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Tuberculosis xxx (2011) 1e9

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Tuberculosis

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REVIEW

Paediatric use of second-line anti-tuberculosis agents: A review

James A. Seddon a,b,*, Anneke C. Hesseling a, Ben J. Marais c, Helen McIlleron d, Charles A. Peloquin e,Peter R. Donald f, Simon H. Schaaf a,f

aDesmond Tutu TB Centre, Faculty of Health Sciences, Stellenbosch University, South AfricabDepartment of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UKc Sydney Institute for Emerging Infectious Diseases and Biosecurity (SEIB) and the Children’s Hospital at Westmead, University of Sydney, AustraliadDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, South AfricaeCollege of Pharmacy, and the Emerging Pathogens Institute, University of Florida, USAf Tygerberg Children’s Hospital, Tygerberg, South Africa

a r t i c l e i n f o

Article history:Received 29 August 2011Received in revised form25 September 2011Accepted 1 November 2011

Keywords:TuberculosisChildrenDrug-resistantSecond-linePharmacokinetics

* Corresponding author. Desmond Tutu TB Centre, DChild Health, Clinical Building, Room 0085, Faculty ofUniversity, PO Box 19063, Tygerberg 7505, South A213789177; fax: þ21 219389792.

E-mail addresses: jseddon@sun.ac.za, jamesA. Seddon), annekeh@sun.ac.za (A.C. Hesseling), benmhelen.mcilleron@uct.ac.za (H. McIlleron), peloquin@prd@sun.ac.za (P.R. Donald), hss@sun.ac.za (S.H. Scha

1472-9792/$ e see front matter � 2011 Elsevier Ltd.doi:10.1016/j.tube.2011.11.001

Please cite this article in press as: Seddondoi:10.1016/j.tube.2011.11.001

s u m m a r y

Childhood multidrug-resistant tuberculosis (MDR-TB) is an emerging global epidemic. With the immi-nent roll-out of rapid molecular diagnostic tests, more children are likely to be identified and requiretreatment. As MDR-TB is resistant to the most effective first-line drugs, clinicians will have to rely onsecond-line medications which are less effective and often associated with more pronounced adverseeffects than first-line therapy. Despite the fact that most of these agents were discovered many years ago,robust information is lacking regarding their pharmacokinetic and pharmacodynamic properties,adverse effects and drug interactions, especially in children. Children differ from adults in the way thatdrugs are administered, the manner in which they are metabolised and in the adverse effects experi-enced. The interaction of these drugs with human immunodeficiency virus infection and antiretroviraltherapy is also poorly documented. This article reviews the available second-line drugs currently used inthe treatment of MDR-TB in children and discusses medication properties and adverse effects whilepotential interactions with antiretroviral therapy are explored.

� 2011 Elsevier Ltd. All rights reserved.

Introduction

It is rarely emphasized that multidrug-resistant (MDR) andextensively drug-resistant (XDR) tuberculosis (TB) also affect chil-dren and that paediatric drug-resistant TB can be viewed as anemerging global epidemic.1 MDR-TB is defined as Mycobacteriumtuberculosis (M. tuberculosis) resistant to the most potent first-lineanti-TB medications, isoniazid and rifampicin, while XDR-TB hasadditional resistance to the most active second-line agents,injectable drugs (aminoglycosides and/or cyclic polypeptides) andfluoroquinolones. There were an estimated 440,000 cases globallyof MDR-TB during 2009.2 Given the fact that childhood TB repre-sents at least 10e20% of the total cases in areas with poor epidemiccontrol,3e5 this translates into a minimum global estimate of

epartment of Paediatrics andHealth Sciences, Stellenboschfrica. Tel.: þ27 722470795/

.seddon@doctors.org.uk (J.1@chw.edu.au (B.J. Marais),cop.ufl.edu (C.A. Peloquin),af).

All rights reserved.

JA, et al., Paediatric use of s

around 40,000 paediatric cases of MDR-TB per year. Accuratereporting and optimal management of these cases are challenging,due to the difficulty in confirming the diagnosis, limited awarenessand experience in dealing with these patients, the complexity andduration of treatment, and the limited availability of adequatedrugs and child-friendly formulations. In addition, in settings witha high burden of MDR-TB and human immunodeficiency virus(HIV), up to 40% of children with MDR-TB are also HIV-infected.6

These children are at risk of multiple opportunistic infections,have specific nutritional and metabolic requirements and absorbmedications in a different manner to those HIV-uninfected. Thecombination of MDR-TB and HIV can have serious psychologicaleffects. Both conditions are stigmatised and are perceived to carrypoor prognosis. HIV-infected children are also treated with anti-retroviral therapy (ART) medications which have the potential tointeract with the second-line anti-TB drugs. Few studies haveexamined the management of children with MDR-TB. Those thathave are small and focus mainly on outcomes with little attentionto the careful documentation of the challenges of treatment.7e19

With the imminent roll-out of more rapid, molecular diagnostictests to identify MDR-TB,20,21 case detection, including that ofchildren, is likely to rise. In order to manage children with MDR-TB

econd-line anti-tuberculosis agents: A review, Tuberculosis (2011),

Table 1

J.A. Seddon et al. / Tuberculosis xxx (2011) 1e92

it is important to understand the currently available medications,their indications, dosages, pharmacokinetic properties and theirpotential adverse effects. This article discusses the availablesecond-line anti-TB drugs in respect to paediatric usage. We alsoreview the potential interaction between second-line drugs and theART medications.

