Harichander et al. BMC Pediatrics(2024) 24:520
https://doi.org/10.1186/s12887-024-04985-8

BMC Pediatrics

RESEARCH

Open Access

Manipulation of solid dosage forms for oral
administration to paediatric patients for drugresistant tuberculosis in South Africa: anobservation study
Sheetal Harichander1*, Varsha Bangalee1 and Frasia Oosthuizen1
Abstract
Background Children represent a particularly vulnerable demographic in the context of drug-resistant(DR) tuberculosis (TB) due to their increased likelihood of close contact with adults diagnosed with the disease.
Approximately 25 000–30 000 children develop DR-TB annually. While treatment success rates for DR-TB in children
surpass those in adults, children and adolescents encounter distinct challenges throughout the diagnosis andtreatment of DR-TB (including MDR-TB, Pre-XDR TB, and XDR-TB).
Aim To identify current practices in drug administration to children diagnosed with DR-TB where appropriate dosage
forms are not available in South Africa.
Method An observational study was carried out at the study site to determine how medication prescribed was
manipulated and administered by nursing staff to paediatric patients in the wards.
Results The observational study identified 8 drugs used in DR-TB at the study site, where some manipulation to theformulation was necessary to enable administration to paediatric patients. Linezolid and para-aminosalicylic acidare the only drugs available and registered in the South Africa in a formulation that is suitable for administration to
paediatric patients. Activities carried out by nursing staff to enable the administration of DR-TB medication included
cutting capsules and tablets and dissolving the tablet or capsule contents in distilled water to obtain the required
suitable dose.
Discussion Lack of availability of suitable dosage forms for paediatrics patients results in several challenges,
such as additional time required for drug preparation, increased time duration of medication administration, andunpalatability of drugs. These challenges may subsequently affect compliance and therapeutic outcomes of thetreatment of paediatric patients, especially as outpatients.
Conclusion Research needs to focus on the development of appropriate dosage forms for the paediatric populationand focus on identifying cases of DR-TB in children. This will assist in building evidence to advocate for registration ofchild-friendly dosage forms thereby ensuring a sustainable supply of medication.

*Correspondence:
Sheetal Harichander
sheetal.harichander@gmail.com
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Harichander et al. BMC Pediatrics(2024) 24:520

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Keywords Dosage forms, Drug-resistant tuberculosis, Paediatrics, Treatment

Background
Tuberculosis (TB) is a communicable disease and oneof the leading causes of death worldwide [1]. Until thecoronavirus (COVID-19) pandemic, TB was the leading cause of death from a single infectious agent, ranking above the human immunodeficiency virus (HIV) andacquired immunodeficiency syndrome (AIDSs) as per theWorld Health Organization (WHO) [1]. TB is caused by
the bacillus, Mycobacterium tuberculosis (MTB), which isspread when people, infected with TB, expel bacteria into
the air e.g. by coughing [1]. The disease typically affects
the lungs but can affect other sites in the body [1]. TB is
curable and preventable [1].
The emergence and spread of drug-resistant (DR) TB,
especially multidrug-resistant (MDR) TB and extensively
drug-resistant (XDR) TB, presents a major challenge toglobal TB control. MDR-TB is defined as resistance toisoniazid and rifampicin with or without resistance toother anti-TB drugs [2, 3]. XDR-TB is caused by MTB
strains that fulfill the definition of MDR-TB and which
are also resistant to any fluoroquinolone and to at least
one additional Group A drug (either bedaquiline or linezolid) [2, 3]. DR-TB affects children and adolescents,
especially in household contacts where there is a higher
risk of contracting the disease from infected adults [4–6].
Research estimates that between 25,000 and 32,000 children develop DR-TB every year, of whom < 5% receive
treatment [7].
Historically, children and adolescents have not been apriority in programs for TB prevention and care [6]. This
population was often thought to play only a minor rolein the transmission of TB, and TB prevention and care
were centred around adults [6]. The treatment of DR-TB
in children is guided by the same principles and uses thesame second-line drugs as in adult patients [6, 7].
There is a lack of appropriate paediatric dosage forms
for DR-TB medications that are available in South Africa(SA) [7]. In recent years, child-friendly second-line TB
drug formulations have gradually become more widely
available [8]. The Stop TB Partnership’s Global Drug
Facility (GDF), the largest global provider of qualityassured TB drugs, has worked to include child-friendly
formulations for bedaquiline, clofazimine, cycloserine/
terizidone, ethambutol, ethionamide, levofloxacin, moxifloxacin and pyrazinamide in their catalogue, and in partnership with the Sentinel Project to support their uptake
globally [8]. While countries remain where these formulations are unapproved and therefore not accessible (e.g.,
the European Union and SA) [8].
Orally formulated, immediate-release, adult-strengthtablets are generally not designed for flexible dosing,and they are difficult to adapt to redosing based on age
and/or weight, as necessary in children [7, 9]. Medicines
are manipulated by the physical alteration of a dosage
form to achieve the required (usually smaller) dose foradministration [10]. Though this is recognized amongprofessionals as a widespread practice, reports about
manipulations of dosage forms to achieve the required
dose are limited [10]. Manipulating dosage forms may betime-consuming, result in toxic or sub-therapeutic doses,
and have unknown effects on the stability and bioavailability of the drug [11–13]. Drug manipulations and dose
calculations may also increase the risk of administration
errors [14].
The palatability of oral drugs is another factor to beconsidered as it can affect patient adherence [15]. Various factors influence palatability, including smell, taste,texture, and dose volume [15]. Recent studies were conducted in SA with children and their caregivers that highlighted the negative experience in terms of acceptabilityof DR-TB treatment [16, 17]. Nurses and caregivers also
experienced challenges related to time that is needed toprepare these doses and tolerability of the children to
the medication. These challenges can negatively impact
adherence to therapy.
This study aimed to determine current practices in thetreatment of children with DR-TB where child-friendly
formulations are unavailable in Johannesburg, SA.

