Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis

Abstract

Ofloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC_0–24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (C_max), AUC_0–8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC_0–24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC_0–24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47; P = 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.

INTRODUCTION

Globally, in 2013 there were an estimated 480,000 new cases of multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to isoniazid (INH) and rifampin (RIF) (1). Precise incidence data in children are unavailable, but modeling estimates suggest that there were 33,000 new pediatric MDR-TB cases in 2010 (2). In addition, assuming an average of two child contacts for each adult MDR-TB source case (3), there may be as many as 900,000 children newly exposed to MDR-TB globally each year. Fluoroquinolones are a key component of existing regimens for treatment (4) and prevention (5) of MDR-TB in adults and children.

Ofloxacin, a fluoroquinolone, has potent activity against M. tuberculosis (6, 7) and has been routinely used in MDR-TB treatment. The current World Health Organization (WHO) recommended adult dose of ofloxacin for MDR-TB is 800 mg daily. Ofloxacin is not metabolized; rather, it is excreted unchanged in the urine (8). It is well absorbed after oral administration, and food intake does not affect its pharmacokinetics appreciably (9–12).

There are limited data on ofloxacin pharmacokinetics in children, particularly in children <5 years of age, to guide appropriate dose selection (11, 13). The WHO recommends a pediatric ofloxacin dose for MDR-TB of 15 to 20 mg/kg of body weight daily (14); however, it is unknown if this dose achieves exposures in children approximating those in adults after the recommended 800-mg dose. Concerns regarding arthropathy (15, 16) had initially limited the use of fluoroquinolones in children. Although safe in short courses (16–18), there are limited data on fluoroquinolone safety in children with long-term use (5, 19).

The more potent fluoroquinolones levofloxacin and moxifloxacin (20, 21) are beginning to replace ofloxacin for MDR-TB treatment. However, because of its low cost and widespread availability, ofloxacin is still used for MDR-TB in many settings, and optimizing its use in children remains important.

The objective of this study was to evaluate the pharmacokinetics and safety of ofloxacin among a large cohort of HIV-infected and uninfected children of representative ages who were routinely receiving ofloxacin for the prevention or treatment of MDR-TB.

MATERIALS AND METHODS

Study design.

This was a prospective observational pharmacokinetic study.

Study setting.

The study took place in the Western Cape, South Africa, where in 2010 the TB notification rate was 954.1 cases per 100,000 population, and from 2009 to 2011 MDR-TB represented 7.1% of culture-confirmed cases in children <13 years old (22, 23). The diagnosis of MDR-TB was based on (i) culture of M. tuberculosis from sputum or other relevant specimens with drug susceptibility testing (DST) demonstrating resistance to INH and RIF, (ii) clinical and radiologic evidence of TB and contact with an MDR-TB source case, or (iii) failure of first-line TB treatment. Treatment for MDR-TB in children was provided independent of the study, according to local and international guidance, based on the DST of the child's isolate or the isolate of their most likely source case. Treatment included at least four drugs likely to be active given for at least 12 to 18 months (14, 24).

In the study setting, child contacts of adult MDR-TB cases are referred to a specialty clinic for preventive therapy. Children <5 years of age and those HIV infected without evidence of TB were prescribed 6 months of a three-drug preventive therapy regimen: ofloxacin, ethambutol, and high-dose INH (5).

Study population.

Children were recruited from a large provincial referral hospital (Tygerberg Children's Hospital) and two provincial TB hospitals (Brooklyn Hospital for Chest Diseases and Brewelskloof Hospital). Children <15 years of age routinely started on ofloxacin for prevention or treatment of MDR-TB were eligible. Exclusion criteria were a weight of <5 kg or hemoglobin of <8.0 g/dl. Children treated for MDR-TB disease were followed longitudinally to assess safety and tolerability during treatment. The safety of this preventive therapy regimen has been previously documented; these children were followed independent of the study (5). Data from 23 children from a substudy of this cohort were previously published and are included in the present analysis (13).

Data collection.

Children were categorized as receiving ofloxacin either for MDR-TB treatment or prevention. TB was categorized as confirmed, probable, or possible according to international consensus definitions (25) and as pulmonary, extrapulmonary, or both. HIV status was ascertained in all participants. Weight-for-age Z-score (WAZ) was calculated using the 1990 British growth reference (26).

