Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0−24) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 μg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.)


Fluoroquinolones, including levofloxacin, display concentration-dependent killing of Mycobacterium tuberculosis (1, 2). Typical daily levofloxacin doses (750 to 1,000 mg) do not reach high AUC/MIC (area under the concentration-time curve over 24 h in the steady state to MIC ratio) targets that have been suggested by studies of the treatment of bacterial pneumonia and murine studies of tuberculosis (TB) (37). High levofloxacin exposures could offer less selection of drug-resistant mutants and a shorter time to sputum culture conversion and relapse-free cure (8, 9). The Opti-Q study (ClinicalTrials registration no. NCT01918397) was a phase II, double-blinded, randomized, dose-ranging clinical trial in patients with multidrug-resistant tuberculosis (MDR TB). We compared 11, 14, 17, and 20 mg/kg/day of levofloxacin administered orally as a single daily dose 7 days per week for 26 weeks, along with an optimized background regimen of second-line TB medications, in patients in Peru and South Africa. Weight banding gave respective doses of 750, 1,000, 1,250, and 1,500 mg daily for patients who weighed ≥60 kg and, due to a minimum dose floor, 750, 750, 1,000, and 1,250 mg daily for patients who weighed <60 kg. Here, we report the noncompartmental pharmacokinetic (PK) results of this comparison.
This study was reviewed and approved by the institutional review board of each participating institution. The study included consenting adults with newly diagnosed, previously untreated, smear-positive (≥2+) pulmonary MDR TB. We used line probe results (MTBDRplus and MTBDRsl; Hain, Nehren, Germany) to screen patients for eligibility pending phenotypic drug susceptibility testing results. Those showing isoniazid and rifampin resistance and fluoroquinolone susceptibility were eligible. Other inclusion criteria included known HIV status (regardless of result and therapy), a weight of ≥40 kg, and a Karnofsky Performance Status score of >60. Full details of eligibility criteria and trial design are available in the published protocol (10). All study treatment doses were directly observed. The optimized background regimen (OBR), comprised of other second-line drugs without a fluoroquinolone, was selected by local investigators in order to conform with local standards of care and guidelines. Levofloxacin 250-mg capsules and matching placebo 250-mg capsules were provided by Macleods Pharmaceuticals and combined in a dose package by the unblinded pharmacist at each site. Each participant received 6 tablets, but investigators, clinicians, and participants were blinded to the dose of levofloxacin. All treatment was ambulatory and supervised by study staff. Study participants were advised to avoid aluminum- and magnesium-containing antacids within several hours of each levofloxacin dosing. Food intake was recorded but not restricted. After 14 to 28 total and at least 3 consecutive daily doses of levofloxacin, plasma samples were collected at 0, 1, 2, 4, 8, 12, and 24 h postdose. Samples were shipped frozen and stored at −80°C until assayed at the University of Florida using a validated high-performance liquid chromatography (HPLC) assay with fluorescence detection. The plasma standard curve for levofloxacin ranged from 0.20 to 15 μg/ml; overall precision was 0.58% to 4.09% (coefficient of variation); quality control sample precision was 2.88% to 3.79%. Phoenix v7.0 (Certara LP, Princeton, NJ) was used for noncompartmental analysis and JMP 10 (SAS Institute, Cary, NC) for Y by X nonparametric statistical analysis (Kruskal-Wallis test, chi-square test) or linear regression (adjusted R2, analysis of variance [ANOVA]). Pairwise comparisons were made using Tukey's honestly significant difference (HSD) test and a comparison of each pair using Student's t test.
Among the 111 participants randomized, 101 participants had evaluable pharmacokinetic data. There were 22, 26, 26, and 27 patients evaluable in the 11-, 14-, 17-, and 20-mg/kg/day levofloxacin dose groups, respectively. Participant characteristics and the levofloxacin doses received are presented in Table 1. Pharmacokinetic results for each of the dosing groups are presented in Tables 2 and 3. The maximum plasma concentration (Cmax) ranged from a low of 5.82 to a high of 35.42 μg/ml (roughly 6-fold range). For comparison, the normal Cmax range for 750 to 1,000-mg doses is 8 to 12 μg/ml (11). Within each dosing group, the Cmax varied approximately 3-fold (Fig. 1). Four of 36 patients (10%) who received a 750-mg dose (using an 11 or 14-mg/kg dose) achieved a Cmax value below 8 μg/ml, the low end of the normal range (11). No patients who received 1,000 mg levofloxacin or more had a Cmax value below 8 μg/ml. Due to weight banding and the 750-mg minimum dose, 14 (54%) patients in the 14-mg/kg group received the same dose as patients in the 11-mg/kg group (Table 1).
