Linezolid‐induced lactic acidosis in critically ill patients: A multicentre study of incidence, severity and predictors

Abstract

Introduction

Linezolid, a synthetic oxazolidinone for resistant gram‐positive infections, is generally associated with mild adverse effects such as gastrointestinal disturbances, but more serious reactions like lactic acidosis (LA) have also been reported. LA may be more pronounced in critically ill patients; therefore, this study aims to determine the incidence, severity and predictors of linezolid‐associated LA in this vulnerable population.

Methods

We conducted a retrospective observational study of adult ICU patients receiving linezolid from January 2021 to May 2025. Data on demographics, comorbidities, linezolid regimen, concomitant medications and laboratory values were collected. Multivariate logistic regression was used to identify predictors of LA.

Results

Of 904 patients screened, 551 were included (mean age 56 years; 73.3% male). LA occurred in 10.7% (n = 59) and was classified as moderate (22%), severe (49%) or critical (29%), with a mean onset of 4 days. Independent predictors of LA included linezolid at a daily dose of 600 mg (aOR = 50.4; p = 0.028), sepsis (aOR = 2.61; p = 0.042), infections other than pneumonia (aOR = 4.0; p = 0.042) and the use of norepinephrine (aOR = 3.56; p = 0.005).

Conclusion

Linezolid‐associated lactic acidosis is a frequent and often severe complication in ICU patients, typically developing early during therapy. Sepsis, non‐pneumonia infections and norepinephrine use were identified as key risk factors. These findings highlight the need for early recognition and vigilant monitoring of high‐risk patients to promote safer use of linezolid in critically ill populations.

What is already known about this subject

• Linezolid, a synthetic oxazolidinone, has been associated with rare but potentially life‐threatening lactic acidosis, likely through inhibition of mitochondrial protein synthesis, which impairs cellular energy metabolism.

• Critically ill patients in the intensive care unit (ICU) are particularly susceptible to adverse drug effects because of underlying organ dysfunction, complex metabolic disturbances, polypharmacy and prolonged exposure to antimicrobial therapy.

• Despite these vulnerabilities, most studies on linezolid‐associated lactic acidosis have been conducted in general hospital populations, leaving the incidence, severity and clinical consequences in ICU patients poorly defined.

What this study adds

• In a large multicentre ICU cohort, linezolid‐associated lactic acidosis occurred in 10.7% of patients and was frequently severe or critical, with the majority of cases developing within the first week of therapy.

• Sepsis, infections other than pneumonia and use of norepinephrine were independently associated with a higher risk of developing lactic acidosis during linezolid treatment.

• These findings highlight the importance of early lactate monitoring and increased clinical vigilance when prescribing linezolid to critically ill, high‐risk patients, providing evidence to inform safer management strategies in this vulnerable population.

1. INTRODUCTION

Linezolid is a synthetic oxazolidinone antimicrobial agent. In 2000, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of infections caused by gram‐positive bacteria, including vancomycin‐resistant Enterococcus faecium (VREF), methicillin‐resistant Staphylococcus aureus (MRSA) and multidrug‐resistant tuberculosis. ¹ , ² As a protein synthesis inhibitor, linezolid works by suppressing bacterial protein production by interfering with translation. It exerts its actions by binding to the 50S ribosomal subunit at the 23S rRNA site, thereby preventing the formation of a functional 70S initiation complex. This blockade halts translation, inhibits protein synthesis and ultimately suppresses bacterial proliferation. ³

The most frequently reported adverse effects of linezolid include gastrointestinal disturbances (e.g., nausea and diarrhoea) and reversible myelosuppression, particularly thrombocytopenia. ⁴ A rare but potentially fatal adverse reaction is linezolid‐induced lactic acidosis (LA), which may progress to multiorgan failure and death. This complication was first described by Apodaca and Rakita in 2003 and has since been recognized as a clinically significant toxicity to consider when initiating therapy. ⁵ , ⁶ Although the precise mechanism is not fully understood, LA is believed to result from linezolid's inhibition of mitochondrial protein synthesis, which compromises oxidative phosphorylation and limits aerobic ATP production. The resulting shift towards anaerobic metabolism leads to lactate accumulation, presenting clinically with nonspecific symptoms such as nausea, vomiting, abdominal pain, malaise or tachypnea. ⁵