All participants underwent intensive pharmacokinetic sampling 2 to 8 weeks after starting ofloxacin. Ofloxacin (200-mg tablets; Sanofi Aventis, Midrand, South Africa) at a dose of 15 to 20 mg/kg once daily was routinely prescribed. On pharmacokinetic sampling days, an exact 20 mg/kg dose of ofloxacin was weighed and administered by the study team after a minimum 4-h fast with a small amount of water. Medications were given either as whole tablets or were crushed and given by mouth or nasogastric tube, depending on what the child would tolerate. Crushed tablets were ground with a mortar and pestle, mixed with a small amount of water in a plastic cup along with any other crushed TB medications, and administered immediately. Any residue in the cup was rinsed 1 to 2 times with additional water and administered to the child. All other anti-TB medications in the regimen were given together with the ofloxacin. One hour after the TB medications, antiretrovirals were administered (if applicable) and a standard breakfast was offered. Samples for pharmacokinetic analysis were drawn predose and then at 1, 2, 4, 8, and either 6 or 11 h postdose. Whole-blood samples were collected in EDTA-containing tubes and immediately centrifuged, and plasma was separated and frozen at −80°C. Ofloxacin concentrations were determined by high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS/MS) using a previously described method validated over a range of 0.0781 to 20.0 μg/ml (27).

Children receiving ofloxacin for MDR-TB treatment had clinical monitoring monthly for the first 6 months and then every 2 months thereafter and laboratory monitoring (potassium, creatinine, alanine aminotransferase [ALT], total bilirubin, thyroid functions) every 2 months. Adverse events were graded according to standardized Division of AIDS (National Institute of Allergy and Infectious Diseases) criteria (28) and were considered attributable to ofloxacin if they were (i) at least possibly drug related and (ii) thought by the investigator to be likely related to ofloxacin or if they were not otherwise attributed to another drug. The person-time of observation began at the initial study visit and ended at either the final study visit or the date of treatment completion; observation periods in which the child received an alternative fluoroquinolone for part of the time (treatment guidelines changed during the study period) were excluded from safety analyses.

Statistical analysis.

Demographic and clinical characteristics were summarized using descriptive statistics. Pharmacokinetic measures were estimated using noncompartmental analysis (NCA). Observed maximum plasma drug concentration (C_max) and time to C_max (T_max) were recorded directly from the concentration-time data. The area under the concentration time curve from 0 to 8 h (AUC_0–8) was calculated using the linear trapezoidal rule. Oral clearance (CL/F), half-life (t_1/2), and AUC_0–24 were estimated in patients with at least 3 concentration data points in the elimination phase, with the latter based on exponential extrapolation from the final three time-concentration data points. Fifteen predose drug concentrations below the limit of quantification (0.078 μg/ml) were set to zero in analyses.

The C_max, AUC_0–8, AUC_0–24, and t_1/2 were compared by age group (0 to <2 years, 2 to <5 years, and ≥5 years), HIV status, nutritional status (WAZ, <−2 versus ≥−2), and administration method (crushed versus whole tablets). Using simple linear regression, the AUC_0–24 and C_max were analyzed separately for associations with age, weight, height, HIV status, nutritional status, gender, ethnicity, disease status (receiving preventive therapy versus treatment for MDR-TB), and administration method. Covariates with a P of <0.05 in univariable analysis, and factors known to affect drug disposition (age and weight) were included in multivariable models. We also assessed whether body surface area (BSA) (29) or lean body mass (LBM) (30) were better predictors than weight and height.

All analyses were performed using Stata 12.1 SE software (StataCorp, College Station, TX).

Ethical considerations.

Written informed consent was obtained from the parents or legal guardian, and informed assent was collected from all children ≥7 years of age. Ethical approval was provided by the Health Research Ethics Committees of the Faculty of Medicine and Health Sciences of Stellenbosch University and the Faculty of Health Sciences of the University of Cape Town.

RESULTS

Baseline characteristics.

Eighty-five children were included (Table 1). All age groups were well represented. The median age was 3.4 years (interquartile range [IQR], 1.9 to 5.2 years). Eleven (13%) participants were HIV infected. Fourteen of the 79 patients with evaluable data (18%) were underweight for age (WAZ, <−2) and 11 of these children were HIV infected (79%). Overall, 72 of 85 (85%) received crushed tablets on the day of pharmacokinetic sampling (97% of those <5 years old and 41% of those ≥5 years old).