TABLE 1 Participant characteristics by treatment arm
CharacteristicValues according to levofloxacin dose (mg/kg) (no. of participants):P valuea (n = 101)
11 mg/kg (22)14 mg/kg (26)17 mg/kg (26)20 mg/kg (27)
Age (median [range]) (yrs)31 (18–69)25 (18–61)28 (18–60)31 (18–67)0.8910
Male (no. [%])13 (59)18 (69)16 (62)13 (48)0.4736
Weight baseline (median [range]) (kg)56 (41–71)59 (42–82)52 (40–75)53 (44–67)0.1688
Creatine clearanceb (median [range]) (ml/min)102 (56–165)102 (54–189)91 (49–180)103 (51–156)0.7630
HIV positive (no. [%])6 (27)4 (15)5 (19)6 (22)0.7784
Levofloxacin dose received     
    750 mg221400 
    1000 mg012240 
    1250 mg00219 
    1500 mg0008 
Kruskal-Wallis or chi-square test.
According to the Cockcroft Gault equation.
TABLE 2 Actual dose and pharmacokinetic parameters sorted by assigned, nominal dose
ParameterMedian value (range) by nominal dose in mg/kg (n = no. of subjects)DifferencesP value
11.0 (n = 22)14.0 (n = 26)17.0 (n = 26)20.0 (n = 27)
Dose (mg)750 (750–750)750 (750–1,000)1,000 (1,000–1,250)1,250 (1,250–1,500)20 > 17 > 14 > 11 
Tmax (h)2 (1–4)2 (1–4)2 (1–4)2 (1–4)20 = 17 = 14 = 110.9747
Cmax (μg/ml)11.90 (5.82–18.69)12.02 (6.90–21.03)14.86 (9.89–29.17)19.17 (13.01–35.42)20 > 17 > 14 = 11<0.0001
AUC0–24 (μg · h/ml)109 (69–204)98 (70–248)145 (103–457)207 (143–534)20 > 17 > 14 = 11<0.0001
t1/2 (h)6.1 (4.2–14.7)6.2 (4.9–11.9)6.7 (4.8–19.4)6.5 (1.8–19.2)20 = 17 = 14 = 110.8062
TABLE 3 Pharmacokinetic parameters sorted by actual dose
ParameterMedian value (range) by actual dose in mg (n = no. of subjects)DifferencesP value
750 (n = 36)1,000 (n = 36)1,250 (n = 21)1,500 (n = 8)
Tmax (h)2 (1–4)2 (1–4)2 (1–4)2 (1–4)20 = 17 = 14 = 110.5159
Cmax (μg/ml)11.93 (5.82–18.69)14.35 (8.77–24.83)19.17 (13.01–35.42)18.29 (14.27–26.30)20 = 17 > 14 > 11<0.0001
AUC0–24 (μg · h/ml)101 (69–204)139 (77–456)193 (129–534)211 (146–277)20 = 17 > 14 > 11<0.0001
t1/2 (h)6.1 (4.2–14.7)6.7 (4.9–19.4)6.7 (1.8–19.2)6.0 (4.9–11.0)20 = 17 = 14 = 110.4654
FIG 1 Box-and-whisker plot of levofloxacin Cmax (in μg/ml) versus randomized dose (in mg/kg). The ends of the boxes correspond to the 25th and 75th percentiles, respectively, and the middle line corresponds to the median. The diamond center line indicates the means, and the top and bottom of the diamonds show the 95% confidence interv al about the means. Separated circles show statistically significantly different pairs.
When the area under the concentration-time curve from 0 to 24 h (AUC0−24) was evaluated by the milligram dose administered, it increased proportionally. Within each mg/kg dosing group, the AUC0−24 varied approximately 3-fold (Fig. 2). The median Tmax was 2 h across all groups, and median half-lives (t1/2) were 6.1 to 6.7 h. Thus, increasing levofloxacin doses did not change the apparent rates of absorption or elimination. In univariate analyses, females had higher Cmaxs and higher AUC0−24s, despite having shorter t1/2s, than the males (Table 4), although there were slightly more female patients in the two higher-dose groups combined (24 [45%] of 53) than in the two lower-dose groups combined (17 [35%] of 48). HIV-positive patients had slightly higher Cmaxs, higher AUC0–24s, and longer t1/2s than the HIV-negative patients (Table 4). Across all ages, older patients had higher AUC0–24s and longer t1/2s than the younger patients (Table 4). In a multivariate analysis of these three key covariates, sex remained significant for Cmax, while sex, HIV status, and age all remained significant covariates for AUC0–24 and t1/2. The independent data safety and monitoring board (DSMB) met every 6 months throughout the study, which was not interrupted at any point due to safety concerns; a full analysis of the safety data is under way.
FIG 2 Box-and-whisker plot of levofloxacin AUC0–24 (in μg · h/ml) versus randomized dose (in mg/kg). Symbols are as described for Fig. 1.
TABLE 4 Pharmacokinetic parameters sorted by demographic characteristics
ParameterSexHIV statusIncrease age
FemaleMaleP value (chi-square)PositiveNegativeP valueAdjusted R2P value
Tmax (h)2 (1–4)2 (1–4)0.93082 (1–4)2 (1–4)0.8088−0.0080.6787
Cmax (μg/ml)16.56 (5.82–35.42)13.64 (6.90–26.66)0.002215.03 (7.25–35.42)14.22 (5.82–33.17)0.19600.0170.1023
AUC0–24 (μg · h/ml)168 (72–534)130 (69–457)0.0151199 (75–534)130 (69–292)0.00080.0880.0015
t1/2 (h)6.0 (4.2–19.2)7.0 (1.8–19.4)0.00157.8 (6.3–19.4)6.0 (1.8–12.4)<0.00010.0970.0009
These results demonstrate that increased doses of levofloxacin in the presence of a background MDR-TB regimen lead to increased levofloxacin Cmaxs and AUC0–24s. Thus, patients with low serum levofloxacin concentrations can be expected to respond to increased dosing. Moreover, if increased serum concentrations of levofloxacin are associated with increased clinical efficacy without dose-limiting toxicity, increased dosing may improve the proportion of favorable treatment responses. If proven safe and efficacious, these pharmacokinetic data support further exploration of high-dose levofloxacin in MDR-TB regimens.