The true incidence of linezolid‐induced LA remains uncertain. Most available evidence is derived from case reports and small case series, with only a few limited observational studies attempting to estimate its occurrence. ⁷ , ⁸ , ⁹ , ¹⁰ In one retrospective study conducted at an 860‐bed university hospital, 72 patients treated with linezolid were compared with 72; age‐ and indication‐matched patients, receiving teicoplanin. LA developed in five patients (6.8%) in the linezolid group, whereas none of the teicoplanin‐treated patients were affected. ⁷ Similarly, a retrospective cohort study comparing linezolid (n = 94) with vancomycin (n = 313) reported a markedly higher incidence of LA in the linezolid group (10.6%) compared with the vancomycin group (0.3%). After propensity score matching, this difference remained significant, with LA occurring in 10.0% of linezolid‐treated patients and none of those treated with vancomycin (p = 0.004). ⁸

Critically ill patients in the intensive care unit (ICU) are particularly vulnerable to adverse drug effects due to the severity of their underlying illnesses, organ dysfunction, complex metabolic disturbances, polypharmacy and prolonged exposure to antimicrobial therapy, all of which may increase the risk of adverse drug reactions. ¹¹ Linezolid‐induced LA in this population may have more pronounced clinical consequences; however, most available studies have been conducted in general hospital populations rather than ICU patients. Moreover, existing studies are small, do not categorize cases according to the severity of LA and rarely examine clinical outcomes or the temporal relationship between linezolid exposure and lactate elevation. These gaps highlight the need to specifically investigate LA in ICU settings to better define its incidence, severity spectrum and risk factors, ultimately informing safer monitoring and management strategies for this high‐risk population. Therefore, the objective of this study is to determine the incidence, severity and predictors of linezolid‐associated LA in critically ill ICU patients.

2. METHODS

2.1. Ethical approval

This study was approved by the Institutional Review Board of the Medical Research Center, Hamad Medical Corporation (HMC), Qatar (MRC‐01‐23‐342). Given its retrospective design, the requirement for informed consent was waived. To protect patient confidentiality, all data were anonymized, and identifiers were replaced with coded variables.

2.2. Study design and setting

This was a retrospective observational study conducted across all ICUs (surgical, trauma, cardiac and medical) at HMC facilities. The critical care network comprised 11 ICU units distributed across eight hospitals: Hamad General Hospital (SICU, MICU, TICU); Al Wakra Hospital (MICU and SICU combined in a single unit); Al Khor Hospital (MICU); the Ambulatory Care Center (SICU); Aisha Bint Hamad Al Attiyah Hospital (MICU); Hazem Mebaireek General Hospital (MICU); Heart Hospital (CICU, CTCCU); and the National Center for Cancer Care and Research (MICU). The study period spanned from January 2021 to May 2025. All pertinent patient records were retrieved through an automated query of the computerized pharmacy system, providing a robust and systematic method for case ascertainment.

2.3. Study sample and eligibility criteria

Universal sampling (i.e., whole‐population sampling) was employed in this study; therefore, all eligible patients within the study period (January 2021 to May 2025) were included, and no separate sample size calculation was required.

This study encompassed all adult patients (≥18 years) admitted to the surgical, trauma or medical ICUs across all HMC hospitals who received linezolid during their hospitalization. Patients were excluded if they (1) received linezolid for less than 48 h (insufficient exposure to potentially elicit mitochondrial toxicity), (2) had incomplete laboratory data precluding confirmation of LA, (3) were not admitted to an ICU during linezolid therapy or (4) presented with elevated baseline lactate levels (>4 mmol/L), to ensure that only new‐onset lactate elevations were captured and to allow a clearer temporal assessment of the relationship between linezolid therapy and the development of LA.

2.4. Data collection and variables

Data were systematically extracted for all adult patients who received linezolid during hospitalization. The extraction sheet included patient characteristics (age, gender, weight, nationality) and linezolid regimen details (dose, route of administration, duration, indication). Relevant comorbidities were recorded, including sepsis, malignancy, diabetes, hepatic impairment, mitochondrial disease, recent surgery or trauma, dialysis status and type of oxygen therapy. Use of concomitant medications known to influence LA risk, such as metformin, propofol, vasopressors and inhaled β‐agonists, was extracted for all included patients regardless of LA status. For patients who developed LA, detailed laboratory values were abstracted, including baseline and subsequent lactate levels, creatinine and creatinine clearance, electrolytes, albumin, bicarbonate and pH. These values were obtained from arterial or venous samples, and when unavailable, blood lactate levels were used. These data were further used to calculate the anion gap for metabolic interpretation.

