infections both in adults and pediatrics. It is one of the few antibiotics that is still effective against multi-drug-resistant Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci (CoNS) and vancomycin-resistant enterococci [1–3]. These pathogens are among the most frequent clinical isolates in serious Gram-positive infections in pediatric patients [4–6]. Even higher prevalence rates of up to 55% have been observed for CoNS in neonatal sepsis [7, 8].

Over the past decade, the use of linezolid has increased markedly owing to the global rise in the prevalence of vancomycin-resistant, intermediate, and heterogeneous Staphylococcus aureus [9, 10], in addition to its favorable pharmacokinetic (PK) properties [3]. Unlike vancomycin, linezolid is available as both intravenous and oral formulations (tablets and suspension) with excellent bioavailability; no dose adjustment is recommended by the manufacturer for renal or hepatic impairment, and it is not associated with nephrotoxicity. It exhibits a low protein binding ability of about 31%. It is widely distributed to well-perfused tissues with very good penetration into the lung, cerebrospinal fluid, bone, skin, and soft tissue [3, 11, 12]. These properties made linezolid an attractive option by many physicians over vancomycin for the treatment of deep-seated infections such as pneumonia, endocarditis, meningitis, and osteomyelitis [13–15], and it should theoretically minimize the interpatient and intra-patient PK variability. However, it has been shown that linezolid plasma exposure can vary significantly between individuals with specific conditions such as severe burn, sepsis, critical illness, or when used concomitantly with other medications [16–21]. These studies and others highlighted the importance of linezolid therapeutic drug monitoring (TDM) in order to improve the efficacy and avoid either under- or overexposure with subsequent therapeutic failure, antibiotic resistance, or toxicity [22–25].

The bactericidal activity of linezolid is time-dependent, trough concentrations ranging from 2–7 mg/L and/or an estimated 24-hour area under the curve over minimum inhibitory concentration (AUC₂₄/MIC) of 80–120 mg·h/L are suggested as the therapeutic target range for linezolid [24–27]. Myelosuppression is one of the most serious reported adverse drug reactions for linezolid, both in adults and pediatrics [28–34]. Studies in adult populations showed that high trough concentrations (> 7.5 mg/L) are associated with an increased risk of linezolid-related hematologic adverse effects [22, 26, 35–37]. Most studies conducted to date concerning this issue have always focused on adults. Only a few studies have explored the incidence and risk factors associated with linezolid hematologic toxicities in pediatrics, with conflicting results ranging from less than 1% up to 57% [31–34].

In addition, although several studies have assessed the PK of linezolid in pediatrics, evidence to describe its pharmacokinetics/pharmacodynamics (PK/PD) target attainment in children and neonates using standard dosing regimens is scarce. Consensus on the optimum linezolid dosing and TDM recommendations for pediatrics to achieve maximum efficacy with minimum toxicity is still lacking. Moreover, most published studies reported data on Asian or Caucasian populations. Ethnic differences such as genetic variation and differences in fat distribution, body weight, and height can impact drug PK [38–39]. To the best of our knowledge, no studies have evaluated the PK/PD of linezolid in the Middle East/North African (MENA) pediatric population. Therefore, the objectives of this study were to assess the percentage of pediatric patients achieving the PK/PD target of linezolid using standard dosing regimens and to assess the incidence and risk factors associated with its hematologic toxicity in a real-world cohort of Saudi pediatrics that included neonates, ICU pediatric patients, and non-ICU pediatrics.

This prospective observational study was conducted at King Saud University Medical City, Riyadh, Saudi Arabia. Inclusion criteria encompassed pediatric patients aged 0–14 years who received linezolid for the treatment of suspected or confirmed Gram-positive infections. Initial dosing recommendations for linezolid were primarily obtained from the online pediatric and neonatal Lexi-Drugs® (Lexicomp, Ohio, USA) [12].