Treatment of MDR-TB in children: general considerations

Children are typically diagnosed with either confirmed orpresumed MDR-TB. Confirmed disease occurs when an organism isisolated from the child and is shown to be either genotypically orphenotypically resistant to isoniazid and rifampicin. Presumeddisease occurs when TB is diagnosed in combination with eitherknown contact with an MDR-TB source case or after the failure ofappropriate first-line therapy where adherence has been verified.When confirmed, the treatment should be tailored to the drugsusceptibility test (DST) pattern of the child’s strain. When diag-nosed presumptively, treatment should be directed by the DST ofthe source case, where available.22 If no DST is available, and thechild is failing therapy, treatment decisions should be based on theprevailing DST pattern of MDR-TB strains circulating in the region.

The challenges to treating MDR-TB in children are only partlydue to the uncertainties surrounding the activity and safety of theavailable drugs. The second-line drugs are rarely produced inpaediatric formulations or appropriate tablet sizes, necessitatingbreaking, splitting, crushing or grinding. Hence dosing may beinaccurate and sub-therapeutic or toxic levels are possible. Thetaste of themedications is often unpalatable. A number of the drugscause vomiting and diarrhoea which may affect the amountabsorbed and causes further uncertainty about the dosing. Thedaily pill burden can be vast as the child may require multiple TBmedications, ART, other antibiotics as well as supplements ofvitamins and calories. (Figure 1) Adherence can be challenging inchildren either too young to understand or not old enough tocooperate. Treatment for MDR-TB in children should always begiven under directly observed therapy (DOT) but in reality, in manysettings, responsibility is often given to the caregiver who is givena week or a month’s supply of drugs. Caregivers may well be thesource case, however, and may have chronic medical problems

Figure 1. The morning pill burden for a teenage boy on ART and treatment for MDR-TB. (Photographer: Damien Schumann).

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themselves, have defaulted treatment, or have additional problemssuch as drug or alcohol abuse. There is an established relationshipbetween TB and alcohol in many contexts and populations23 and intreatment cohorts of MDR-TB alcohol and drugs are common andassociated with both default24 and poor prognosis.25

There is a paucity of rigorous clinical studies of TB treatmentamongst children. Despite their approval more than forty years ago,there are major gaps in our knowledge of the pharmacokinetics ofanti-TBdrugs in children, particularlyof the second-line agents.26 Thepharmacokinetics of anti-TB drugs is modulated by several factors.Age is an important variable as young children achieve lower serumconcentrations for most first-line TB drugs compared to adults whengiven at the same mg/kg dosages.27e30 Other potentially importantdeterminants include malabsorption and immune-compromiseresulting from HIV infection,31,32 poor nutritional status33 and vari-able pharmacogenetics.28,34 Recent global interest in paediatric TBresulted in critical review of existing treatment recommendationsand a number of new recommendations have been made regardingthe appropriate dosing of first-line TB drugs in children;35 however,there is scant evidence on which to base dosing guidelines for thesecond-line TB drugs. Toxicity is a major concern, but paediatric dataare limited. Co-administrationwith ARTmay potentiate drug toxicityor result in drugedrug interactions that compromise the efficacy orsafety of the anti-TB regimen or ART. Knowledge of the effects of age,HIV co-infection and concomitant ART in children on the pharma-cokinetics of second-line TB agents is limited.

Characteristics of the second-line drugs in children

The available TB drugs used in the treatment of MDR-TB areplaced in five groups, summarized in Table 1.36 When designinga regimen to treat children with MDR-TB, the World Health Orga-nisation (WHO) suggests initially using any first-line drugs towhich the organism is still susceptible. An injectable drug should beadded from group two, a fluoroquinolone from group three andthen further agents from groups four and five tomake up a regimencontaining at least four, preferably five drugs, to which theorganism is susceptible. Guidelines for children are similar and