Methodology
Study design

This observational study was conducted at Sizwe Tropical Diseases Hospital, a specialized TB hospital located in
Johannesburg, Gauteng province, SA in 2022.
Setting

SA is classified as a high TB burden country in all threeof the WHO classifications – TB, TB-HIV and drugresistant TB [1]. It is one of only 10 countries included in
all three of these classifications [1]. In SA, notificationsof paediatric TB cases (under 15 years) have exhibited asignificant decline since 2015 [18]. This reduction could
stem from either an actual decrease in case numbers or asmaller proportion of cases being detected [18]. The public health system in SA is guided by the Essential Medicines List (EML) with supporting Standard Treatment
Guidelines (STGs). Although the Stop TB Partnership’s
GDF have included child-friendly formulations in the
catalogue for some second-line TB drugs, these formulations are not registered for use in SA. SA had applied
for a donation from the Stop TB Partnership’s GDF but
these child-friendly formulations have not been made

Harichander et al. BMC Pediatrics(2024) 24:520

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Table 1 Definitions of dosage form manipulations. (adaptedfrom [20, 21])

Table 2 DR-TB drugs and dosage forms registered for use inSouth Africa

Dosage form
CapsuleDrug
Bedaquiline (BDQ)
Clofazimine (CFZ)
Delamanid (DLM)
Ethambutol (ETH)
Ethionamide (Eto)
Isoniazid (INH)

Dosage form
Tablets
Gel Capsule
Tablets
Tablets
Tablets
Tablets

Levofloxacin (LFX)

Tablets

GranulesSuspension
Tablets

Type of manipulation• Opened and the contents dispersed in astandard volume of distilled water. A proportion of liquid was administered.
• Opened and the contents measured before
being suspended in a standard volume of
distilled water, and administered.
• Reconstituted with distilled water and a
proportion administered.
• Broken/cut and a segment administered.
• Broken/cut and a segment dispersed in astandard volume of distilled water and a portion administered.
• Whole tablet dispersed in a standard volumeof distilled water and a portion administered.

available across all 9 provinces and remain unregisteredfor use. Lack of evidence of safety and efficacy in children
in these formulations hinders inclusion into the National
Department of Health STGs and EMLs [19].
Children with DR-TB across the province of Gauteng
are referred to Sizwe Tropical Diseases Hospital to be
initiated on treatment. The children are usually admitted
for long periods of time due to clinical reasons or in theabsence of a reliable caregiver.
Data collection

Data was obtained via direct observation of the nursing staff while they prepared antitubercular medication
for administration to the children on randomly assigneddays between May and June 2022. Registered drugs andtheir dosage forms that were available were documented.
Administration of medications not manipulated were notobserved.
Data analysis

Analysis of the data included comparing dosage
manipulations to the patient information leaflet andpaediatric dosing guidelines and a review of available literature to determine whether dosage manipulations wereappropriate.
Ethics

Ethical approval for the study was obtained from the
Biomedical Research Ethics Committee of the University of KwaZulu-Natal (Reference BREC/00003668/2021)
and permission to use the data was obtained from theGauteng Department of Health and Sizwe Tropical
Diseases Hospital (Reference GP202107 055). Gatekeeper permission was obtained in writing by the sisterin charge. The nurses were informed about the scope ofthe study and gave verbal consent before being observedin the ward. Written informed consent was sought fromthe caregivers of the two children admitted at the time ofLinezolid (LZD)