Data collection:

The following data were collected for each patient: age, gender, weight, height, linezolid dosing information, indication, duration of treatment, concomitant antibiotics, presence or absence of septic shock, 30-day mortality, whether the patient is on renal replacement therapy, serum albumin, serum creatinine (SCr), platelet count, hemoglobin levels, white blood cell count, and neutrophil count (the baseline and at the end of treatment). The creatinine clearance (CrCl) was estimated using the modified Schwartz "bedside" formula [40]:

$$CrCl (mL/min)=0.413*\frac{Height \left(cm\right)}{SCr (mg/dL)}$$

We did not estimate the CrCl for neonates because of the lack of validated formulas for them. Impaired renal function was defined as CrCl < 60 mL/min [34].

Sampling, and analytical assay:

In this study, opportunistic sampling techniques were employed [41, 42]. Residual samples from pediatric patients who received linezolid and underwent clinical biochemical tests at the hospital lab over a 6-month period from October 2022 to March 2023, were collected. Plasma was separated by centrifugation and stored at -80°C until analyzed. Samples were analyzed using a high-performance liquid chromatography/ultra-violet (UV) system equipped with a UV100 variable-wavelength UV/VIS detector [43]. The analytical column was OSD (250 × 4 mm inner diameter, 5 µm particle size) (Merck, Darmstadt, Germany). The mobile phase consisted of a mixture of acetonitrile and 50 mM potassium dihydrogen phosphate (30:70 v/v, pH 3.5). Prior to analysis, 250 µL of each plasma sample was vortexed for 10 seconds. Samples were then deproteinized with 500 µL of methanol, vortexed again for 30 s, and centrifuged at 15,000 rpm for 10 min. Finally, 50 µL of the clear supernatant from each sample was injected into the high-performance liquid chromatography apparatus. Cefixime (Sigma) was used as an internal standard. A series of standard solutions, with concentrations ranging from 0.1 to 100 mg/L, was prepared to establish a standard curve. Samples with linezolid concentrations of 0.5, 1.0 and 7.5 mg/L were used as quality controls.

PK/PD analysis:

As some samples were collected long before the next scheduled dose, we made an adjustment for the timing of sample collection. Samples taken within one hour of the next scheduled dose were classified as “true” trough concentrations. Trough concentrations of samples collected at other time points were then estimated using a Bayesian approach, incorporating the model described by Yang et al. as Bayesian priors [44]. Bayesian predictions were performed using Monolix software version 2020R1. We determined the proportions of pediatric patients with linezolid trough concentrations categorized as either within the therapeutic range (2–7 mg/L), high (> 7 mg/L) or low (< 2 mg/L) [26].

Toxicity:

We evaluated the hematological toxicity of linezolid using the definition of the laboratory values established in accordance with the Food and Drug Administration label for linezolid [28]. Hematological toxicity was defined as platelet, hemoglobin, or white blood cell counts below 75% of the lower limit of normal for normal and/or baseline levels, or a neutrophil count below 50% of the lower limit of normal. The baseline levels were defined as the lab. values at the initiation of linezolid therapy. If no data were available on the first day of linezolid therapy, the nearest lab. values prior to linezolid therapy were then used as the baseline.

Statistical analysis:

Categorical variables are expressed as numbers and percentages, whereas continuous variables are presented as medians with interquartile ranges [IQRs]. The Mann–Whitney U test was used to compare continuous variables, while the Chi-square test or Fisher's exact test was used to analyze categorical variables. Statistical significance was defined as P < 0.05. All statistical analyses were performed using SPSS software version 22.0.

Patient characteristics and treatment:

