72 AJTCCM VOL. 31 NO. 2 2025
ORIGINAL RESEARCH: BRIEF REPORT
We describe a rare case of perinatally acquired extensively drug-resistant tuberculosis in an infant. e infant was successfully treated with
an individualised all-oral multidrug regimen containing delamanid, a drug rarely described in the treatment of perinatal tuberculosis.
Keywords. Drug-resistant tuberculosis, perinatal tuberculosis.
Afr J Thoracic Crit Care Med 2025;31(2):e2346. https://doi.org/10.7196/AJTCCM.2025.v31i2.2346
Tuberculosis (TB) is the leading cause of death from a curable
infectious disease worldwide.[1] Multidrug-resistant (MDR)/
rifampicin-resistant (RR)-TB (MDR/RR-TB) remains a signicant
public health concern, with increasing case notications globally
and an estimated 410 000 people who developed MDR/RR-TB in
2022.[1]
e World Health Organization (WHO) updated its denitions
for drug-resistant (DR)-TB to reflect the expanded access to
oralbedaquiline-containing regimens for RR-TB treatment.[2] MDR-TB
is dened as disease caused by Mycobacterium tuberculosis resistant
to rifampicin and isoniazid (INH), both core drugs used inthe
treatment of drug-sensitive TB.[1,2] Pre-extensively drug-resistant TB
(pre-XDR-TB) now describes MDR-TB with additional resistance to
uoroquinolones (levooxacin or moxioxacin),[1,2] while XDR-TB
is now dened as resistance to rifampicin, INH, uoroquinolones,
and at least one other group A drug (i.e.bedaquiline or linezolid).[1,2]
Although TB is generally transmitted by inhalation of droplet nuclei
containing M. tuberculosis, mother-to-child transmission may also
occur. is may happen as a result of haematogenous dissemination
via the umbilical vein during the antenatal period, through aspiration
of infected amniotic uid or genital secretions during the intrapartum
period, or through inhalation of infected droplet nuclei during the
postpartum period.[3]
A 3-month-old male infant was referred to a specialised DR-TB
unit in KwaZulu-Natal Province, South Africa (SA). He was born at
31weeks’ gestation via normal vertex delivery in November 2021,
weighed 1320 g and had Apgar scores of 9 and 10 at 1 and 5 minutes,
respectively. He did not receive BCG vaccination at birth because
Perinatal transmission and cure of extensively drug-resistant
tuberculosis in an infant
V Singh,1,2 MB ChB, Dip HIV Man (SA) ; R Perumal,3,4,5 MB ChB, MMed (Int Med), MPhil, MPH, PhD, FCP (SA), Cert Pulmonology (SA) ;
M Wessels,6 MB ChB, Dip HIV Man (SA), DCH (SA), PG Dip (Comm Paeds), FC Paed (SA) ; F Hai,7 MB ChB ;
K Lutchminarain,1,2 MB BCh, FC Path (SA) Micro, MMed (Micro) ; K Naidoo,3,4 MB ChB, PhD ;
K Swe Swe-Han,1,2 MBBS, DTM&H, PG Dip (Infection Control), FC Path (SA) Micro, MMed (Micro), PhD
1 Department of Medical Microbiology, Albert Luthuli Laboratory, National Health Laboratory Service, Durban, South Africa
2 Department of Medical Microbiology, School of Laboratory Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal, Durban,
South Africa
3 Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa
4 South African Medical Research Council-Centre for the AIDS Programme of Research in South Africa (CAPRISA) HIV-TB Pathogenesis and Treatment Research
Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
5 Department of Pulmonology and Critical Care, Division of Internal Medicine, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban,
South Africa
6 Queen Nandi Regional Hospital, KwaZulu-Natal Provincial Department of Health, South Africa
7 King Dinuzulu Hospital Complex, KwaZulu-Natal Provincial Department of Health, South Africa
Corresponding author: V Singh (vikarsingh001@gmail.com)
Study synopsis
What the study adds. is brief report oers insight into a clinical case of perinatally acquired extensively drug-resistant tuberculosis
(XDR-TB), and outlines the individualised treatment plan that led to a successful treatment outcome.
Implications of the ndings. e report highlights the need for evidence-based guidance on XDR-TB in this paediatric population, as well
as further research on preventive strategies for mitigating mother-to-child transmission of TB.
AJTCCM VOL. 31 NO. 2 2025 73
ORIGINAL RESEARCH: BRIEF REPORT
his mother had pre-XDR-TB disease during pregnancy. He was HIV
exposed, received HIV prophylaxis (nevirapine) and TB preventive
therapy (TPT) (INH 5 mg/kg/d) aer delivery, and was exclusively
formula fed.