Drug groups for the treatment of drug-resistant tuberculosis.36

Group Group name Drugs Abbreviations

1 First-line oral agents IsoniazidRifampicinEthambutolPyrazinamideRifabutinRifapentine

H or INHR or RMPE or EMBZ or PZARfb or RbtRfp or Rpt

2 Injectable agents KanamycinAmikacinCapreomycinStreptomycin

KmAmCmS

3 Fluoroquinolones MoxifloxacinLevofloxacinOfloxacin

MfxLfxOfx

4 Oral bacteriostaticsecond-line agents

EthionamideProthionamideCycloserineTerizidonePara-aminosalicylic acid

Eto or ETHPto or PTHCsTrdPAS

5 Agents with unclearefficacy or concernsregarding usage

ClofazimineLinezolidAmoxicillin-clavulanic acidThiacetazoneMeropenem-clavulanic acidImipenem/cilastatinHigh dose isoniazidClarithromycin

CfzLzdAmx/ClvThzMrp/ClvImp/ClnHigh-dose HClr

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J.A. Seddon et al. / Tuberculosis xxx (2011) 1e9 3

should initially be guided by the DST pattern of the presumedsource case, while every effort should be made to collect a viableculture from the child for optimal treatment tailoring.37,38 As DST topyrazinamide is difficult to perform and the phenotypic DST toethambutol is unreliable, these drugs should not be assumed to beeffective if they had been used prior to the diagnosis of MDR-TB,even if DST indicates susceptibility. Even though per definitionthe organism is resistant to isoniazid, high doses are used in somepatients. Resistance to isoniazid is usually caused by mutations ineither the katG gene or the inhA promoter region. KatG mutationsare usually associated with complete resistance but resistance dueto inhA mutations can often be overcome by giving isoniazid ata higher dose (15e20 mg/kg).39 As drugs from group five haverelatively weak or uncertain activity against M. tuberculosis, it isrecommended that if these drugs are required then at least fivedrugs should be given to which the organism is susceptible.22,36

Injectablemedications used in the treatmentof drug-resistant TBinclude the aminoglycosides, amikacin and kanamycin, as well asthe cyclic polypeptide, capreomycin. Streptomycin, another ami-noglycoside, was previously usedwidely in re-treatment TB cases incombination with first-line medications and this has led to highlevels of resistance to streptomycin in strains already resistant torifampicin and isoniazid. Hence, it is rarely used in the treatment ofMDR-TB. However, streptomycin can be used in the treatment ofXDR-TB, if the organism is found to be susceptible, as there is limitedcross-resistance with the other injectable medications. High levelsof cross-resistance between amikacin and kanamycin mean that ifa strain is found to be resistant to one, the other is very unlikely to beof use.40 For children, amikacin is usually given in preference tokanamycin as it has a lower minimum inhibitory concentration(MIC) and the available ampoule sizes are smaller, preventingwastage. Amikacin and kanamycin are generally preferred to cap-reomycin as the first choice injectable for MDR-TB in children withcapreomycin reserved, in most programmes, for the treatment ofXDR-TB. However, there is evidence that if a strain is resistant to anaminoglycoside it will already be resistant to capreomycin.41,42

Alternatively, if resistant to capreomycin there is a chance that itwill still be susceptible to amikacin or kanamycin. The amikacinMICfor M. tuberculosis (strain type H37Rv) is 0.5e1.0 mg/ml43e45 whichcompares to 2e4 mg/ml for both kanamycin and capreomycin.43e45

Here, MIC in liquid broth culture refers to the concentration atwhich the drug inhibits mycobacterial growth as compared toa culture containing a 1:100 dilution of mycobacteria (i.e. 99%inhibition). Pharmacokinetic profiles have been studied in childrenreceiving short-courses of aminoglycosides for bacterial infectionsgiven intravenously (IV)46 but not in prospective studies of childrenon prolonged courses of treatment, where it is typically givenintramuscularly (IM). Half-lives (t1/2) of 2.5e3.5 h are reported foramikacin and kanamycin given IV.47 As the maximum serumconcentration (Cmax) is dose-dependent consideration should begiven to therapeutic drug monitoring at the start of therapy toestablish the ideal dose for each child.44 Tmax is at the end of theinfusion for IV injections and is estimated to be between 30 and60 min for IM injections. Elimination is by urinary excretion anddoses should be reduced in patients with renal impairment.Guidelines recommend that the dose of amikacin in children shouldbe from 15 to 22.5 mg/kg daily22,36 and kanamycin or capreomycinfrom 15 to 30 mg/kg. Oral absorption is very poor and so adminis-tration for all three agents is only possible via IM or IV injection.