In total, 17 pediatric patients (5 neonates and 12 older children) were included in the analysis. Of these, 7 (39%) were female, and 10 (61%) were male. For neonates, the median [IQR] post-natal age was 10 [4–24] days, weight was 4 [2.4–4.3] kg, and SCr level was 0.8 [0.5–1.4] mg/dL. Only one neonate was preterm, and the remaining 4 were full-term. The main indication for linezolid in all neonates was late-onset neonatal sepsis. For the older pediatric group (age > 1 month), the median (IQR) age was 5 [0.94–10.75] years, weight was 21 [16.9–46.5] kg, SCr was 0.4 [0.3–0.8] mg/dL and CrCl was 95 [63–132] mL/min. Among these patients, seven (58%) were admitted to the ICU. Only one ICU patient had renal impairment (CrCl < 60 mL/min) and another one had end-stage renal disease on peritoneal dialysis. The most common indication for linezolid use in the older pediatric group was pneumonia, and febrile neutropenia, followed by meningitis and osteoarthritis. Three patients (25%) in the older pediatric group had sepsis/septic shock, The 30-day mortality rate was 12% (n = 2), one in the neonatal group and one in the ICU older pediatric group. The most common concomitant antibiotic was meropenem in 9 patients (53%), followed by ceftriaxone in 4 patients (23.5%) and piperacillin/tazobactam in 3 patients (17.6%). A summary of the patients’ clinical and demographic characteristics is presented in Table 1. Eight patients switched to linezolid after starting vancomycin, either because of the rise in SCr value after vancomycin (n = 4) or for therapy upgrade whenever there was no clinical improvement (n = 4). The remaining nine patients started linezolid empirically as a first line because of vancomycin allergy (n = 2), renal impairment (n = 1) or inadequately without any clinical reason for not using vancomycin (n = 6). The median linezolid dose administered was 30 [25-30.4] mg/kg/day. Only one patient received linezolid orally; all other patients received it as a 120-minute intravenous infusion, with a median duration of treatment of 16 [5–19] days in the neonatal group and 7 [4–13] days in the older pediatric group.

Table 1

Baseline characteristics of the patients
	Neonates (n = 5)	Older pediatrics (n = 12)	Overall (n = 17)
ICU patients Medical ward patients	5 (100%) -	7 (58%) 5 (42%)	12 (70%) 5 (30%)
Age (days for neonates and years for older pediatrics)	10 [4–24]	5 [0.94–10.75]	1 (0.06-7)
Gender: Male n (%)	5 (100%)	5 (42%)	10 (59%)
Weight (kg)	4 [2.4–4.3]	21 [16.9–46.5]	18 (4.3,31.8)
Height (cm)	54 [43–60]	117 [90–157]	107 (58,143)
Baseline Lab. Values:
Serum creatinine (mg/dL)	0.8 [0.5–1.4]	0.4 [0.3–0.8]	0.6 (0.4–0.9)
Creatinine clearance (mL/min)	NA	95 [63–132]	95 (63,132)
Albumin (g/L)	25 [23–33]	29 [23–37]	28.4 (23.7–34.3)
Platelet (10⁹/L)	87 [83–293]	171 [41–270]	160 (59–264)
Baseline platelet count < 150 x 10⁹/L)	3 (60%)	5 (42%)	8 (47%)
WBC (10⁹/L)	8.6 [4.2–16.7]	11.8 [3-20.9]	11.24 (3.6–19)
Hemoglobin (gm/L)	103 [73–119]	93 [87–103]	94 (87–107)
Neutrophil count (10⁹/L)	5.5 [2.8–10.6]	8.9 [2.6–17.1]	8.4 (2.9–14.2)
Linezolid dose (mg/kg/day)	30 [25–31]	30 [25.5–30.4]	30 (27-30.5)
Duration of treatment (days)	16 [5–19]	7 [4–13]	8 (4–17)
Linezolid Indication:
Sepsis/ Septic shock	5 (100%)	3 (25%)	8 (47%)
Febrile neutropenia	-	3 (25%)	3 (17.6%)
Pneumonia	-	3 (25%)	3 (17.6%)
Meningitis	-	2 (16.7%)	2 (11.8%)
Osteoarthritis	-	2 (16.7%)	2 (11.8%)
Myocarditis	-	1 (8.3%)	1 (5.9%)
Bacteremia	-	1 (8.3%)	1 (5.9%)
Concomitant Drugs:
Meropenem	4 ((80%)	5 (42%)	9 (53%)
Piperacillin/tazobactam	-	3 (25%)	3 (17.6%)
Ceftriaxone	-	4 (33.3%)	4 (23.5%)
Ceftazidime	1 (20%)	-	1 (5.9%)
Acyclovir	1 (20%)	1 (8.3%)	2 (11.8%)
Amphotericin B	2 (40%)	1 (8.3%)	3 (17.6%)
Switched to linezolid from vancomycin	2 (40%)	6 (50%)	8 (47%)
Data represented as median [IQR] or n (%).