Baseline arterial PaO₂ was also collected to aid in differentiating between Type A (hypoxic) and Type B (non‐hypoxic) LA. Specifically, patients with adequate oxygenation (PaO₂ within the normal range) who developed lactate elevation were more likely to have Type B LA, potentially attributable to linezolid. In contrast, patients with hypoxemia or systemic hypoperfusion—commonly seen in sepsis—were classified as having Type A LA, reflecting tissue hypoxia as the primary driver of lactate accumulation. ¹²

For this cohort, temporal verification was performed to ensure that exposure to concomitant medications occurred prior to or at the time of peak lactate level, thereby preserving the appropriate temporal relationship and avoiding misclassification of downstream treatments as risk factors.

Finally, the onset of LA (days from linezolid initiation) and management strategies were recorded.

2.5. Outcome definitions

LA was defined according to commonly accepted criteria as an elevated blood lactate level (>4 mmol/L) in the presence of a decreased blood pH (<7.35). ¹³ The severity of LA was categorized according to peak lactate levels: mild (2–4 mmol/L), moderate (4–5 mmol/L), severe (5–10 mmol/L) and critical (>10 mmol/L) ¹⁴ ; however, no mild cases are reported in the results, as they do not meet the formal definition of LA.

2.6. Analytical methods

Data collected were analysed using Statistical Package for Social Sciences (SPSS®) Version 21 (IBM Statistics for Windows; IBM Corp, Armonk, New York, USA). Both descriptive and inferential statistics were used for data analysis. Frequencies and percentages were used to summarize categorical variables, while continuous data were presented as mean ± standard deviation (SD) or median (IQR).

Multivariate logistic regression was utilized to analyse the association between LA development during linezolid use and the predefined variables, including age, gender, dose, route, duration, indication, comorbidities (sepsis, malignancy, diabetes, hepatic impairment, mitochondrial disease, recent surgery/trauma, baseline kidney function stage, dialysis), type of oxygen therapy and concurrent medications (metformin, propofol, vasopressors, inhaled beta‐agonist). Baseline arterial PaO₂ was also incorporated into the regression model to account for oxygenation status as a potential confounder and to help differentiate between the types of LA. All variables were deemed clinically relevant and thus were included in the model regardless of their univariable significance. The model estimates were reported as adjusted odds ratio (aOR) with 95% confidence intervals (95% CI). p value of less than 0.05 was deemed significant.

2.7. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22. ¹⁵ , ¹⁶

3. RESULTS

3.1. Patient enrollment and exclusions

We initially assessed a total of 904 patients. Of these, 195 patients were excluded due to inadequate linezolid exposure (<48 h), 54 patients due to missing baseline or follow‐up lactate levels, 44 patients for insufficient data, 32 patients for elevated baseline lactate level, 23 patients because they were not admitted to the ICU and 5 patients due to data duplication or admission on linezolid. This resulted in a final cohort of 551 patients included in the analysis.

3.2. Baseline demographic and clinical characteristics

The mean age of the 551 assessed patients was 56 years (SD 34), and 404 (73.3%) were male. Ethnically, Arabs represented 50.3% (n = 277), South Asians 43.7% (n = 241), Africans (non‐Arab) 2.4% (n = 13) and others 3.6% (n = 20). Comorbidities included sepsis in 60.1% (n = 331), diabetes in 41.7% (n = 230), malignancy in 10.3% (n = 57), hepatic impairment in 8.9% (n = 49), mitochondrial disease in 0.2% (n = 1), recent surgery or trauma in 16.7% (n = 92) and regular dialysis in 16.3% (n = 90). Renal function was frequently impaired: Stage 1 (33.0%, n = 182), Stage 2 (16.5%, n = 91), Stage 3A (10.3%, n = 57), Stage 3B (14.3%, n = 79), Stage 4 (17.2%, n = 95) and Stage 5 (8.5%, n = 47) (Table 1).

TABLE 1.

Baseline characteristics.