TABLE 1.

Baseline demographic and clinical characteristics of children receiving ofloxacin for treatment or prevention of drug-resistant tuberculosis

Characteristica	No. (%) with MDR-TB disease (n = 55)	No. (%) receiving MDR-TB preventive therapy (n = 30)
Age at enrollment
0 to <2 yr	16 (29.1)	8 (26.7)
2 to <5 yr	17 (30.9)	22 (73.3)
5 to <15 yr	22 (40.0)	0 (0.00)
Male sex	32 (58.2)	15 (50.0)
Certainty of TB diagnosis
Bacteriological confirmation	20 (36.4)
Probable TB	32 (58.2)
Suspected TB	3 (5.5)
TB disease type (n = 55)
PTB only	40 (72.7)
EPTB only	5 (9.1)
PTB and EPTB	10 (18.2)
HIV infected	11 (20.0)	0 (0.0)
Weight-for-age Z-score <−2.0 (n = 79)b	11 (22.5)	3 (10.0)
Height-for-age Z-score <−2.0 (n = 81)c	19 (35.9)	4 (14.3)
Weight-for-length Z-score <−2.0 (n = 60)c	2 (6.3)	1 (3.6)

^aPTB, pulmonary tuberculosis; EPTB, extrapulmonary tuberculosis.

^bWeight-for-age Z-scores only available for patients aged <10 years.

^cThe sample size is <85 due to missing data.

Pharmacokinetics and determinants of drug exposures.

With a dose of 20 mg/kg, the mean AUC_0–8 (n = 85) was 44.2 μg · h/ml and AUC_0–24 (n = 72) was 66.7 μg · h/ml; other summary measures with reported adult values for comparison are shown in Table 2. Pharmacokinetic values by age group, HIV status, WAZ category, and type of administration are presented in Table 3. Half-life was shorter in the youngest children, and there was a trend toward a higher C_max in children receiving crushed tablets. In simple linear regression, no variables assessed were significantly associated with C_max, and only weight was significantly associated with AUC_0–24. In multivariable analysis, C_max was reduced by 0.44 μg/ml for each 1-year increase in age (95% confidence interval [CI], −0.74 to −0.13; P = 0.005) and was increased by 0.13 μg/ml for each 1-kg increase in body weight (95% CI, 0.10 to 0.24; P = 0.029). In multivariable analysis, AUC_0–24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% CI, 0.44 to 2.47; P = 0.006). Controlling for age and weight, no other assessed variables contributed to these models. Neither LBM nor BSA improved the model fit over weight.

TABLE 2.

Summary statistics for ofloxacin pharmacokinetic measures in children receiving treatment or prevention for multidrug-resistant tuberculosis^a

Parameterb	No. of children	Values for children in the present study	Values for adults with TB given an 800-mg ofloxacin dosec
Cmax (μg/ml)	85	8.97 (2.47–14.4)	10.5 (8.0–14.3)
Tmax (h)	85	2.0 (1.0–4.0)	1.03 (0.5–6)
t1/2 (h)	72	3.49 (1.89–6.95)	7.34 (3.53–28.3)
CL/F (liter/h/kg)	72	0.31 (0.11–1.06)	0.12 (0.02–0.32)
V (liter/kg)	72	1.45 (0.86–6.49)	1.28 (0.78–2.83)
AUC0–8 (μg · h/ml)	85	44.2 (12.1–75.8)
AUC0–24 (μg · h/ml)	72	66.7 (18.8–120.7)	103 (48–755)

^aAll values are presented as means (ranges), except for T_max, CL/F, and V, which are presented as medians (ranges); adult values are all reported as medians (ranges).

^bC_max, maximum serum concentration; T_max, time to maximum serum concentration; t_1/2, half-life; CL, clearance; F, fraction absorbed; V, volume of distribution; AUC_0–8, area under the concentration time curve from 0–8 h; AUC_0–24, area under the concentration time curve from 0–24 h.

^cn = 11 (10).

TABLE 3.