PK/PD analysis:

For 9 patients, sampling was performed within 1 hour of the next dose, and the measured levels were considered true troughs. The trough concentrations were estimated for the remaining 8 patients using the individual predicted value via a Bayesian approach.

Overall, linezolid trough concentration in all patients ranged from 0.5 − 14.4 mg/L, with a median [IQR] of 6.2 [3.2–7.3] mg/L. The median trough concentration in the neonatal group was significantly higher than that of the older group (7.1 [6.2–11.0] vs. 3.9 [1.95,6.5] mg/L, respectively, P = 0.04) (Fig. 1). Meanwhile, although not statistically significant, the median trough concentration in the ICU older pediatric group was lower than that of the non-ICU older pediatric patients (3.8 [1.6–6.5] vs. 6.1 [1.9-7.0] mg/L, respectively, P = 0.75) (Fig. 2).

Nine patients (53%), 2 neonates and 7 older pediatrics, achieved a trough concentration within the recommended range of 2–7 mg/L. Five patients (29%), 3 neonates and 2 older pediatrics had trough levels > 7 mg/L, whereas three (18%) had trough levels of < 2 mg/L (1 ICU and 2 non-ICU older pediatrics). Table 2 shows the percentage of patients who achieved linezolid target, supratherapeutic or subtherapeutic trough levels in each group.

Table 2

Percent of patients achieved linezolid pharmacokinetic/pharmacodynamic (PK/PD) target, supratherapeutic and subtherapeutic concentrations:
	Neonates (n = 5)	Older pediatrics ICU patients (n = 7)	Older pediatrics Non-ICU patients (n = 5)
Trough Conc. (mg/L)	7.1 [6.2–11.0]	3.8 [1.6–6.5]	6.1 [1.9-7.0]
Patients achieved PK/PD trough target (2–7 mg/L)	2 (40%)	5 (72%)	2 (40%)
Patients had trough levels > 7 mg/L	3 (60%)	1 (14%)	1 (20%)
Patients had trough levels < 2 mg/L	-	1 (14%)	2 (40%)
Data represented as median [IQR] or n (%).

Hematological Toxicity:

Thrombocytopenia was the most observed hematologic toxicity. It was reported in eight patients (47%) (3 (60%) out of the 5 neonates and 5 (42%) older pediatrics). Three patients (17.6%) developed anemia (one neonate and 2 children) and none developed neutropenia or leukopenia. All patients who developed anemia had also thrombocytopenia. Characteristics of patients who developed thrombocytopenia were summarized in Table 3. For the eight patients who developed thrombocytopenia, the median duration of treatment was significantly longer compared to those who did not develop hematologic toxicities (15 [8–25] vs. 5 [2-7.5] days, respectively, P = 0,006). All patients who developed hematologic toxicities received linezolid treatment for ≥ 7 days. Although not statistically significant, the median trough concentration was higher in patients who experienced hematologic toxicities compared to patients who did not (6.5 [3.9–11.0] vs. 4.6 [2.3–6.8] mg/L, respectively, P = 0.183) (Fig. 3). Eight patients had a low baseline platelet count of less than 150 x 10⁹/L, six out of these eight (75%) had hematologic toxicities. The baseline platelet count was significantly lower in patients who developed thrombocytopenia compared to those who did not 84 [44–166] vs. 245 [113–336] x10⁹/L respectively, P = 0.038). Six patients (75%) out of the eight who developed thrombocytopenia had sepsis/septic shock. Likewise, six patients (75%) out of the eight who developed thrombocytopenia were on concomitant meropenem therapy. Table 4 summarizes the characteristics of patients who did or did not develop linezolid-associated thrombocytopenia.