The fluoroquinolones have a central role in the management ofMDR-TB in children. Resistance to earlygenerationfluoroquinolones(ofloxacin)maynot necessarily imply resistance to later generations(moxifloxacin or levofloxacin).48 The MICs and mutant preventionconcentrations (MPCs) of the fluoroquinolones follow a sequentialprogression with lower concentrations required to prevent growth

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in the higher generation fluoroquinolones.49MICs, onplates of 7H11media, of 0.5, 0.71, 0.35, 0.177 and 0.125 mg/ml were reported forciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacinrespectively, using a definition of the lowest concentration requiredto inhibit any growth within four weeks 44,50 Few studies haveassessed the pharmacokinetics of the fluoroquinolones in children;the available data is largely fromstudies in older childrenwith cysticfibrosis.51e53 None have been conducted in children treated forMDR-TB.54 Caparelli et al.55 studied children aged six months tosixteen years after single gatifloxacin doses of 5, 10 and 15 mg/kgbodyweight (maximum 600 mg). Drug clearance was more rapidthan in adults and children required a higher mg/kg dosage toachieve similar blood concentrations. This was confirmed in a studyby Chien et al.56 who studied 85 children, also aged six months tosixteen years, given IV or oral levofloxacin. IV and oral dosing led tocomparable blood concentrations. They concluded that childrenyounger than five years of age clear levofloxacin almost twice as fastas adults and consequently are exposed to approximately one half ofthe dose. They recommend that children older than five yearsreceive 10 mg/kg daily but children less than five should be given10 mg/kg twice daily. Early bactericidal activity (EBA) studiesshowed that ofloxacin,57 levofloxacin, moxifloxacin and gati-floxacin58 all have activity close to that of isoniazid and activityexceeding that of isoniazid after several days of treatment.Whetherthis later effect relates to sterilizing activity is uncertain. Althoughciprofloxacin has a lowMIC, it is not recommended in the treatmentof MDR-TB due to its poor EBA.59

Thioamides include ethionamide and prothionamide; as themechanism of action for the two is similar and cross-resistance iscomplete only one of the two should be used. The thioamides sharea number of biochemical pathways with isoniazid in their activationand, dependent on mutation, can show cross-resistance.60,61 Ethi-onamide has a narrow therapeutic margin between efficacy andtoxicity with a MIC in broth (99% growth inhibition) of 0.25e0.5 mg/ml.45 Inadults, absorption from the intestinal tract is almost completeand is little affectedby foodorantacids.62Proteinbinding is30%63andethionamide distributes with ease throughout the body, including tothe CSF. In adults, peak plasma concentrations occur approximately2 h post dose and Cmax has been found to be between 1.9 and 2.5 mg/ml following an oral dose of 500 mg.62,64,65 For adults, increasing thedosage above 750 mg results in severe intolerance and so for clinicalpurposes, the recommended peak serum concentration for suscep-tible strains of M. tuberculosis is 2.5 mg/ml. Studies in children arelimited. Published data include an isolated case report and a studyevaluating cerebrospinal fluid (CSF) levels of ethionamide in childrenwith TB meningitis.64,66 Recently, a study from South Africa hasdemonstrated that dosages of 15e20mg/kg achieve adequate serumconcentrations in children.67 Younger children (�2 years of age)eliminated the drug more rapidly than older children and HIV co-infection was associated with lower concentrations.

Cycloserine is an analogue of D-alanine, is bacterostatic and actsby inhibition of peptidoglycan synthesis. The alternative drug, ter-izidone, comprises two molecules of cycloserine attached toa molecule of terephtalaldehyde. The MIC for terizidone is veryvariable.68 Cycloserine has a MIC in broth (99% growth inhibition)between 25 and 75 mg/ml.44,45 Cycloserine is completely and rapidlyabsorbed after oral administration with a tmax of 2e4 h.68,69 Distri-bution is widespread, including to the CSF. Although unaffected byorange juice or antacids, absorption is significantly delayed whentaken with a high fat meal.70 There are no pharmacokinetic data toguide paediatric dosing in different age groups for either drug.

Para-aminosalicylic acid (PAS) is produced in two formulations:free acid PAS (enteric-coated slow-release granules) and sodiumsalt PAS (granules and tablets). The mechanism of action is unclearbut may be related to thymidylate synthesis or disruption of

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acquisition of iron. MIC for drug-susceptible strains in broth is<1 mg/ml71 (using the Alamar blue colourimetric method) andslightly higher (4e8 mg/ml) for some MDR-TB strains.44 PAS is50e60% protein bound and t1/2 of the free drug is 45e60 min.Absorption is increased with food44 and CSF penetration is poor.Since PAS has no post-antibiotic effect, it is recommended thattwice daily dosing is used to constantly keep its concentrationabove MIC.72 Treatment with either formulation results in similarblood concentrations. Despite being the oldest TB drug, only onesmall English language study of four children has reported paedi-atric pharmacokinetic data.73 Children were given 300 mg/kg/day,in five divided doses of 60 mg/kg. Tmax was at 60 min with Cmaxbetween 6.25 mg/ml and 12 mg/ml. CSF peak concentrations weregenerally greater than 1 mg/ml.