Granules for
suspension
Linezolid (LZD)
Tablets
Moxifloxacin (MXF)
Tablets
Para-aminosalicylic acid (PAS) Granules
Pyrazinamide (PZA)
Tablets
Terizidone (TRD)
CapsulesStrength
100 mg
100 mg
50 mg
400 mg
250 mg
100 mg and
300 mg
250 mg, 500 mg
and 750 mg
20 mg/ml
600 mg
400 mg
4g
500 mg
250 mgdata collection. All methods were carried out in accordance with relevant guidelines and regulations.
Definitions

Manipulation of dosage forms was defined as all activities
before administration that are undertaken to administer
the medicine to the paediatric patient. One manipulation
could comprise different steps and could, therefore, be a
combination of different manipulation types. Table 1 provides the definitions for dosage form manipulations thatwere identified in this study.

Results
During the observation period, four nurses wereobserved in the ward preparing prescribed DR-TB medication to two children admitted over a period of 10 days.
Table 2 provides an overview of drugs and dosage
forms registered for use in South Africa and available forthe treatment of at the time of data collection in 2022.
LZD and PAS are the only drugs registered in dosage
forms suitable for administration to paediatric patientsin SA without further manipulations. All other drugs
are only registered in tablet or capsule form and must be
manipulated for paediatric administration.
The manipulation and administration of prescribed
DR-TB treatment was observed in two children that wereadmitted at the hospital during data collection and arelisted below as per Table 3.
The children are weighed once a week, on a Saturday,
to aid in calculating the appropriate medication dose.
The manipulation and administration of 8 prescribeddrugs were observed at the study site, as per Table 4. A
total of 10 manipulations and administration sessions
were observed. All four nurses observed were observed
during the same observation period and administered

Harichander et al. BMC Pediatrics(2024) 24:520

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Table 3 Children that were observed for medication administration practices
Child Age
Gender Weight Date of admission/initiation RegimenA
23 months Female 10.5 kg 22 February 2022
• Linezolid 8mls (160 mg) once daily• Levofloxacin 250 mg once daily• Para-aminosalicylic acid 2 g once daily• Clofazimine 100 mg three times per week on Monday, Wednesday and Friday• Terizidone 175 mg once daily• Bedaquiline 100 mg three times per week on Monday, Wednesday and Friday• Pyridoxine 12,5 mg once daily• Multivitamin 5mls once dailyB
16 months Male
7.7 kg 24 February 2022
• Levofloxacin 150 mg once daily• Clofazimine 100 mg three times per week on Monday, Wednesday and Friday• Terizidone 125 mg once daily• Para-aminosalicylic acid 2 g once daily• Isoniazid 150 mg once daily• Delamanid 25 mg twice a day• Linezolid 6mls (120 mg) once daily• Ferrous sulphate 2,5mls once daily• Multivitamin 2,5mls once daily• Eltroxin 0,05 mg once daily• Pyridoxine 12,5 mg once daily• Folate 2 mg once daily

the prescribed treatment to both children. The most frequently manipulated dosage forms were tablets (50%,n = 4) and capsules (25%%, n = 2).
BDQ, CFZ, DLM, LZD, and PAS were administeredindividually to the patient. The dose manipulation for
CFZ is done as per Table 4 according to the prescribed
dose for the patient. It is difficult to predict if all the liquid is squeezed into the child’s mouth as the capsule is ashade of dark brown and its contents cannot be viewed.
The liquid present inside is thick and greasy.
For the administration of INH, LFX, TRD, folic acid,and pyridoxine, required doses were withdrawn via
syringe from the manipulated volume as per Table 4, andadded to a single medicine cup. Ferrous and multivitaminsyrup doses were also added to the measuring cup for asingle administration to the patient. As the ferrous supplement and the multivitamin are formulated as syrups
for oral consumption, these were added to try and mask
the taste of the added tablets and capsules, which could
be unpalatable. This resulted in a significant volume ofliquid to be administered to the patient.
Manipulations for the 7 drugs observed were done inaccordance with guidelines [3, 22–24]. The method ofadministration for CFZ is not recommended in any package insert or guideline, but that this was considered themost practical method in this setting.