	All included patients (n = 551)		Lactic acidosis (n = 59)
Male (n, %)	404	73.3%	43	72.9%
Age (mean, std)	56	34	57.18	19.24
Nationality (n, %)
Arab	277	50.3%	34	57%
South Asian	241	43.7%	24	40%
African (non‐Arab)	13	2.4%	2	3%
Others	20	3.6%	0	0%
Comorbidities (n, %)
Sepsis	331	60.1%	47	79.6%
Malignancy	57	10.3%	11	18.6%
Diabetes	230	41.7%	27	45.7%
Hepatic impairment	49	8.9%	10	17%
Mitochondrial disease	1	0.2%	0	0%
Recent surgery/trauma	92	16.7%	8	13.6%
Dialysis	90	16.3%	18	30.5%
Kidney function (n, %)
Stage 1 (GFR 90 or higher)	182	33.0%	16	27.1%
Stage 2 (GFR 60–89)	91	16.5%	7	11.9%
Stage 3A (GFR 45–59)	57	10.3%	8	13.6%
Stage 3B (GFR 30–44)	79	14.3%	11	18.6%
Stage 4 (GFR 15–29)	95	17.2%	6	10.2%
Stage 5 (GFR less than 15)	47	8.5%	11	18.6%
Concurrent medications (n,%)
Vasopressor	261	47.4%	46	76.7%
Norepinephrine	207	37.6%	35	58%
Phenylephrine	18	3.3%	3	5%
Dopamine	10	1.8%	3	5%
Vasopressin	6	1.1%	0	0%
Dobutamine	4	0.7%	0	0%
Two or more vasopressors	16	2.9%	5	8%
Propofol	130	23.6%	11	18.6%
Inhaled beta‐agonist	88	16.0%	6	10.2%
Metformin	2	0.4%	0	0%
Oxygen therapy
Mechanical ventilation	326	59.2%	40	67%
High‐flow nasal cannula (HFNC)	64	11.6%	7	12%
Room air	58	10.5%	4	6.8%
Nasal cannula	54	9.8%	5	8%
BIPAP	17	3.1%	1	2%
ECMO	9	1.6%	2	3%
CPAP	8	1.5%	0	0%
Simple mask	7	1.3%	0	0%
Venturi mask	7	1.3%	0	0%
Rebreather mask	1	0.2%	0	0%

Vasopressors were used in 47.4% (n = 261), predominantly norepinephrine (37.6%, n = 207), with smaller numbers receiving phenylephrine (3.3%, n = 18), dopamine (1.8%, n = 10), vasopressin (1.1%, n = 6), dobutamine (0.7%, n = 4) and 2.9% (n = 16) requiring two or more agents. Adjunct therapies included propofol (23.6%, n = 130), inhaled beta‐agonists (16.0%, n = 88) and metformin (0.4%, n = 2).

Only 10.5% (n = 58) of patients were maintained on room air; the remainder required oxygen therapy, including mechanical ventilation (59.2%, n = 326), high‐flow nasal cannula (11.6%, n = 64), nasal cannula (9.8%, n = 54), BIPAP (3.1%, n = 17), CPAP (1.5%, n = 8), simple mask (1.3%, n = 7), Venturi mask (1.3%, n = 7), non‐rebreather mask (0.2%, n = 1) and ECMO (1.6%, n = 9).

3.3. Linezolid regimen characteristics

In our patients who received linezolid, the standard dose of 600 mg was used in 99.6% (n = 549), while only 0.4% (n = 2) received 300 mg. The intravenous route was predominant (88.6%, n = 488), with oral administration used in 11.4% (n = 63). Treatment duration was 7 days or less in 64.4% (n = 355), 7–14 days in 29.6% (n = 163) and more than 14 days in 6.0% (n = 33) (Table 2).

TABLE 2.

Characteristics of linezolid regimens.

Dose	300 mg	2	0.4%
	600 mg	549	99.6%
Route	IV	488	88.6%
	Oral	63	11.4%
Duration	7 days or less	355	64.4%
	7 to 14 days	163	29.6%
	More than 14 days	33	6.0%
Indication	Pneumonia or COVID	382	69.3%
	Skin and soft tissue infections	45	8.2%
	Bacteremia	32	5.8%
	Tuberculosis	20	3.6%
	Intra‐abdominal infections/abscess/leakage	11	2.0%
	CNS infections	14	2.5%
	Urinary tract infections	10	1.8%
	Empyema/pleural effusion	9	1.6%
	Sepsis and/or septic shock	6	1.1%
	Infective endocarditis	4	0.7%
	Retropharyngeal infection/tonsilitis	3	0.5%
	Other	15	2.7%
Linezolid stopped		15	2.7%