The group five medications have either uncertain efficacy againstM. tuberculosis or an uncertain place in the treatment of MDR-TB.Clofazimine is an old drug, discovered in 1954. Used extensively totreat Mycobacterium leprae, it has only recently been used in thetreatment of M. tuberculosis disease. The mechanism of action isunknown but it has an MIC in broth of �1 mg/ml (99% growth inhi-bition)45,74 and may have a synergistic effect when used in combi-nation with amikacin.75 Oral absorption is 45e62% and is increasedwith a high fat meal.76 Serum concentrations are often very low44,76

but as the drug tends to concentrate inside macrophages it may bemore effective at killing intracellular organisms than the concentra-tions in serum would suggest. A recent study from Bangladeshdemonstrated that adults with MDR-TB benefit from the addition ofclofazimine to their treatment regimens.77 No pharmacokineticstudies have been conducted in children. Linezolid is an oxazolidi-none, a new class of antibiotic with a novel mechanism of action.Cross-resistance is therefore unlikely but it does appear that the MICis increased in strains already resistant to otherfirst-line drugs.44 Thepharmacokinetics of linezolid has been studied in children of variousages78,79 and childrenhavemore rapid clearance and shorter t1/2 thanadults, indicating a need for more frequent dosing. However, theoptimal dosing frequency in children with TB has not been estab-lished. It is well absorbed after oral administration and distributeswidely, including good CSF penetration.80 EBA in an adult study wassimilar for once or twice daily dosing with 600 mg81 and the limitedclinical experience inchildrenon treatment forXDR-TBhas seengood

Table 2A summary of the dose and adverse effects of the second-line drugs used in the treatme

Drug Dose recommended Formulation siz

Kanamycin 15e30 mg/kg once daily 1 g vialAmikacin 15e25 mg/kg once daily 100 mg, 250 mgCapreomycin 15e30 mg/kg once daily 1 g vialOfloxacin 15e20 mg/kg once daily 200 mg, 400 mg

Levofloxacin 10 mg/kg once daily(twice daily for <5 years)

250 mg, 500 mg

Moxifloxacin 7.5e10 mg/kg once daily 400 mgEthionamide/Prothionamide 15e20 mg/kg once daily 125 mg and 250Cycloserine/Terizidone 15e20 mg/kg once daily 250 mg capsulePAS 150 mg/kg granules daily

in two or three divided dosesSachets of 4 g

Clofazimine 5 mg/kg once daily 50 mg, 100 mgLinezolid 10 mg/kg twice daily

(once daily for >10 years)600 mg tablets

Amoxicillin/clavulanate,Imipenem, Meropenem

As for bacterial infections Amoxicillin/clavformulationsMeropenem e 5Imipenem e 25

Thiacetazone 5e8 mg/kg once daily 150 mg tablets

Clarithromycin 7.5e15 mg/kg twice daily 500 mg tablets

High dose isoniazid 15e20 mg/kg once daily 100 mg tablets

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outcomeswith twice daily dosing in younger children and once dailyin those older.82,83 Thiacetazone was previously used extensively totreat TB and only fell out of favour with severe Stevens Johnsonreactions seen in associationwithHIV. TheMIC (complete inhibition)is 0.4e1.0 mg/ml84 and cross-resistancewith ethionamide is 29e79%.In adults, it is well absorbed after oral administration with Cmax1.59 mg/ml, tmax 3.3 h and t1/2 15e16 h.85 There are no publishedpharmacokinetic studies in children. The final drugs in class five arethe beta-lactams and the macrolide clarithromycin. Amoxicillin andthe carbapenems (imipenem and meropenem) have some activityagainst M. tuberculosis, but MICs are not achievable in serum. Whencombined with clavulanic acid, however, the MIC is lower andbecomes possible to achieve in serum.86e88 The addition of etham-butol seems to provide a synergistic effect, even if given at sub-inhibitory concentrations.89 Amoxicillin and clavulanic acid arerapidly absorbed orally but the carbapenems must be given paren-trally.MeropenemhasgoodCSFpenetrationandhas alsobeen shownto be active against ‘persistent’ strains grown in anaerobic media.86

Clarithromycin has been used extensively to treat bacterial infec-tions, non-tuberculous mycobacteria as well asMycobacterium lepra.Although MICs are high using agar 7H10 at 99% inhibition of growth(4e�16 mg/ml)90,91 it may have a bi-directional synergistic role withsome of the first-line drugs e improving the efficacy of the first-linedrugs aswell as thefirst-line drugs reducing itsMIC.92,93Moreover, itworks mainly intracellularly and so this highMICmay not accuratelyreflect its bactericidal activity. Studies in children (aged 6 months to10 years) have shown that it is well absorbed orally and reaches Cmax

(3.59 mg/ml) after about 3 h. High doses are tolerated and food seemsto increase bioavailability.94