Discussion
Several studies have been conducted previously thatdetail the challenging DR-TB journey for children andtheir caregivers due to the many obstacles that impact
diagnosis and management [12, 16, 17, 25]. Historically,
DR-TB treatment for children involved treatment withmedication with significant adverse drug reactions [14,26–29]. Recent advancements, such as the introduction of new and repurposed drugs, shorter regimens,
improved formulations, and injectable-free, all-oral regimens, offer promise [30, 31]. However, the widespread
availability of these innovations, particularly for children,
remains limited in many countries [16].
There has been a gradual expansion in the availabilityof child-friendly formulations of second-line TB drugs
in the last few years [8, 32]. The Stop TB Partnership’s
GDF, renowned as the largest global provider of quality-assured TB drugs, has taken steps to integrate childfriendly formulations for various medications, including
bedaquiline, clofazimine, cycloserine/terizidone, ethambutol, ethionamide, levofloxacin, moxifloxacin, andpyrazinamide, into their product offerings [8, 32]. Furthermore, in partnership with the Sentinel Project, they
have been facilitating the global adoption of these formulations. Although some countries have yet to approvethese formulations, rendering them inaccessible (e.g., theEuropean Union and SA), those with access should prioritize their procurement [33]. At the time that the study
was conducted, there were no child-friendly formulations
except for LZD that were available at the study site andmanipulations were done in accordance with guidelines
published with the exception of CFZ.
The administration of solid dosage forms manipulated
for the treatment of DR-TB in children can be time-consuming, challenging, and non-adherence is a major causeof treatment failure [34]. Multiple factors may contribute to this issue, including the absence of paediatric formulations, high pill burden, poor palatability, extended
therapy duration, and medication toxicity [35]. The main
reasons for the manipulation of solid dosage forms inthis study were the lack of suitable dosage forms and theHarichander et al. BMC Pediatrics(2024) 24:520

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Table 4 Drug administration in the paediatric ward
Drug
Bedaquiline

Clofazimine

Delamanid

Isoniazid

Levofloxacin

Linezolid

Terizidone

P-aminosalicylic acid

Formulation
100 mg uncoated tablet

Type of Manipulation
Tablet dispersed in distilled water.

Dose manipulations observed
Dispersed one tablet (100 mg) in a a standard volume of distilledwater (10mls) and the required volume administered.
Administered on its own (not mixed with other preparations).
100 mg gel capsule
Capsule is cut
The tip of the capsule is cut.
The liquid in the capsule is squeezed directly into the child’s mouth.
OR
A needle is inserted into the capsule to withdraw the liquid, whichis then administered to the child via the syringe.
Administered on its own (not mixed with other preparations).
50 mg film coated tablet Tablet dispersed in disDispersed one tablet (50 mg) in a standard volume of distilled
tilled water.
water (10mls) and the required volume administered.
If the dose is 50 mg, draw 10 ml to administer to the child.
Calculation:
50 mg – 10mls = 50 mg – x= 10mls
Administered on its own (not mixed with other preparations).
300 mg scored tablet
The tablet is cut/broken
One tablet (300 mg) is broken in half. The half tablet (150 mg) isin half and dispersed indispersed in a standard volume of distilled water (10mls).
distilled water.
The prepared dose is withdrawn and added to the medicine cup to
be mixed with the other doses for administration.
250 mg film coated tablet The tablet is dispersed in Dispersed one tablet (250 mg) in a standard volume of distilled
distilled water. The dosewater (10mls) and the required volume administered.
is calculated and then the E.g., Dose prescribed is 150 mg once daily.
required proportion of
Calculation:liquid is administered.
250 mg – 10mls = 150 mg – x= 6mls required for administration
The calculated dose is drawn into a syringe and added to the
medicine cup to be mixed with the other doses for administration.
The remaining dose is discarded.
20 mg/ml suspension
No manipulation isrequired. Suspension isreconstituted.
250 mg capsule
Capsule contents areOpen and dissolve the contents of one capsule (250 mg) in a stanopened and dissolved in dard volume of water (10mls).
distilled water. The dose
Sufficient time is allowed for the capsule contents to dissolve
is calculated and then the (around 30 min).
required proportion ofE.g., Dose prescribed is 175 mg once daily.
liquid is administered.
Calculation:
250 mg – 10mls = 175 mg – x
x = 7mls
The calculated dose is drawn into a syringe and added to the
medicine cup to be mixed with the other doses for administration.
The remaining dose is discarded.
4 g sachet
Mixed in a yoghurt.
Available as granules that are mixed in yoghurt and administered
to the patient before food at 6 am.