The most frequent indication was pneumonia/COVID‐19 (69.3%, n = 382), followed by skin and soft tissue infections (8.2%, n = 45), bacteremia (5.8%, n = 32) and tuberculosis (3.6%, n = 20). Less common indications included intra‐abdominal infections/abscess/leakage (2.0%, n = 11), CNS infections (2.5%, n = 14), urinary tract infections (1.8%, n = 10), empyema/pleural effusion (1.6%, n = 9), sepsis/septic shock (1.1%, n = 6), infective endocarditis (0.7%, n = 4) and retropharyngeal infection/tonsillitis (0.5%, n = 3). Linezolid therapy was discontinued in 2.7% (n = 15) of patients.

3.4. LA incidence and parameters

A total of 59 patients (10.7%) developed LA during linezolid therapy. Of these, 22.0% (n = 13) were classified as moderate, 49.2% (n = 29) as severe and 28.8% (n = 17) as critical (Figure 1). The mean time to onset of LA was 4 days (SD 4). Among affected patients, the mean arterial pH was 7.2 (SD 0.15), and the mean anion gap was 19.7 (SD 12). Hypoxemia (PaO₂ < 60 mmHg) occurred in 25.4% (n = 15). Baseline renal dysfunction was common in patients who developed LA, observed to varying degrees (Table 3), with 98.3% (n = 58) demonstrating elevated serum creatinine during LA; with a mean creatinine level of 216.7 μmol/L (SD 172.4).

FIGURE 1.

Severity of linezolid‐induced lactic acidosis.

TABLE 3.

Clinical and laboratory features of lactic acidosis.

Developed lactic acidosis		59	10.7%
	Moderate	13	22.0%
	Severe	29	49.2%
	Critical	17	28.8%
Onset of lactic acidosis (mean, std)		4	4
Baseline kidney function	Stage 1 (GFR 90 or higher)	16	27.1%
	Stage 2 (GFR 60–89)	7	11.9%
	Stage 3A (GFR 45–59)	8	13.6%
	Stage 3B (GFR 30–44)	11	18.6%
	Stage 4 (GFR 15–29)	6	10.2%
	Stage 5 (GFR less than 15)	11	18.6%
Creatinine level elevation		58	98.3%
Creatinine level during LA (mean, std)		216.7	172.4
PH (mean, std)		7.2	0.15
Anion gap (mean, std)		19.7	12
PaO2 (less than 60)		15	25.4%

3.5. Predictors of LA

A multivariable logistic regression model was used to identify factors independently associated with the development of LA during linezolid therapy. The model was statistically significant, indicating that at least one variable had a meaningful effect on LA occurrence (Table 4).

TABLE 4.

Multivariate regression analysis results.

Risk factor	p value	aOR	95% C.I. For aOR
			Lower	Upper
Female (ref. male)	0.997	1.002	0.444	2.258
Age more than 65 years old (ref. 65 years or less)	0.436	0.696	0.279	1.734
600 mg (ref. 300 mg)	0.028	50.412	1.511	1682.385
PO (ref. IV)	0.756	0.809	0.214	3.068
Indication (ref. pneumonia)	0.532
SSTI	0.156	2.384	0.719	7.905
Bacteremia	0.903	0.905	0.179	4.563
TB	0.358	2.039	0.446	9.334
Empyema	0.278	3.642	0.352	37.647
Intraabdominal infections	0.999	0.000	0.000
UTI	0.580	1.990	0.174	22.800
CNS infections	0.990	0.985	0.105	9.263
Others	0.027	4.003	1.169	13.707
Comorbidities
Sepsis	0.042	2.612	1.037	6.582
Malignancy	0.071	2.569	0.924	7.141
Diabetes	0.596	1.223	0.581	2.575
Hepatic impairment	0.267	1.801	0.637	5.094
Mitochondrial disease	1.000	0.468	0.000
Recent surgery/trauma	0.812	0.886	0.325	2.415
Dialysis	0.565	1.376	0.465	4.072
Developed hypoxia	0.997	11x10^15	0.000	4.072
Oxygen therapy (ref. mechanical ventilation)	0.997
HFNC	0.496	1.479	0.480	4.557
Room air	0.701	0.749	0.171	3.272
Nasal cannula	0.545	0.643	0.154	2.687
BIPAP	0.998	0.000	0.000
ECMO	0.560	1.737	0.271	11.136
CPAP	0.999	0.000	0.000
Simple mask	0.999	0.000	0.000
Venturi mask	0.999	0.000	0.000
Rebreather mask	1.000	0.000	0.000
Other medications
Metformin	0.999	0.000	0.000
Propofol	0.209	0.574	0.242	1.364
Vasopressors	0.148
Norepeniphrine	0.005	3.560	1.479	8.570
Phenylephrine	0.903	0.866	0.084	8.918
Dopamine	0.196	4.753	0.448	50.389
Vasopressin	0.999	0.000	0.000
Dobutamine	0.999	0.000	0.000
Two or more vasopressor	0.126	4.111	0.671	25.186
Inhaled beta‐agonist	0.792	0.871	0.312	2.433
Duration of therapy (ref. less than 7 days)	0.440
7–14 days	0.262	0.607	0.253	1.453
More than 14	0.694	1.304	0.347	4.903
Kidney function category (ref. Stage 1)	0.545
Stage 2	0.252	0.505	0.157	1.626
Stage 3A	0.713	0.789	0.223	2.795
Stage 4	0.884	0.913	0.268	3.114
Stage 5	0.220	0.458	0.132	1.593
Stage 6	0.690	1.344	0.314	5.744