Safety and toxicity

Monitoring and describing adverse effects (Table 2) in childrenis challenging; young children cannot articulate pain, nausea,vertigo, peripheral neuropathy, anxiety or confusion. Rashes arecommon due to a variety of aetiologies and the testing of hearingand vision is more difficult than in adults. However, it is particularlyimportant to detect adverse effects as, in addition to life-threatening and unpleasant effects, growth and neuro-cognitivedevelopment may be affected. Children treated for MDR-TB are

nt of drug-resistant tuberculosis.

e Main adverse effects

Ototoxicity, nephrotoxicity, 500 mg and 1 g vials As for kanamycin

As for kanamycinSleep disturbance, GI disturbance, arthritis,peripheral neuropathy,As for ofloxacin

As for ofloxacin, prolonged QT syndromemg tablets GI disturbance, metallic taste, hypothyroidism

s Neurological and psychological effectsGI intolerance, hypothyroidism, hepatitis

tablets/capsules Skin discolourationand syrup Diarrhoea, headache, nausea, myelosuppression,

neurotoxicity, lactic acidosis and pancreatitisulanate e various

00 mg and 1 g vials0 mg and 500 mg vials

GI intolerance, hypersensitivity reactions,seizures, liver and renal dysfunction

Stevens Johnson Syndrome in HIV-infected patients,GI intolerance, hepatitis, skin reactionsGI intolerance, rash, hepatitis, prolonged QTsyndrome, ventricular arrhythmiasHepatitis, peripheral neuropathy

econd-line anti-tuberculosis agents: A review, Tuberculosis (2011),

J.A. Seddon et al. / Tuberculosis xxx (2011) 1e9 5

usually on multiple medications and determining the drugresponsible for an adverse effect can be difficult. This is of concernas HIV frequently complicates MDR-TB and overlapping drugtoxicity should be considered.95,96

In the treatment of MDR-TB any first-line drugs to which theorganism is still susceptible are used. The adverse effects of thefirst-line medications have been well described and children seemto develop adverse effects less frequently than adults.22,97e100

Isoniazid can cause peripheral neuropathy,101 while pyrazinamideand isoniazid can lead to hepatitis. All can cause rash, gastroin-testinal upset and arthritis.102e104 Isoniazid used at high dose hasnot beenwell studied and adverse effects may bemore pronouncedthan with the traditional dose. Although the incidence ofethambutol-related optic neuritis is much lower in children than inadults, concerns remain regarding toxicity. 105,106

The aminoglycosides and polypeptides can cause peripheralneuropathy, hypersensitivity and rash, but the main toxicities ofconcern are nephrotoxicity, ototoxicity and vestibular derange-ment. Fatal renal failure and electrolyte imbalances, particularlyhypokalaemia, have been reported in adults treated with capreo-mycin.107 Hearing loss is irreversible, usually developing first in thehigh frequencies and then progressing to the speech recognitionfrequencies. If high frequency loss is detected early and the drugcan be stopped without compromising the child’s health,communication may be preserved. Therefore, unless monitoredregularly hearing loss is only detected once communication prob-lems develop. No studies have assessed toxicity using these agentsin children with TB. Studies in neonates108 and children with cysticfibrosis109 demonstrate limited toxicity63 but assessment ofhearing loss in children receiving longer courses of aminoglyco-sides following liver transplantation, as occurs in MDR-TB treat-ment, found hearing loss in 15 of 66 children evaluated, usinga 35 dB loss at one frequency to define hearing loss.110 Adult studiesof MDR-TB treatment demonstrate high rates of hearing loss,vestibular dysfunction and renal impairment, the latter two oftenreversible.111e113 In adults the cumulative dose is the greatestindicator of ototoxicity with a mean onset time of nine weeksfollowing treatment initiation.47 Certain familial mitochondrialmutations predispose patients to hearing loss114e117 and aspirinmay offer some protection. These mutations and their relationshipwith hearing loss have not been studied in children, however.

The fluoroquinolones were shown in the 1970s to cause carti-lage damage in the joints of juvenile beagles118 and althoughmultiple studies and reviews have subsequently demonstrated safeuse in children,119e126 concerns remain. They can also causepsychological/neurological disorders, sleep problems, gastrointes-tinal upset and peripheral neuropathy. The newer fluoroquinolonesseem to be associated with fewer adverse effects than the oldermedications,127 but caution must be exercised with moxifloxacindue to possible QT interval prolongation.128 When used in thetreatment of MDR-TB, they are generally well tolerated in bothadults and in children with few significant adverse effects.120

However, a large number of adverse effects have been docu-mented in adults receiving a fluoroquinolone and pyrazinamide forpreventive therapy.129,130 The reason for this is not clear.