Table 3

Characteristics of patients who developed thrombocytopenia:
Pt. no.	Age	Treatment duration (days)	SCr (mg/dL)	Baseline platelet (x 10⁹/L)	Platelet after linezolid (x10⁹/L)	Linezolid trough level (mg/L)	Concomitant drugs	Comorbidities
1.	30 days	16	86	37	14	6.2	Meropenem, Amphotericin B	ICU, neonatal sepsis
2.	5 days	8	72	80	39	7.5	Meropenem, Amphotericin B	ICU, neonatal sepsis
3.	18 days	22	54	246	30	14.4	Meropenem, Azithromycin	ICU, neonatal sepsis/septic shock
4.	10 months	27	32	33	10	6.5	Meropenem, Caspofungin	ICU, ALL, sepsis/septic shock
5.	7 years	7	29	52	17	3.8	Meropenem, Amikacin	ICU, ALL
6.	1 year	8	56	41	28	4	Meropenem, Gentamicin	ICU, sepsis/septic shock
7.	11 years	34	65	149	59	6.1	Piperacillin/ tazobactam	ICU, myocarditis
8.	11 years	14	176	171	70	12.2	Ceftriaxone, Acyclovir	ICU, AKI, meningitis, sepsis/septic shock
ALL: Acute Lymphocytic Leukemia, AKI: Acute Kidney Injury, ICU: Intensive care Unit, SCr: Serum creatinine.

Table 4

Clinical characteristics of patients who did or did not develop linezolid-associated thrombocytopenia
	Thrombocytopenic (n = 8)	Non-thrombocytopenic (n = 9)	P-value
Age (years)	0.92 [0.06–10.75]	1 [0.32–6.5]	0.963
Age group (Neonates/older pediatrics)	3 (60%) / 5 (42%)	2 (40%) / 7 (58%)	0.490
Gender (male)	5 (62%)	5 (56%)	0.771
Baseline PLT (x10⁹/L)	84 [44–166]	245 [113–336]	0.038
Baseline PLT < 150 x10⁹/L	6 (75%)	2 (22%)	0.030
SCr (mg/dL)	0.68 [0.42–0.93]	0.39 [0.35–1.32]	0.481
CrCl (ml/min)	92 [56–159]	95 [50–135]	1.000
Trough level (mg/L)	6.5 [3.9–11.0]	4.6 [2.3–6.8]	0.183
Duration of linezolid therapy (days)	15 [8–25]	5 [2-7.5]	0.006
ICU admission	8 (100%)	4 (44%)	0.12
Sepsis/septic shock	6 (75%)	2 (22%)	0.030
Concomitant use of meropenem	6 (75%)	2 (22%)	0.030
Concomitant use of piperacillin/ tazobactam	1 (12.5%)	2 (22%)	0.596
Data represented as median [IQR] or n (%). Statistically significant P-values are highlighted in bold.

This is the first study to evaluate the achievement of the PK/PD target and the incidence of hematological toxicity of linezolid in hospitalized pediatric patients from the MENA region. The results of our analysis indicate that only 53% of all pediatric patients did achieve linezolid target trough levels of 2–7 mg/L despite following standard dosing regimens; 29% had supratherapeutic concentrations and 18% had subtherapeutic levels. Optimizing linezolid dosing in pediatrics is crucial in order to ensure efficacy, avoid treatment failure and increased linezolid resistance in multi-drug-resistant Gram-positive organisms, as well as minimize the risk of adverse effects [35–37]. Evidence to describe plasma exposure or to determine the percentage of patients achieving the PK/PD target of linezolid in children and neonates using standard dosing regimens is sparse. However, our results are consistent with a previous retrospective analysis of pediatric patients in Italy by Cojutti et al., which included 14 pediatric patients aged 2–11 years and concluded that utilizing standard doses of linezolid resulted in therapeutic plasma concentrations of linezolid in only approximately 50% of all cases [25]. Although the median [IQR] trough levels in the older pediatrics of our study (3.9 [1.95–6.5] mg/L) were slightly higher than those reported by Cojutti et al., which was 2.57 [1.33–5.12] mg/L, despite the administration of similar doses [25]. This difference might be attributed to the ethnic differences in PK or PD, such as genetic variation, and differences in body weight, height, and fat distribution[45]. Moreover, our results show that the median linezolid trough concentration in neonates is significantly higher than that of the older pediatric population (7.1 [6.2–11.0] vs. 3.9 [1.95,6.5] mg/L, respectively, P = 0.04). This could be attributed to reduced linezolid clearance in neonates due to immature renal and hepatic function [46]. No studies in neonates have been published to describe the achievement of linezolid PK/PD target to compare our results with.