Calculations of the dose are guided by the formula: Dose available = Prescribed dose / x. Each tablet was considered to be equivalent to 10mls

lack of strength suitable for paediatric patients for DR-TB
that were available. Manipulation of solid dosage forms
for administration can be complicated and therefore
open to errors and the possibility of incorrect dosing.
Few guidelines exist and support dose manipulations ofsolid dosage forms for paediatric administration based on
scientific research. Although dose manipulations for paediatrics may be common practice for many disease conditions, these manipulations are done according to practiceand not scientific research. Studies should be conducted
to determine if the bioavailability remains the same when

the dosage form is manipulated for all second-line drug
treatment to ensure patient safety and optimum treatment outcomes.
During the observation of nurses preparing themanipulated doses, time played a major role as the task
was relatively long given the many drugs prescribed for
DR-TB. In some instances, the tablets had to be broken
in half which can often result in the damaging the entire
tablet. The capsules had to be opened. The distilled water
needed to be measured and each tablet or capsule dispersed individually. Once each dose had been prepared,

Harichander et al. BMC Pediatrics(2024) 24:520

the required dose was then withdrawn and added to asingle medicine cup. There was a large volume of liquidthat needed to be administered to the child. The flavourand colour of the liquid seemed to affect the tolerabilityof the child as they would often reject the medicine by
spitting it out or crying. Although the nurses had developed strategies to ensure that the children consume all
the medicine, the process is difficult on both the childand the nurse. Previous studies have detailed the physicaland emotional trauma that nurses, children and caregivers go through in this process. Nurses have even complained about the cumbersome and inconvenient processof preparation and administration of these manipulated
doses to the children.
The findings of the study emphasize the urgent needfor child-friendly formulations to be made available forall second-line drugs. Children afflicted with DR-TB constitute a vulnerable demographic, often lagging behind inaccessing advancements in paediatric care and specifically in DR-TB management. Furthermore, focus should
be towards locating undiagnosed cases of TB in children,
ensuring they receive suitable treatment, and establishing a stronger evidence base to advocate for all consistent
supply of formulations that are child-friendly for all second-line drugs that is available globally.
To our knowledge, this is the first study to report thecurrent practices in dosage form manipulations for paediatric DR-TB treatment. The study was conducted facing some limitations. The observation was done in one
hospital and one ward therefore the results are not representative of the population. At the time of data collection,
only two patients (less than 2 years of age) were admitted, therefore observation was limited. Additionally, theobservations did not include administration and manipulation by caregivers. The above findings present the situation about DR-TB at the time the study was conducted
and may not be a permanent feature at the study site andthroughout the country.

Conclusion
There is an increasing number of children worldwide
needing treatment for DR-TB. Paediatric DR-TB patients
have traditionally been treated with off-label adult pharmaceuticals or extemporaneous compounding, which is
not ideal for paediatric patients due to a lack of productsafety, efficacy, and evidence-based guidelines. [35] Furthermore, there are limited formulations suitable forchildren that are widely available. This has resulted in the
manipulation of existing formulations to liquid preparations, either by dissolving tablets or opening capsules, toadminister to paediatric patients. Establishing the correct dose and our ability to administer it to the child successfully are equally important. We need to encourage
and work with manufacturers to adapt medicines to the

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needs of children but should also ensure that pharmacists and carers have information to adapt dosage forms
safely and to extemporaneously formulate if necessary.
Although there has been development of child-friendly
dosage forms in recent years these drugs lack availability
and registration in many countries. The healthcare sector needs to focus on identifying cases of children with
DR-TB to build evidence to advocate for registration ofchild-friendly dosage forms thereby ensuring a sustainable supply of medication.
Acknowledgements
The authors would like to thank the nursing staff for the opportunity toobserve manipulations of dosage forms in clinical practice.
Author contributions
S.H., V.B., and F.O. conceived the study design. S.H. obtained the data from thestudy site.S.H. performed the analysis of the data. S.H. wrote the draft of themanuscript with V.B. and F.O. assisting with further drafts and revisions. All
authors reviewed and approved the final version of the manuscript.
Funding
This research received no funding.
Data availability
Data is provided within the manuscript.

Declarations
Ethics approval and consent to participate
Ethical approval for the study was obtained from the Biomedical Research
Ethics Committee of the University of KwaZulu-Natal and permission to use
the data was obtained from the Gauteng Department of Health and Sizwe
Tropical Diseases Hospital. Informed consent was signed by all participants.
All methods were carried out in accordance with relevant guidelines andregulations.
Consent for publication
None.
Competing interests
The authors declare no competing interests.
Disclaimer
The findings and conclusions in this manuscript are those of the authors anddo not necessarily represent Sizwe Tropical Diseases Hospital or South Africa.
Author details
1
School of Health Sciences, University of Kwazulu-Natal, WestvilleCampus, Private Bag X54001, Durban 4000, South Africa
Received: 6 December 2023 / Accepted: 30 July 2024

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