Few studies have assessed the adverse effects of the thioamideson children. Both ethionamide and prothionamide are commonlyassociated with adverse effects131e133 and can cause profoundgastrointestinal upset; severe nausea and vomiting can compro-mise adherence for both adults and children. The severity ofsymptoms usually subsides with time but symptoms can bereduced by initially splitting the daily dose or introducing the druggradually with escalation of the dose over time. The full dose, givenonce daily, should, however, be aimed for within a few weeks ofstarting treatment. The thioamides show structural similarities to

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the potent thyrostatic drug methimazole, which seems to inhibitthyroid hormone synthesis by inhibition of organification.134 Asa result, hypothyroidism can occur.135e140 Pellagra-like rash,141

hepatitis133,142e148 and hypoglycaemia149 have also been docu-mented as well as rare central nervous system adverse effectsincluding seizures, encephalopathy and acute psychosis.141 Pro-thionamide seems to be marginally better tolerated in adults.150

Cycloserine and terizidone have been poorly studied in children.In adults, cycloserine has been widely implicated in neuropsychi-atric adverse effects such as anxiety, depression, confusion,psychosis, irritability, tremor, convulsions and aggression.151e154 Ithas also been associated with hypersensitivity reactions in thosewith HIV155 and with an episode of encephalitis.156 From the verylimited data that are available, terizidone seems to be bettertolerated. Emerging data suggest that terizidone has fewer adverseeffects (1%) than cycloserine (11%).157

The newer granular formulation of PAS is well tolerated and easilyadministered to children. PAS can cause hypothyroidism,140,158,159 aneffect which may be potentiated by the concomitant use of ethion-amide.140 Gastrointestinal problems,160,161 hepatitis,162 thromboc-ytopenia,163e165 hypoglycaemia,166 vasculitis, arthralgia, eosinophilia,malabsorption167,168 and a lymphoma-like syndrome (lymphade-nopathy, rash and hepatomegaly)169e172 are other potential adverseeffects. Hypersensitivity reactions, characterised by fever, conjuncti-vitis and rash, may occur in up to 5e10% of patients on PAS, usuallywithin the first couple of months.161,162,170,171 It may be possible todesensitise those with hypersensitivity to PAS by starting with a lowdose and slowly increasing.173 However this is not recommended.172

Toxicity of the group five drugs is considerable but adverseeffects are less common in children compared to adults. There ismuch experience in the use of clofazimine as it has been givenextensively in the treatment of leprosy. It commonly causesgastrointestinal symptoms such as diarrhoea, nausea, vomiting andabdominal pain. The majority of patients develop a red-brownhyperpigmentation of the skin and conjunctiva which is reversiblebut may take many months to revert. A recent leprosy trial in Indiaand China included 422 children less than 15 years of age. Clofazi-mine was very well tolerated and few drug reactions were noted.Skin discolourationwas usually short-lived and felt to be acceptableto patients.174 Adverse effects in children on short courses of line-zolid are rare but include headache and gastrointestinal dis-turbance.79,175e178 With prolonged use in adults withdrawal of thedrug is frequently required due to myelosuppression (includingpancytopenia) and peripheral and optic neuropathy; lactic acidosishas also been reported.179e185 Reports of linezolid use in childrenwith MDR-TB have found it to be well tolerated.14,83,179,180 Thiace-tazonewas usedwidely to treat TBprior to the advent of HIV. Severe,life-threatening Stevens Johnson reactions were associated withthiacetazone use in HIV-infected adults186,187 and children.188

Although it is contraindicated only in HIV-infected individuals, itis now rarely available in most countries. Other adverse effectsinclude gastrointestinal disturbances, skin reactions, hepatotoxicity,haemolytic anaemia and agranulocytosis.189 The most commonadverse effects of the beta-lactams are gastrointestinal and hyper-sensitivity reactions. Occasionally liver and renal derangement canoccur. The macrolides can cause gastrointestinal (GI) disturbances,hepatotoxicity, prolonged QT syndrome and rash.

Effect of HIV co-infection and interaction with ART

Co-infectionwith both TB andHIV is common in areaswhere bothdiseases arewidespread.190,191Rapid initiationofART inchildrenwithMDR-TB is critical due to the advanced spectrum of TB disease andhigh mortality observed in this paediatric subpopulation.6 The druginteractions between ART and first-line TB drugs have been

econd-line anti-tuberculosis agents: A review, Tuberculosis (2011),

Table 3Potential interactions and combined toxicity between the second-line tuberculosis drugs and antiretroviral treatment.95,96

Drug Pharmacokinetic interactions Increased risk of adverse effects

Injectables Unlikely Nephrotoxicity with tenofovir*Fluoroquinolones Moxifloxacin concentration may be reduced

by ritonavirMoxifloxacin concentration may be increasedby unboosted atazanavir*Buffered didanosine may reduce oral absorptionof all fluoroquinolones

Psychiatric symptoms with efavirenzHepatitis with nevirapine, efavirenz or protease inhibitorsProlongation QT interval with protease inhibitors and efavirenz