Note: Bold formatting is used to denote statistically significant values based on a predefined significance threshold (p < 0.05).

After adjustment for all covariates, patients receiving linezolid at a dose of 600 mg had significantly higher odds of developing LA compared to those receiving 300 mg (aOR = 50.4; 95% CI 1.51–1682.385; p = 0.028). Patients treated for infective endocarditis, pleural effusion or retropharyngeal infection/tonsillitis demonstrated an increased risk of developing LA compared to pneumonia (aOR = 4.0; 95% CI 1.169–13.707; p = 0.042). Sepsis (aOR = 2.612; 95% CI 1.037–6.582; p = 0.042) was an additional independent predictor that significantly increased the odds of developing LA while receiving linezolid. Among vasopressor agents, norepinephrine use was strongly associated with LA (aOR = 3.56; 95% CI 1.479–8.57; p = 0.005).

Other factors—including age >65 years, gender, diabetes, hepatic impairment, recent surgery or trauma, kidney function, dialysis status, development of hypoxia, route and duration of linezolid therapy and type of oxygen support—were not significantly associated with the development of LA (p > 0.05).

4. DISCUSSION

4.1. Summary of main findings

A total of 551 patients receiving linezolid were included in this analysis across multiple ICU settings in Qatar. The incidence of linezolid‐associated LA was 10.7%. Notably, 64.7% of LA cases developed within the first week of therapy. Among affected patients, 49.2% were classified as severe and 28.8% as critical. After adjustment for all covariates, several factors were independently associated with the development of LA during linezolid therapy. Patients receiving linezolid at a dose of 600 mg had significantly higher odds of LA compared with those receiving 300 mg. Certain infection indications, including infective endocarditis, pleural effusion, and retropharyngeal infection/tonsillitis, were also associated with increased risk compared with pneumonia. In addition, sepsis and norepinephrine use were independently associated with higher odds of LA.

4.2. Findings in the context of other research

4.2.1. Onset of LA

According to FDA reports, linezolid‐associated LA most commonly developed during the second week of therapy, with only 6 of 65 cases (9.2%) occurring within the first seven days of treatment initiation. ¹⁷ In contrast, our findings demonstrated that 64.7% of cases arose within the first week of exposure. This discrepancy is likely attributable to differences in study settings. Whereas the FDA data were derived from a broad range of clinical contexts, our study was confined to ICUs, where patients are critically ill. Critical illness is often accompanied by systemic inflammation, tissue hypoperfusion, multiorgan dysfunction, and polypharmacy, all of which can impair oxidative metabolism and reduce lactate clearance. ⁵ , ¹⁸ Under these conditions, linezolid's mitochondrial inhibitory effects may accelerate lactate accumulation, leading to a more rapid onset of LA compared with the more physiologically stable, heterogeneous populations represented in non‐ICU studies.