At 2months of age, the infant was taken to his primary healthcare
facility with a history of fever, and was found to have a temperature
of 38.3oC. He was treated as an outpatient and received single doses
of ceriaxone and paracetamol. Subsequent outpatient visits were
required for nonspecic complaints of diarrhoea, and progressive
respiratory symptoms including cough and wheeze. Twoweeks
later, at 10weeks of age, he developed signs of respiratory distress
and was admitted to a regional mother-and-child hospital for further
investigation.
Physical examination at admission revealed features of respiratory
distress, bilateral expiratory wheezes, and no hepatosplenomegaly.
Initial blood investigations showed anaemia (haemoglobin
concentration 6.6 g/dL), raised inammatory markers (C-reactive
protein 33 mg/L, erythrocyte sedimentation rate 37 mm/h), and a
negative Toxoplasma gondii, rubella, cytomegalovirus and herpes
simplex virus screen. HIV polymerase chain reaction and COVID-19
rapid antigen tests were negative. Blood, urine and stool culture revealed
no pathogens, and the results of cerebrospinal uid analysis were
normal. Chest radiography showed bilateral diuse reticulonodular
inltrates and features of mediastinal lymphadenopathy. Abdominal
ultrasonography revealed no hepatic complex, lymphadenopathy or
features suggestive of TB. Initial Xpert MTB/RIF Ultra assay (Cepheid,
USA) on gastric aspirate detected M. tuberculosis complex and a
mutation in the rpoB gene, conrming rifampicin resistance.
During the admission, a telephonic discussion with the specialised
DR-TB unit revealed that the infant’s mother was receiving treatment
for microbiologically conrmed pre-XDR-TB. is information led
to the decision that the infant be started on an age- and weight-
appropriate regimen comprising linezolid (LZD), clofazimine (CFZ),
terizidone (TRD), delamanid (DLM) and para-aminosalicylic acid
(PAS) (Table1). Prior to treatment commencement, his haemoglobin
concentration was optimised to 10.5 g/dL. When the mother’s extended
drug susceptibility testing (DST) showed an XDR-TB resistance
pattern, with resistance to bedaquiline (BDQ), the infant was kept
on the initial regimen because of his improving clinical condition.
He completed 15months of treatment, with resolution of the initial
clinical features, and remained with serially negative mycobacterial
culture results from diagnosis onwards.
Approximately 4months before conception, in November 2020, the
infant’s mother had been diagnosed with MDR-TB and commenced
on the basic long MDR/RR-TB regimen, which comprised LZD,
BDQ, levooxacin (LFX), CFZ and TRD. She received treatment
for 6months and was then lost to follow-up. She was re-diagnosed
with pre-XDR-TB at an antenatal care visit at 28weeks’ gestation,
with positive smear microscopy for acid-fast bacilli on sputum and
positive culture for M. tuberculosis. She was recommenced on the
same drug regimen 3weeks before delivery. At the time, she remained
on antiretroviral therapy with a suppressed viral load and a CD4 cell
count of 149 cells/µL.
In January 2022, 3months aer recommencing treatment, her
sputum culture remained positive for TB, and extended DST showed
XDR-TB.
Perinatal TB is an umbrella term that encompasses both congenital
and postnatal acquisition of TB.[3] Although each has distinct
transmission characteristics for diagnosis, dierentiation of the two
forms of perinatal TB is mainly of epidemiological importance, as
both are managed using the same approach.[4] e updated diagnostic
criteria for congenital TB includes proven TB lesions and at least one
of:[3,5] (i) lesions in the rstweek of life; (ii) a primary hepatic complex
or caseating hepatic granuloma; (iii) TB infection of the placenta
or the maternal genital tract; and (iv) exclusion of the possibility
of postnatal transmission by thorough investigation of contacts,
including the infant’s hospital attendants, and by adherence to existing
recommendations for treating infants exposed to TB.
Diagnosis of TB in the paediatric population is dicult owing to
the paucibacillary nature of the disease, diculty in obtaining good-
quality respiratory tract specimens, low sensitivity of microbiological
assays on sputum and gastric aspirate specimens, and the risk of
misdiagnosis due to overlap of nonspecic TB symptoms with other
common childhood diseases.[6] For these reasons, it is recommended
that treatment be based on the DST prole of the likely source patient
until DST results for the child are available.[7]
In the case of the infant in our report, there was insufficient
information to conrm congenitally acquired TB, as the placenta
was not sent for histopathological evaluation. In addition, abdominal
ultrasonography performed during admission did not suggest any
features of hepatomegaly or abdominal TB pathology. It is possible
that transmission may have occurred during delivery or the postnatal
period, owing to the delayed symptom presentation at 2months
of age. However, it was established that the mother and infant had
had minimal contact during the neonatal period, including only
two contact sessions with appropriate use of personal protective
equipment by the mother. e infant had remained in the care of
his grandmother while the mother received her DR-TB treatment
in an inpatient setting. On thorough screening by symptoms and
microbiological investigations, all close contacts of the mother and
infant, including the grandmother, were negative for TB.