We thank all the study participants who contributed their time to this study. We are grateful to the local TB program staff who assisted in the clinical management of study participants. Finally, we thank the CDC Tuberculosis Trials Consortium members and staff for encouragement and thoughtful advice throughout the study.
This work was supported by the U.S. National Institutes of Health NIAID grant U01 AI100805, CFAR grant P30 AI042853, the U.S. CDC DTBE TBTC, and the U.S. National Institutes of Health NIAID grant 1K24 AI114444. Additional support was provided by the Providence/Boston Center for AIDS Research (P30AI042853) and the Boston University/Rutgers Tuberculosis Research Unit (U19AI111276).


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Information & Contributors


Published In

cover image Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Volume 62Number 10October 2018
eLocator: 10.1128/aac.00770-18


Received: 19 April 2018
Returned for modification: 29 May 2018
Accepted: 8 July 2018
Published online: 24 September 2018


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  1. tuberculosis
  2. levofloxacin
  3. pharmacokinetics
  4. antitubercular agents



Infectious Disease Pharmacokinetics Lab, University of Florida, Gainesville Florida, USA
Patrick P. J. Phillips
Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California, USA
MRC Clinical Trials Unit at UCL, London, United Kingdom
Carole D. Mitnick
Department of Global Health & Social Medicine, Harvard Medical School, Boston, Massachusetts, USA
Kathleen Eisenach
University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Ramonde F. Patientia
Stellenbosch University and Task Applied Science, Cape Town, South Africa
Leonid Lecca
Socios en Salud Sucursal Peru, Lima, Peru
Eduardo Gotuzzo
Universidad Peruana Cayetano Heredia, Lima, Peru
Neel R. Gandhi
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
Department of Medicine (Infectious Diseases), Emory School of Medicine, Emory University, Atlanta, Georgia, USA
Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
Donna Butler
Westat, Bethesda, Maryland, USA
Andreas H. Diacon
Stellenbosch University and Task Applied Science, Cape Town, South Africa
Bruno Martel
Socios en Salud Sucursal Peru, Lima, Peru
Juan Santillan
Universidad Peruana Cayetano Heredia, Lima, Peru
Kathleen Robergeau Hunt
Westat, Bethesda, Maryland, USA
Dante Vargas
Socios en Salud Sucursal Peru, Lima, Peru
Florian von Groote-Bidlingmaier
Stellenbosch University and Task Applied Science, Cape Town, South Africa
Carlos Seas
Universidad Peruana Cayetano Heredia, Lima, Peru
Nancy Dianis
Westat, Bethesda, Maryland, USA
Antonio Moreno-Martinez
TB Investigation Unit of Barcelona, Barcelona, Spain
CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
Pawandeep Kaur
Department of Global Health, Boston University School of Public Health, Boston, Massachusetts, USA
C. Robert Horsburgh Jr.
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Departments of Epidemiology, Biostatistics and Global Health, Boston University School of Public Health, Boston, Massachusetts, USA


Address correspondence to Charles A. Peloquin, [email protected].

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