4.2.2. Incidence and severity of LA

The incidence of LA in our study was 10.7%. In comparison, an analysis of the FDA adverse event reporting system reported an incidence of 4.42% in a general patient cohort. ¹ Similarly, Im et al. observed an incidence of 2.7% among a non‐ICU inpatients treated with linezolid, using a strict definition of definite LA (pH < 7.24 and lactate >4 mmol/L), compared with a matched cohort receiving teicoplanin. ² Conversely, a study conducted in a tertiary hospital in Japan reported a higher incidence of 10.6% among linezolid‐treated patients, ³ a finding more consistent with our results and notably higher than those reported in broader or non‐ICU populations. This similarity may be explained by the higher prevalence of critical illness and polypharmacy in tertiary hospitals, which—as discussed previously—play a key role in the variability of reported incidence rates across studies.

In our cohort, 22% of patients were classified as having moderate LA, while 49.2% experienced severe LA, and 28.8% developed critical LA. The severity of LA is often underreported in published studies and case series, despite its established association with adverse outcomes. Severe LA is particularly concerning, as it is linked to profound hemodynamic instability, including reduced myocardial contractility and impaired responsiveness to vasopressors. These pathophysiological derangements can precipitate multiorgan failure and substantially increase mortality risk. ¹⁹ , ²⁰ Therefore, the inclusion of LA severity grading in future studies may provide a more comprehensive understanding of its clinical impact.

4.2.3. Patient factors associated with LA

ICU‐related factors

Sepsis

In our study, sepsis was significantly associated with increased odds of developing linezolid‐associated LA (aOR = 2.612; 95% CI 1.037–6.582; p = 0.042). This contrasts with the findings of Mori et al., who reported no significant difference in risk between patients with SOFA (sequential organ failure assessment) scores ≥11 and those with lower scores. ⁸ The absence of association in their study may reflect a limited sample size—only 30 patients were included in the SOFA subgroup—resulting in insufficient statistical power.

Sepsis likely amplifies the risk of linezolid‐associated LA because both conditions disrupt cellular energy metabolism. Linezolid inhibits mitochondrial protein synthesis, diminishing oxidative phosphorylation and promoting lactate accumulation. Concurrently, sepsis contributes through tissue hypoperfusion, mitochondrial dysfunction and impaired lactate clearance secondary to hepatic or renal dysfunction, which may also delay linezolid elimination. Collectively, these factors synergistically elevate lactate levels and increase the likelihood of LA. ²¹ , ²² Although sepsis typically causes type A LA and linezolid is more often linked to type B LA, both mechanisms often coexist in critically ill ICU patients, compounding the risk and severity of LA. ²³ , ²⁴

Vasopressor use

Use of the vasopressors norepinephrine was independently associated with an increased likelihood of developing linezolid‐associated LA. Although norepinephrine has been associated with hyperlactatemia in critically ill patients—particularly at higher doses—this relationship is often difficult to separate from confounding by shock severity and impaired lactate clearance, and it remains debated whether norepinephrine exerts a clinically meaningful direct lactate‐raising effect. ²⁵ , ²⁶ , ²⁷ , ²⁸ In contrast, epinephrine is the vasopressor most consistently reported to cause a direct increase in lactate via β‐adrenergic (especially β2)–mediated stimulation of aerobic glycolysis in skeletal muscle, which can occur independent of tissue hypoxia; lactate may then be recycled by the liver (Cori cycle). ²⁹ Notably, none of the patients in our cohort received epinephrine; therefore, we could not evaluate this mechanism within our data.

In critically ill populations, distinguishing whether LA arises from underlying disease severity, vasopressor exposure, or linezolid therapy remains challenging. Nevertheless, the observed association between norepinephrine use and LA underscores the need for heightened clinical vigilance and close lactate monitoring in patients receiving linezolid who also require vasopressor support.

Comorbid diseases

Diabetes

Several studies have explored patient‐related factors influencing the risk of LA. Im et al. reported that preexisting diabetes was not significantly associated with linezolid‐induced LA. Consistent with these findings, our study, which included 230 patients with diabetes, demonstrated via multivariate logistic regression that diabetes was not a significant risk factor for linezolid‐associated LA. ⁷

Hepatic impairment

Although Mori et al. attempted to assess the impact of liver dysfunction, limited case numbers precluded meaningful conclusions. ⁸ In our study, hepatic impairment was not significantly associated with linezolid‐induced LA (1.9 vs. 0.069; 95% CI, 0.637–5.094). Hepatic impairment was identified based on abnormal liver function tests (LFTs); using validated scoring systems, such as the Child–Pugh classification, could provide a more accurate evaluation of clinically relevant hepatic dysfunction. However, the retrospective design limited the availability of such data. ³⁰

Renal impairment

In our study, renal function was assessed both at baseline and during linezolid therapy. We found that renal impairment did not significantly increase the risk of LA. Similarly, Im et al. reported that renal impairment, defined as an eGFR <50 mL/min, was not associated with a higher incidence of LA. ⁷ In contrast, Mori et al. demonstrated that severe renal impairment (eGFR <30 mL/min) was linked to a markedly increased risk, with an odds ratio of 7.4 (95% CI, 1.0–84.4; p = 0.02). ⁸ Unlike previous studies, our analysis considered both renal impairment and dialysis use.