Pharmacokinetic measures for ofloxacin (20 mg/kg) in children receiving treatment or prevention for multidrug-resistant tuberculosis, by age, HIV status, nutritional status, and administration method^a

Parameter	No. of children	Cmax (μg/ml)	P value	AUC0–8 (μg · h/ml)	P value	No. of children	AUC0–24 (μg · h/ml)	P value	t1/2 (h)	P value
Age group
0 to <2 yr	24	10.43 (1.96)		45.9 (8.8)		23	63.9 (15.3)		3.01 (0.53)
2 to <5 yr	39	8.52 (2.37)		43.8 (12.0)		35	66.5 (20.9)		3.52 (0.75)
≥5 yr	22	8.18 (2.01)	<0.001	43.1 (8.9)	0.632	14	71.7 (17.8)	0.473	4.18 (1.22)	<0.001
HIV status
HIV infected	11	8.42 (1.51)		42.5 (9.0)		9	63.4 (16.4)		3.35 (0.59)
Not HIV infected	74	9.05 (2.44)	0.404	44.4 (10.6)	0.560	63	67.1 (19.0)	0.579	3.51 (0.93)	0.614
WAZ
<−2.0	18	8.94 (2.35)		42.7 (11.4)		15	61.0 (20.1)		3.06 (0.49)
≥−2.0	67	8.98 (2.35)	0.953	44.6 (10.1)	0.498	57	68.2 (18.1)	0.190	3.60 (0.94)	0.004
Administration
Whole	11	7.87 (1.67)		42.2 (10.6)		8	72.4 (23.4)		4.32 (1.45)
Crushed	72	9.16 (2.40)	0.089	44.6 (10.4)	0.481	62	66.1 (18.1)	0.375	3.39 (0.76)	0.114

^aHIV status, nutritional status, and administration method comparisons were generated using t tests; age group comparisons were generated using one-way analyses of variance (ANOVAs); all values are presented as means (standard deviations). A total of 85 children participated in the study.

Safety.

Forty-six children contributed a total of 23.8 years of observation time on ofloxacin to the safety assessment, with a median time per child of 4.9 months (IQR, 1.2 to 10.2 months) (Table 4). Adverse events were mostly mild in severity; vomiting and pruritus were the most frequent. Most adverse events were not attributed to ofloxacin but represented known toxicities related to companion MDR-TB drugs. The only grade 3 or 4 events were two episodes of asymptomatic ALT elevation due to confirmed acute hepatitis A, which resolved without complication after brief interruptions of some TB medications while awaiting the hepatitis A results.

TABLE 4.

Adverse events in children treated for multidrug-resistant tuberculosis with ofloxacin^a

Adverse event	Adverse event by grade							Adverse effects possibly, probably, or definitely attributed to ofloxacin by grade
	No. of patients with event	Grade 1	Grade 2	Grade 3	Grade 4	Total no. of events	Event rate (per person-yr)	No. of patients with event	Grade 1	Grade 2	Grade 3	Grade 4	Total no. of events	Event rate (per person-yr)
Arthralgia	1	1	0	0	0	1	0.042	0	0	0	0	0	0
Arthritis	0	0	0	0	0	0		0	0	0	0	0	0
Pain other than traumatic injury	10	10	2	0	0	12	0.504	1	1	0	0	0	1	0.042
Headache	7	5	3	0	0	8	0.336	1	1	0	0	0	1	0.042
Neurosensory alteration	0	0	0	0	0	0		0	0	0	0	0	0
Insomnia	2	0	2	0	0	2	0.084	2	0	2	0	0	2	0.084
Fatigue/malaise	3	3	0	0	0	3	0.126	1	1	0	0	0	1	0.042
Nausea	8	9	0	0	0	9	0.378	2	2	0	0	0	2	0.084
Vomiting	12	16	1	0	0	17	0.714	3	4	0	0	0	4	0.168
Anorexia	4	3	1	0	0	4	0.168	0	0	0	0	0	0
Cutaneous reaction	4	5	0	0	0	5	0.210	1	1	0	0	0	1	0.042
Pruritus	12	13	0	0	0	13	0.546	4	4	0	0	0	4	0.168
Acute systemic allergic reaction	0	0	0	0	0	0		0	0	0	0	0	0
ALT	8	5	1	1	1	8	0.336	5	4	1	0	0	5	0.210
Bilirubin	0	0	0	0	0	0		0	0	0	0	0	0

^aFourty-six patients were followed for a median time of 149.5 days (IQR, 36 to 308 days); total number of person-years was equal to 23.80.

