Levofloxacin weight-adjusted dosing and pharmacokinetic disposition in a morbidly obese patient

Sir,

Obese patients may show differences in several pharmacokinetic parameters of many commonly used antimicrobials,¹ and they often require a correction of the recommended dosages for non-obese subjects. Unfortunately, studies evaluating antimicrobial dosages in obese patients are limited and only a few are focused on patients with morbid obesity. Among fluoroquinolones, dosage recommendations are available only for ciprofloxacin, but data from these studies are contradictory.^2,3 Levofloxacin is increasingly recommended in clinical guidelines for the treatment of respiratory infections, including pneumonia,⁴ and the lack of studies evaluating its plasma concentrations in obese patients can potentially result in treatment failures in this population. We have had the opportunity to study the basic pharmacokinetic/pharmacodynamic parameters of levofloxacin in a patient with severe morbid obesity.

A patient in their mid-50s with severe morbid obesity (weight, 179 kg; height, 1.74 m; and body mass index, 56.2 kg/m²), chronic obstructive pulmonary disease and sleep apnoea–hypopnoea syndrome treated with nasal continuous positive airway pressure (CPAP) was admitted to an emergency department. The patient presented with an acute hypercapnic respiratory failure secondary to a lower respiratory tract infection and cocaine abuse. On admission, the chest X-ray did not show opacities. Blood test results were: serum creatinine, 73.37 μmol/L; creatinine clearance, 78 mL/min; leucocyte count, 6990/mm³ (75.4% neutrophils); and C-reactive protein, 3.2 mg/L. The values of arterial blood gases drawn on room air were: pH, 7.21; PaCO₂, 80 mmHg; and PaO₂, 28 mmHg. Non-invasive mechanical ventilation was immediately initiated and administered for 20 h, followed by nocturnal CPAP in addition to oxygen and standard medical treatment. Sputum cultures yielded Streptococcus pneumoniae susceptible to levofloxacin (MIC = 1 mg/L).

An actual body weight-adjusted levofloxacin dose of 4 mg/kg/12 h (750 mg/12 h) infused intravenously over 1.5 h was started (this dose was calculated according to a ciprofloxacin dosing recommendation in obese individuals²).

On day 3 of levofloxacin treatment, when presumably steady state had been achieved (levofloxacin elimination half-life =6–8 h), serum concentrations were obtained. Serial blood samples were drawn 0, 1.5, 3, 4, 5, 8 and 12 h after the start of the infusion. The calculated pharmacokinetic parameters are detailed in Table 1.

The patient did not receive any medication known to alter the pharmacokinetics of levofloxacin. During levofloxacin treatment, renal function improved (creatinine clearance = 102.3 mL/min) and glucose levels were unchanged. No electrocardiographic abnormalities or any adverse effect related to levofloxacin administration were found. The patient received this dose of intravenous levofloxacin for a total of 6 days, followed by oral levofloxacin at 500 mg/12 h for an additional 4 days. Clinical cure of the respiratory infection was rapidly achieved and the patient was discharged.

Written informed consent was obtained from the patient to use this treatment regimen and to obtain blood samples.

Very few studies have examined fluoroquinolone pharmacokinetics in obese patients,^2,3 and, to our knowledge, this is the first pharmacokinetic evaluation of levofloxacin in a patient with severe morbid obesity. Levofloxacin was administered at an actual body weight-adjusted dose of 4 mg/kg/12 h based on a ciprofloxacin dosage recommendation for obese patients.² With this regimen, the values of C_max and CL were similar to those obtained in non-obese healthy volunteers receiving a dose of 750 mg/24 h,⁵ the dose recommended for the treatment of community-acquired pneumonia in adults,⁴ but the AUC_0–24 was double (143.27 mg h/L, twice the value of the AUC_0–τ because levofloxacin was administered twice daily). It has also been previously recommended that the dose of quinolones should be based on a weight correction factor of 45% of excess body weight.³ This dose was administered to a morbidly obese patient who reached a therapeutic peak plasma concentration, but no other pharmacokinetic parameters were reported.⁶ It has been suggested that this lower adjusted dosing could result in low interstitial levofloxacin levels due to impaired levofloxacin penetration in the tissues of obese patients.² In our patient, levofloxacin had larger absolute V_ss and t_1/2 compared with those described in non-obese patients, which may be explained by a significant distribution of levofloxacin into excess weight.¹

Regarding pharmacodynamic parameters, an AUC_0–24/MIC ratio of 143.27 was achieved, a value that exceeds the optimal ratio for favourable outcomes in patients with S. pneumoniae infections.⁷

In conclusion, an intravenous levofloxacin dose of 750 mg/12 h (4 mg/kg/12 h) in our patient with morbid obesity achieved double the adult exposure following a standard dose of 750 mg per day to non-obese healthy volunteers. Consequently, it could be queried whether it is necessary to administer higher body weight-adjusted doses of levofloxacin in this population.

Additionally, the observed longer t_1/2, resulting from an increase in V, suggests that it would be suitable to administer an initial loading dose to achieve the steady state rapidly, but followed by the administration of doses given less frequently than 12 hourly in order to avoid further drug accumulation. Nevertheless, these findings should be confirmed with further pharmacokinetic studies including a higher number of patients to ensure efficacy and avoid dose-related toxicity.

Funding

This study was carried out as part of our routine work. M. V. is supported by FIS through grant CP04/00121 from the Spanish Health Department in collaboration with the research institute of the Hospital de la Santa Creu i Sant Pau, Barcelona, and is a member of the CIBERSAM Network.

Transparency declarations

None to declare.

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