Levofloxacin: safety and tolerability in HIV positive and negative children treated for MDR-TB
Levofloxacin was safe and well tolerated in children with and without HIV in long-term use. The data provide additional support for its inclusion in paediatric TB treatment and prevention regimens. 
These findings were presented as a poster at TB2016 authored by South African investigators from: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch University, Cape Town; and Western Cape Government Department of Health, Brewelskloof Hospital, Worcester.
Levofloxacin is a fluoroquinolone and a key component of MDR-TB treatment in children. The drug is also included in two phase 3 trials of preventive therapy in MDR-TB exposed adults and children. The most notable side effects of fluroquinolones include: arthropathy, neuropsychiatric symptoms and QT interval prolongation. There have been persistent concerns about the safety of fluoroquinolones in children because of arthropathy in juvenile animals. Prospective data on levofloxacin in children is scarce, particularly on its long-term use.
The data were from a prospective, observational, cohort study conducted in Western Cape, South Africa. Children with MDR-TB in this cohort are routinely treated with a 6-7 drug regimen. The regimens include: a fluoroquinolone, a second-line injectable, ethionamide, terizidone, high-dose isoniazid, ethambutol, pyrazinamide, and occasionally other drugs such as PAS. At the beginning of the study levofloxacin was dosed at 10-15 mg/kg once daily and later at 15-20 mg/kg once daily.
There were 70 participants in the study with a median age of 2.1 years (range 0.4-7.3). Of these: 44% were 0-2; 50% were 2-5; and 6% were 6-15 years of age. Approximately half the group were girls; 17% were HIV-infected; and 23% and 35% respectively were underweight or short for their age. The children were followed for a total of 68.5 person years; median time 11.6 months (IQR 9.2-14.7).
The investigators reported that overall most adverse events were grade 1 or 2; the most frequent were vomiting (24 events in 19 children; 0.351 events/person-year) and ALT elevation (27 events in 22 children; 0.394 events/person-year). There were no arthritis events and only three grade 1 arthralgia events in three children (event rate 0.044 events/person-year).
Among grade 1 or 2 adverse events attributed to levofloxacin, vomiting (16 events in 14 children; 0.234 events/person year) and ALT elevation (18 events in 16 children; 0.263 events person year) remained the most reported.
There were three grade 3 and five grade 4 adverse events; seven were ALT elevation (none were attributed to levofloxacin) and one grade 3 headache, possibly related to levofloxacin. No adverse events led to permanent discontinuation of levofloxacin.
The investigators concluded that levofloxacin was safe and well tolerated and can be an option in TB treatment and preventative regimens. But they noted that making an assessment of adverse events associated with levofloxacin in multidrug regimens was hard – many adverse events were likely due to other second-line TB drugs. It is also likely that the event rates they reported overestimate those actually due to levofloxacin.
They suggested that mild arthralgia might be underestimated in young children but serious arthropathy is unlikely to have been missed. Neuropsychological events also might be underestimated. The investigators will report on QT prolongation elsewhere.
There are limited data on the use of second-line TB drugs in children. Second-line drugs are more toxic than those used in first-line treatment and adverse events are hard to monitor in children. Paediatric formulations are not usually available and doses using divided and/or crushed tablets are uncertain.
Pharmacokinetic data on which to base optimal dosing have been mostly absent until quite recently – thanks to the work of the Stellenbosch group who performed this levofloxacin evaluation. TB drugs are also frequently used with antiretrovirals in children with HIV and TB.
The data above are from a large ongoing study designed to characterise the pharmacokinetics and toxicity of second-line TB drugs for treatment and prevention of drug resistant TB in HIV positive and negative children, by age and HIV status.
We have previously reported findings from this excellent initiative as they have been presented. [2, 3, 4, 5]
- Garcia-Prats A et al. Safety and tolerability of levofloxacin in HIV-infected and uninfected children treated for multi-drug resistant tuberculosis. TB2016. 16-17 July 2016. Durban, South Africa. Poster abstract 101. Code PO11.
- Clayden P. Paediatric TB: glimpses of PK data and a potential new approach to drug development. HTB. 1 February 2013.
- Clayden P. Preventing and treating TB in children – more baby steps . HTB. 1 December 2013.
- Clayden P. Pharmacokinetics and safety of moxifloxacin in children. HTB. 29 January 2015.
- Clayden P. Pharmacokinetics of old and new TB drugs for children. HTB. 1 Feruary 2016.