DISCUSSION

Ofloxacin given at the WHO-recommended dose of 20 mg/kg to children was safe and well-tolerated, but exposures in this substantial pediatric cohort were considerably lower than those achieved in adults taking the standard MDR-TB treatment dose of 800 mg daily.

Although ofloxacin has been widely used for treatment and prevention of MDR-TB in children, the appropriate dosage has not been established. Indeed, only one other study evaluating the pharmacokinetics of ofloxacin in children has been conducted to our knowledge. In a study in Vietnam, 17 children (aged 5 to 17 years) with typhoid fever received a single oral dose of 7.5 mg/kg of ofloxacin (11). A C_max of 5.73 μg/ml and an AUC_0–12 of 26.5 μg/ml were achieved (11). The C_max (8.97 μg/ml) and AUC_0–8 (44.1 μg · h/ml) in our study are lower than would be expected with a 2.5× higher dose given that ofloxacin exposures should be dose proportional in the dosing range tested (8, 10). It is unclear if this is because of differences in the study population or drug formulation used, but our findings underline the importance of not relying on a single study conducted in one geographic location to inform global dosing recommendations in children.

The differing AUC_0–8 and AUC_0–24 trends by age in univariable analysis may be due to the fact that the proportion of the total daily AUC that is captured in the first 8 h after dosing is greater in younger children (data not shown) due to more rapid absorption and clearance compared to older children. Children with slower absorption and elimination, and most likely a higher AUC, would be more likely to be excluded from our estimates of AUC_0–24. Indeed, AUC_0–24 was not estimated in a higher proportion of older children (Table 3), suggesting we may have underestimated the AUC_0–24 in children ≥5 years old. The differences in t_1/2 by age in univariable analysis and association of AUC_0–24 with weight are consistent with the principle of allometric scaling, in which smaller body size is associated with more rapid clearance.

Our large sample allowed us to evaluate covariate effects on the pharmacokinetics of ofloxacin. In multivariable analysis, age and weight were associated with AUC_0–8 and C_max, and weight was associated with AUC_0–24. HIV and undernutrition are frequent concomitant conditions among children with MDR-TB and have been associated with failure to culture convert at 2 months and death (31). HIV infection may affect concentrations of some TB medications (32); however, we did not observe any significant effect of HIV infection on ofloxacin pharmacokinetics. This is consistent with the available adult literature (9, 10). Undernutrition also did not have a clinically significant impact on ofloxacin pharmacokinetics. These data suggest that worse outcomes among children with HIV coinfection or undernutrition are not likely due to reduced concentrations of ofloxacin, the key bactericidal drug in the regimen.

The lack of child-friendly formulations of second-line TB medications is a major challenge for MDR-TB treatment in children, and the impact of formulation manipulation, such as the crushing or breaking of adult tablets, has not been evaluated fully. Many children in our study were unable to swallow whole ofloxacin tablets and took them crushed. In univariable analysis, there was a trend toward a higher C_max with crushed tablets; however, crushing did not contribute to the multivariable model, which included age and weight. The associations of C_max with age and weight described here are somewhat unexpected and should be interpreted cautiously, as crushing was highly associated with younger age and less so with weight, and it may have been difficult to separate these effects in the model. There was no association between crushing and AUC_0–8 or AUC_0–24. Although this does not replace a formal assessment of relative bioavailability of crushed versus whole tablets, it suggests that crushing tablets does not negatively impact drug exposures and crushing may, in fact, increase the rate or magnitude of absorption.

