Linezolid Dosing in a Morbidly Obese Patient with Methicillin-Resistant Staphylococcus aureus (MRSA) Pneumonia

Design

Case presentation

A 30-year-old morbidly obese male was admitted for treatment of MRSA left leg cellulitis. Past medical history included diabetes, pulmonary embolism, and obstructive sleep apnea. Documented body mass index (BMI) was 84 kg/m².

He was started on vancomycin, however later developed hearing loss and required a switch to daptomycin. By day 21 of hospitalization, he continued to have intermittent fevers and difficulty wakening and ultimately grew positive MRSA sputum cultures despite daptomycin treatment. Chest x-ray imaging resulted in left lung consolidation, which led to intubation and admission to the intensive care unit. Cultures showed sensitivity to linezolid, with a minimum inhibitory concentration (MIC) of 2 mg/L, and therefore, daptomycin was switched to linezolid 600 mg every 12 hours via nasogastric tube.

Serum concentrations of linezolid were obtained at three different points on day 27: 0.4 mg/L (0.5 hours prior to morning dose), 2.78 mg/L (2 hours post-morning dose), and 1.04 mg/L (6 hours post-morning dose). Over a 24-hour interval, the area under the concentration-time curve (AUC) was 30.28 mg*h/L, AUC_0-24h/MIC was 15.14, and time over MIC (T>MIC) was 30%. Unlike study findings including obese patients with BMI 30-54.9kg/m², this patient's AUC/MIC and T>MIC were below target. Despite these values, the patient was extubated after 7 days of linezolid therapy and did clinically improve.

Study Author Conclusions

This case, along with others, suggests that patients with BMI >55 kg/m² may have altered pharmacokinetic and pharmacodynamic linezolid parameters, which may or may not influence clinical response. Additional studies of linezolid pharmacokinetics and clinical outcomes in patients with BMI >55 kg/m² are required. Based on the available literature, the authors report they would consider using standard dosage with careful monitoring of clinical response.

Pharmacokinetics of high dosage of linezolid in two morbidly obese patients

Design

Case presentation

Two morbidly obese patients were discussed together. The first was a < 50 year old male with a body mass index (BMI) of 72 kg/m2 was admitted to the intensive care unit (ICU) for community-acquired pneumonia. The second was a > 60 year old male with a BMI of 66 kg/m2 and acute hypercapnic respiratory failure was admitted to the ICU for diagnosis of healthcare-associated pneumonia and septic shock. Intravenous linezolid was administered at 600 mg Q8hours.

Blood samples were taken to measure plasma concentrations and calculate AUC, Cmax, Cmin and other parameters. Patient 1 had subtherapeutic values for Cmax, Cmin, and AUC, indicating increased clearance and reduced exposure. Patient 2 had adequate Cmax, Cmin and AUC/MIC ratios, suggesting satisfactory drug exposure. Compared to healthy volunteers, both patients had higher volume of distribution, confirming the relationship between weight and volume. The results suggest linezolid pharmacokinetics are strongly influenced by obesity, with standard doses potentially insufficient. Higher than normal doses may be needed for optimal treatment outcomes in obese patients.

Study Author Conclusions

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Design

Prospective, open-label, pharmacokinetic study

N= 20

Objective

To determine the pharmacokinetics of linezolid 600 mg intravenous (IV) every 12 h in moderately and morbidly obese adult bariatric patients as defined by body mass index (BMI) and to determine the relationship between several body size descriptors in this population and individual pharmacokinetic parameters

Study Groups

Moderately obese (n= 10)

Morbidly obese (n= 10)

Inclusion Criteria

At least 18 years old

Exclusion Criteria

Known allergy to linezolid or any other oxazolidinone antibiotic; pregnant or breast feeding; BMI ≥ 55 kg/m²

Methods

Patients were classified as moderately obese (class I and II obesity; BMI 30 to 39.9 kg/m²) or morbidly obese (class III obesity, BMI ≥ 40 kg/m²) prior to study initiation. Patients received five 600 mg linezolid doses q12h IV over 30 minutes, infused via programmed infusion pump through a peripheral IV catheter. Doses were infused after a 1 h fast and was followed by a 2 h fast. Blood samples were collected at 0, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, and 24 h following the fifth dose administered; serum concentrations of linezolid were determined using a high-performance liquid chromatography (HPLC) assay.

Duration

5 days

Outcome Measures

Pharmacokinetic parameters

Baseline Characteristics

Moderately obese (n= 10)

Morbidly obese (n= 10)

Age, years

Female

Total body weight, kg

BMI, kg/m²

Results

Endpoint

Moderately obese (n= 10)

Morbidly obese (n= 10)

p-value

Protein binding, %

Parameters*

AUCτ, μg · h/mL

Cmax, μg/mL

CL, L/h

Vc, L

Vd, L

RCLF

130.3 ± 60.1

20.9 ± 5.0

7.83 ± 1.77

26.4 ± 8.9

44.1 ± 9.9

0.83 ± 0.13

109.2 ± 25.5

18.8 ± 2.6

7.39 ± 2.02

22.3 ± 10.3

62.2 ± 40.3

0.88 ± 0.11

0.32

0.237

0.619

0.358

0.089**

0.349

* AUCτ, AUC calculated from 0-12 h after the 5th dose; Cmax, observed maximum concentration; RCLF, remaining CL fraction; Vc, volume of the central compartment; Vd, total volume of distribution

** Comparison failed a normality test and was analyzed by a Mann-Whitney rank sum test. Excluding a single patient in the morbidly obese group with a calculated Vd of 175.9 liters, the mean Vd for the group is 49.6 ± 6.0 L (p= 0.170).

Protein binding was not observed to be concentration-dependent.

Adverse Events

Common Adverse Events: headache (n= 11) and increased gas/flatulence (n= 5)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

In summary, these data demonstrate that standard doses of 600 mg linezolid every 12 h in individuals weighing up to approximately 150 kg should provide AUCτ exposures similar to those of nonobese patients. Additionally, BMI is a poor predictor for adjusting dosing regimens in the obese population, and a more accurate descriptor of body mass should be utilized. Finally, a correlation between Vd and several body weight descriptors was observed, suggesting that concentrations in patients weighing more than the participants included in this study may be altered, as described by previous studies.

InpharmD Researcher Critique

Although this is one of the only studies evaluating IV linezolid in the morbidly obese population, patients with a BMI ≥ 40 kg/m² were included, with a cutoff of 55 kg/m². The average BMI within the morbidly obese patient group was 45.3 kg/m², thus extrapolation of results to patients with a BMI >50 kg/m² is limited.