A potential explanation for the difference is that many ICU patients in our cohort underwent intermittent dialysis sessions as needed during their admission. Dialysis and other forms of renal replacement therapy (RRT) play a central role in correcting severe metabolic acidosis in critically ill patients, especially when medical management alone is insufficient. ³¹ , ³² This ICU‐specific context may account for the absence of a significant association between renal impairment and LA in our study, although the precise mechanisms remain uncertain.

4.3. Clinical implications

Currently, linezolid therapy requires regular complete blood count (CBC) monitoring—weekly for high‐risk patients and more frequently as clinically indicated. For tuberculosis (TB) treatment, guidelines recommend baseline CBC, close monitoring during the first 6–8 weeks, and monthly assessments of hematologic parameters, neuropathy and vision thereafter. ³³ However, there are no established guidelines for monitoring linezolid‐associated LA, nor are there clear recommendations on when therapy should be discontinued or which alternative agents should be considered if LA develops. In our cohort, only 2.7% of patients with LA discontinued therapy, reflecting a relatively low discontinuation rate. This highlights the urgent need for evidence‐based criteria defining the threshold for intervention and the optimal timing for discontinuation to guide clinical decision‐making.

4.4. Strengths and limitations

A key strength of our study is the relatively large sample size, surpassing that of most prior investigations on this topic. The study population—critically ill patients in ICU—represents a high‐risk group that has been underrepresented in prior research. The multicentre design further enhances the generalizability of our findings, as data were collected across diverse ICU settings, including cardiac, surgical, trauma, and medical units. Additionally, the systematic assessment of LA severity is a unique feature of this study, providing clinically relevant insights to guide future management of linezolid‐associated cases.

Nevertheless, some limitations should be acknowledged. The retrospective design may have resulted in incomplete or missing data due to gaps in medical record documentation.

While the ICU setting is a strength, it introduces potential confounding, as LA in critically ill patients may arise from multiple etiologies such as sepsis, shock, hypoperfusion, or concomitant medications. To mitigate this, we adjusted for key clinical variables—such as PaO₂ levels, comorbid conditions, and concomitant medications—in the multivariate analysis; however, fully isolating the causal role of linezolid in LA remains challenging given the complexity of critical illness. Consequently, residual confounding is possible, and causality cannot be definitively established. Furthermore, the observational design precludes assessment of mechanistic pathways, and some subclinical or transient cases of LA may have been missed if lactate measurements were not performed systematically. These limitations warrant cautious interpretation of our findings and underscore the need for prospective studies to further delineate the role of linezolid in LA among critically ill patients.

5. CONCLUSION

In this multicentre retrospective study of critically ill ICU patients, linezolid‐induced LA occurred in 10.7% of cases, with nearly half classified as severe and over a quarter as critical. Most cases developed within the first week of therapy, highlighting the rapid onset of this potentially life‐threatening adverse effect in high‐risk populations. Independent predictors of LA included sepsis, infections other than pneumonia and the use of norepinephrine. These findings underscore the need for heightened vigilance, close monitoring, and early recognition of LA in ICU patients receiving linezolid. Given the limited guidance on monitoring and management, future studies should focus on developing evidence‐based protocols to optimize patient safety, including risk stratification, laboratory surveillance and criteria for treatment modification or discontinuation.

AUTHOR CONTRIBUTION

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

CONFLICT OF INTEREST STATEMENT

The authors declare no competing interests.

Naseralallah L, Aboujabal B, Noureddine Z, Aboujabal K, Koraysh S. Linezolid‐induced lactic acidosis in critically ill patients: A multicentre study of incidence, severity and predictors. Br J Clin Pharmacol. 2026;92(7):2239‐2249. doi: 10.1002/bcp.70496

DATA AVAILABILITY STATEMENT

No additional datasets were generated or analysed during the current study.