When efficacy of a TB drug has been established in adults, efficacy studies may not be required in children, but studies characterizing a drug's pharmacokinetics and safety in children are essential. This allows the selection of dosages that achieve concentrations associated with treatment success in adults (9, 10). In a study of ofloxacin pharmacokinetics after an 800-mg dose (median dose, 14.5 mg/kg) in adults with MDR-TB at two sites in South Africa, estimated pharmacokinetic parameters were a t_1/2 of 7.8 h and a C_max of 8.8 to 10.4 mg/liter (9). In a U.S. study, 11 adults with TB (median age, 42 years [range, 22 to 57 years]; median weight, 64 kg [range, 50 to 86 kg]; 3 HIV infected) underwent intensive pharmacokinetic sampling on ofloxacin at steady state with a median dose of 800 mg (range, 600 to 1,200 mg). Assays were performed using high-performance liquid chromatography, and data were analyzed using population pharmacokinetic modeling (Table 2). Using simulations based on their population model generated from these data and from an additional group in this study having sparse pharmacokinetic sampling, estimated pharmacokinetic parameters after an 800-mg once-daily dose were an AUC of 100.7 μg · h/ml and a C_max of 9.35 μg/ml (10). The C_max in our children was only slightly below these reported adult values, although the children received a higher milligram per kilogram dose (20 mg/kg) compared to the adults (9). However, the estimated AUC_0–24 in our children of 66.7 μg · h/ml was far below the adult value (103 μg · h/ml) (10). This is likely related to the more rapid clearance of ofloxacin in children; calculated t_1/2 in children in our study was 3.5 h compared to 7 to 8 h in the adult studies. That currently recommended dosages of ofloxacin result in AUCs in children well below those of adult targets has important implications for MDR-TB treatment and prevention, particularly given the fluoroquinolones' high bactericidal activity (33) and their key role in current treatment regimens (34). The AUC is believed to be the most important pharmacodynamic measure for the fluoroquinolones against M. tuberculosis (35). As our data were derived in an optimal setting with an exact 20-mg/kg dose, drug exposures with unsupervised dosages closer to the lower end of the recommended range (15 to 20 mg/kg) may be even lower. Although additional studies corroborating the findings in our study would be useful, it may not be prudent to wait on such studies before reevaluating pediatric dosing. Population pharmacokinetic modeling can be used to predict dosages most likely to achieve adult targets; this information is urgently needed, and such an analysis is planned from this cohort. Higher dosages should be introduced carefully, though, to assess their safety and tolerability, particularly given that the C_max may exceed the C_max in adults receiving 800 mg daily.

Ofloxacin was generally safe and well tolerated. The overall person-time of observation for adverse events was more limited than expected, as many children were switched from ofloxacin to levofloxacin or moxifloxacin during their treatment, following a national treatment guideline change midstudy. Adverse effects were of low grade, and there were no ofloxacin-related grade 3 or 4 events. There was no evidence of arthralgia or arthropathy in our cohort. Subtle arthralgia may not have been reported, but it is unlikely clinically significant arthralgia or arthritis would have been missed. There were two reports of insomnia attributable to ofloxacin, a well-described adverse effect of this medication (5, 36). Anecdotally, we have seen self-limited, mild insomnia and nightmares attributable to ofloxacin not infrequently; our data may underestimate the incidence, as many children were admitted to hospital wards early in their treatment and sleep disturbance may be less noticeable by ward staff than by parents. Our safety assessment is limited by the lack of a control group and by the difficulty in attributing adverse effects to individual drugs in a multidrug regimen that typically includes ethambutol, pyrazinamide, amikacin, ethionamide, terizidone, and high-dose INH. Our approach was, however, conservative and more likely to have overestimated ofloxacin-related adverse effects. These data add to a growing body of evidence that the fluoroquinolones are safe in children, including in long-term use (37). The lack of adverse effects may be related to the relatively low exposures, and safety should continue to be monitored closely if dosages are increased.

Treatment outcomes in this cohort were generally good and will be reported elsewhere; however, one child had documented acquisition of ofloxacin resistance during treatment. This HIV-infected child had a complicated course with large recurrent tuberculous brain abscesses requiring the use of multiple immunosuppressant medications and was treated with multiple fluoroquinolones prior to resistance development, making it difficult to ascribe the resistance acquisition solely to ofloxacin concentrations. Additionally, this child's ofloxacin C_max and AUC were each above the median. Despite generally good outcomes, optimized dosing of the fluoroquinolones in children remains an important priority and may potentially improve outcomes further and facilitate the use of shorter, injectable sparing MDR-TB treatment regimens.

In conclusion, in this large cohort of children receiving ofloxacin, exposures were lower than those in adults. Although ofloxacin is being phased out of MDR-TB treatment regimens in favor of more potent fluoroquinolones, it is still used in many places and it is likely underdosed in children. That ofloxacin was safe and well tolerated is reassuring, particularly if higher dosages that will be needed to reach adult reference exposure targets are to be evaluated. A better understanding of the pharmacokinetics and safety profiles of all second-line anti-TB drugs is essential to ensure the provision of appropriate drugs at appropriate dosages to children with MDR-TB to optimize treatment outcomes.