In our study, thrombocytopenia was the most observed linezolid-associated hematological adverse effect, affecting approximately half of the patients. This finding aligns with previous literature highlighting linezolid's potential to induce thrombocytopenia in neonates and pediatric populations [32–34, 47]. Despite the widespread use of linezolid in clinical practice, there is no consensus on the incidence of its hematological toxicity in pediatrics, and the rates vary markedly from country to country, possibly due to ethnic differences [31–34]. Moreover, our results indicate a higher incidence of thrombocytopenia among neonates compared to older pediatric patients (60 vs. 42%, respectively), possibly reflecting differences in drug metabolism or susceptibility to hematologic toxicity across pediatric age groups [46].

Anemia, while less frequent than thrombocytopenia, was also noted in a subset of our patient population, all of whom concurrently exhibited thrombocytopenia. This observation suggests that myelosuppression is the most likely common underlying mechanism or pathway contributing to both hematologic toxicities [48].

All patients who developed hematologic toxicities in our study had received linezolid treatment for more than seven days, highlighting the potential dose-duration relationship in the development of these adverse events. The median duration of linezolid treatment was significantly longer in patients who developed thrombocytopenia compared to the patients who did not (15 [8–25] vs. 5 [2-7.5] days, respectively, P = 0.006). This finding comes in agreement with previous studies that identified that linezolid treatment duration of more than 10–14 days was a significant risk factor for developing hematological toxicity [32, 47, 49]. A meta-analysis by Kato et al showed that the incidence of thrombocytopenia increased by 5 times in pediatric patients receiving linezolid treatment for more than 14 days [32].

Despite the absence of significant differences in median trough concentrations between patients with and without hematologic toxicities (6.5 [3.9–11.0] vs. 4.6 [2.3–6.8], P = 0.183), a trend towards higher trough levels was observed in those who developed thrombocytopenia. This suggests that high linezolid exposure may predispose patients to heightened susceptibility to linezolid-induced hematologic adverse events. This finding was supported by previous studies; for example, Ogami et al. found that thrombocytopenia occurred in 3 (21%) out of 14 pediatric Japanese patients. Patients who developed thrombocytopenia had significantly higher average linezolid trough concentrations than those who did not (19.9 vs. 7 mg/L, respectively) [33]. Likewise, Duan et al. reported that thrombocytopenia occurred in 19.9% of neonatal patients with sepsis, and patients who developed thrombocytopenia had significantly higher troughs compared to those who didn’t (11.42 vs. 5.5 mg/L, respectively) [47]. In another study conducted on 413 Chinese pediatric patients, thrombocytopenia and anemia were the most prevalent linezolid-associated hematological toxicity that was reported in 17.8% and 15.2% of the patients, respectively. Patients with an AUC₂₄ > 120 mg/L.h were more likely to exhibit anemia within 7 days after the end of linezolid treatment, whereas those with an AUC₂₄ > 93 mg/L/h were more likely to exhibit thrombocytopenia at 8–15 days post-treatment [50]. Collectively, these results suggest that linezolid-associated hematological toxicity is influenced by both treatment duration and exposure, and hence, blood levels should be routinely monitored in patients receiving linezolid therapy, starting early during treatment.