Ethionamide/Prothionamide Unknown Peripheral neuropathy with stavudine or didanosinePsychiatric symptoms with efavirenzHepatitis with nevirapine, efavirenz or protease inhibitorsGI intolerance with zidovudine or protease inhibitors

Cycloserine/Terizidone Renally cleared so interactions unlikelyNephrotoxicity caused by tenofovir* couldaffect serum concentrations

Peripheral neuropathy with stavudine or didanosinePsychiatric symptoms with efavirenzStevens Johnson Syndrome with nevirapine and efavirenz

PAS Unlikely Hepatitis with nevirapine, efavirenz or protease inhibitorsGI intolerance with zidovudine or protease inhibitors

Clofazimine May increase etravirine* and proteaseinhibitor concentrations

GI intolerance with zidovudine or protease inhibitors

Linezolid Unlikely Peripheral neuropathy with stavudine or didanosineGI intolerance with zidovudine or protease inhibitorsLactic acidosis with stavudine, didanosine or zidovudineBone marrow toxicity with zidovudine

Amoxicillin/Imipenem/Meropenemwith clavulanic acid

Unlikely Nephrotoxicity with tenofovir*

Thiacetazone Not advised in HIV-infected patients due to risk ofStevens Johnson Syndrome

Not advised in HIV-infected patients due to risk ofStevens Johnson Syndrome

Clarithromycin Concentrations increased by ritonavirConcentrations reduced by efavirenz and nevirapineClarithromycin reduces zidovudine concentrations

Combination with non-nucleoside reverse transcriptaseinhibitors (NNRTIs) not recommended due to increasedconcentrations of the 14-hydroxy metabolite which isassociated with rashes

* Currently not advised for use in children.

J.A. Seddon et al. / Tuberculosis xxx (2011) 1e96

extensively reviewed.192,193 Rifampicin reduces the concentrations ofmany concomitantly administered drugs including the key anti-retroviral non-nucleoside reverse transcriptase inhibitors andprotease inhibitors.Datadescribing thepharmacokinetic interactionsbetween ART and the second-line anti-TB drugs are incomplete andthe metabolic pathways of some of the drugs are poorly charac-terised. Hence, unanticipated interactions might occur. However, thepotential for clinically important changes in ART or anti-TB drugconcentrations is less for most second-line anti-TB regimenscompared to the rifampicin-containing first-line regimens. ART andsecond-line antituberculosis drugs have many adverse effects incommon. High rates of neuropathy, hypokalaemia, hypothyroidismand marked renal impairment have been reported in adult pop-ulations with MDR-TB and a high proportion of HIV-infectedpatients.194,195 Drug interactions between anti-TB and ART drugsare therefore important to consider.95,96 However, the risks attrib-utable to the anti-TB and ART drug combinations versus those due topotential confounding factors such as the extent of immunesuppression, co-morbidities (e.g. chronic viral hepatitis, or diabetes),concomitant medication or toxins and nutritional status, are uncer-tain. Table 3 summarises possible interactions and adverse effectsthat may be exacerbated. Few studies have assessed second-linedrugs in combination with ART in adults and no studies have doneso in children.

Conclusions

Themanagement of paediatricMDR-TB is challenging, largely dueto the complicated and toxic drugs currently used. It is vital thatclinicians managing such children are familiar with the availabledrugs. Given the scale of the challenge it is concerning that so littleprimary data are available to inform practitioners. Traditionally thetreatment of children with TB was not regarded to be a public healthpriority and cases were under-reported due to the challenges in

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establishing a definitive diagnosis. As themajority of affected childrenare in poorer areas of the world, the development of drugs to treatpaediatric TB and particularly paediatric MDR-TB has not beena priority for drug companies due to the likely lack of return oninvestment. In addition, the regulation of paediatric drugs is compli-cated and different mechanisms exist in different countries. The tidemaybe changing due to increased awarenessbut rigorous prospectivestudies are required to assess the pharmacokinetics, tolerability andtoxicity of the second-line anti-TB drugs, in children of different agesand with/without HIV co-infection. Research on effective and safertreatment strategies in children with MDR-TB is urgently needed.

Financial support

This work was supported by a grant (GHN-A-00-08-00004-00)from TREAT TB, USAID (JAS and HSS), the Sir Halley Steward Trust(JAS), the South African Medical Research Council (HSS) and theNational Research Foundation of South Africa (HSS and PRD). HMreceived partial support from SATBAT through the Fogarty Inter-national Center (U2RTW007370/3, 5U2RTW007373).

Competing interests: None declared.

Funding: The funding agencies had no role in the design orconduct of the study, in the collection, management, analysis orinterpretation of the data, or in the preparation, review, or approvalof the manuscript.

Ethical approval: Not required.

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