Other significant risk factors for hematological toxicity that were identified in our study include low platelet count at baseline, sepsis/septic shock and concomitant meropenem use. We identified that a baseline platelet count of less than 150 x 10⁹/L is a significant risk factor for linezolid-induced thrombocytopenia. A similar finding was reported for low baseline platelet count by Duan et al in neonates [47] and by Choi et al in adults [51], and by Thi Phuong et al for sepsis/septic shock in adults [52]. Other studies demonstrated that the concomitant use of meropenem, piperacillin/tazobactam, levofloxacin, or caspofungin was a risk factor for the development of thrombocytopenia in patients receiving linezolid [53–55]. It was an anticipated finding that the number of patients receiving meropenem and linezolid combination therapy in ICU patients would be higher than other combination therapies considering the antimicrobial resistance profile of the ICUs. Other antibiotics were not identified as risk factors for linezolid-associated thrombocytopenia in our study, which may be attributed to the small number of patients treated with other antibiotics. The exact mechanism by which linezolid-meropenem combination therapy increases the risk of thrombocytopenia is unclear. The possible explanations include the additional myelosuppression effect that inhibits the production of platelets and the accelerated activation of the complement system that promotes the destruction of platelets [48, 56, 57].

The high prevalence of linezolid-associated hematological toxicities among our study population could be attributed to the high proportion of patients with concurrent multiple risk factors. This finding underscores the complex interplay between these factors and highlights the importance of vigilant monitoring for detecting such risk factors prospectively in addition to timely intervention, especially in patients receiving prolonged courses of linezolid therapy.

Linezolid’s appropriate indications include intolerance to or failure of vancomycin therapy [58, 59]. However, linezolid was prescribed inappropriately as a first-line agent in 35% of our patients. A similar result was previously reported by Matrat et al in a neonatal ICU in France [13]. Buccelatto et al. reported a 3-fold increase in linezolid prescriptions from 2004 to 2011 in Italian hospitalized children [14], while Bagga et al. described a 5-fold increase in linezolid use between 2007 and 2014 in an American children’s hospital [15]. These findings underscore the imperative for judicious antimicrobial prescribing practices and the need for enhanced antimicrobial stewardship programs to optimize antibiotic use, mitigate the risk of resistance, and ensure patient safety [60].

The main limitations of our study were its small sample size and single-center design. These limitations make it challenging to develop a regression model to assess the risk factors associated with linezolid toxicity and to evaluate the correlation between PK/PD indices and clinical outcomes. Studies with larger sample sizes are required to assess the PK/PD profile and toxicity of linezolid in the pediatric population.

About half of the pediatric patients in our cohort failed to achieve the linezolid PK/PD target using standard dosing recommendations. Our study findings, along with previous research, underscore that linezolid-associated hematological toxicity is associated with multiple risk factors, including both treatment duration and exposure, concomitant illness, and medications. A trade-off is necessary between the level of drug exposure required for treatment and safety. The exposure target (trough level or AUC₂₄/MIC) in pediatrics should be further studied, especially for patients with complications and concomitant medications. Healthcare professionals should be vigilant and ensure close monitoring if linezolid is to be initiated in pediatric patients with multiple risk factors for hematological toxicity. Antibiotic therapy de-escalation should be considered as soon as culture results are available.

Ethics approval:

The study was conducted under the Declaration of Helsinki principles and was approved by the IRB at King Saud University Medical City (IRB approval number: E-22-6559).

Consent to Participate:

No consent was required as our study was a non-interventional study.

Acknowledgment:

The author acknowledges financial support from the Researchers Supporting Project number (RSP2023R39), King Saud University, Riyadh, Saudi Arabia.

Funding:

No specific funding was received.

Conflict of interest:

The authors declare that they have no conflict of interest.

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No competing interests reported.

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Evaluation of Pharmacokinetic Pharmacodynamic Target Attainment and Hematological Toxicity of Linezolid in Pediatric Patients

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Sampling, and analytical assay:

PK/PD analysis:

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Patient characteristics and treatment:

PK/PD analysis:

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