It is important to note that INH TPT was probably ineective in
this case because the mother had conrmed inhA and katG gene
mutations, and phenotypic INH resistance. ere are limited data on
TPT for RR-TB. e use of LFX for MDR-TB preventive therapy is
recommended; however, evidence gaps on TPT for patients exposed
to pre-XDR- and XDR-TB strains persist.[8]
Two serial gastric aspirate specimens were sent for Xpert Ultra
testing on consecutive days before treatment commencement, both
of which detected M. tuberculosis complex with rifampicin resistance.
All subsequent specimens sent for genotypic and phenotypic testing
did not detect TB.
At the time of treatment commencement, WHO guidance on DR-
TB treatment in the paediatric population did not recommend DLM
and BDQ for children <3 and <6years of age, respectively. is has
subsequently changed. e patient was discussed with a paediatrician
experienced in the management of DR-TB, who suggested an exclusive
oral regimen including the use of DLM on this individual case basis.
e nal drug regimen included LZD, CFZ, TRD, PAS and DLM for a
15-month duration. e patient did not have any adverse drug eects,
and this regimen continued until treatment cessation, 15months
later. It is important to note that CFZ could not be counted on as an
74 AJTCCM VOL. 31 NO. 2 2025
ORIGINAL RESEARCH: BRIEF REPORT
eective drug in this regimen because the source patient’s DST showed
resistance to the drug.
There is limited evidence-based guidance on treatment
regimens for MDR/RR-TB in children.[6,7] e WHO recommends
exclusive oral regimens for children of all ages.[6] However, neither
international nor local guidelines provided recommendations for
XDR-TB regimens in paediatric patients at the time when our infant
was cared for. Subsequently, in 2022 the WHO updated its DR-TB
treatment guidelines, recommending BDQ and DLM for children
of all ages.[6]
Owing to the rarity of perinatal MDR/RR-TB, there is no clinical
trial evidence to guide optimal treatment in this patient population.
Arecent case report of conrmed pre-XDR-TB in a premature neonate
demonstrated a successful treatment outcome associated with the use
of a regimen containing BDQ and DLM. However, the regimen also
included a second-line injectable drug, amikacin.[9]
SA guidelines recommend that regimens should consist of at least
four drugs to which the organism is likely to be susceptible for the
entire duration of therapy, with the possible addition of a h drug
for the rst fewmonths of therapy. In cases of severe disease or with
a high bacillary burden, emphasis is placed on the inclusion of WHO
group A and B drugs, as well as DLM, in the treatment regimen.
[6,7] e treatment duration ranges from a minimum of 6months to
12-18months, depending on the site and severity of disease, and the
extent of drug resistance.[6,7]
In this case, owing to the extensiveness of drug resistance in the
presumed index case, the infant was treated with ve drugs for a
15-month duration, which included one group A drug (LZD), two
group B drugs (CFZ, TRD) and two group C drugs (DLM, PAS). e
infant had a successful outcome, achieving treatment completion
after 15 months with microbiological, radiological and clinical
improvement.
A factor that may have contributed to a good outcome was that
the patient received inpatient care for the entire treatment duration,
which included scheduled administration of medication and close
monitoring by trained healthcare professionals.
Although the delay in diagnosis did not obviously compromise this
patient’s outcome (in the absence of proper evaluation of post-TB
lung disease), a high index of suspicion for perinatally acquired TB
ought to have remained on the dierential diagnosis in his respiratory
illness presentation. Timeous diagnosis and treatment are essential
to prevent poor outcomes, as was noted in a previously reported
case of congenitally acquired MDR-TB where delayed diagnosis and
inadequate drug therapy contributed to mortality.[10]
Although rare, this case emphasises the need for evidence-based
guidance for XDR-TB regimens for perinatally acquired TB, as well
Table1. Summary of drug therapy and microbiological TB ndings of the case patient during the course of treatment
Pre-treatment Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10 Month 11 Month 12 Month 13 Month 14 Month 15
TB results 15 Feb 2022
Ultra positive
Rifampicin resistant
TB culture:
No growth aer
42days
16 Feb 2022
Ultra positive
Rifampicin resistant
LPA (clinical
specimen)
unsuccessful
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
Contaminated
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
Patient weight (kg) 3.36 3.6 3.6 3.6 4.7 5.4 5.7 6.1 6.0 6.5 6.6 6.7 8.0 7.5 8 7.5
Drug and formulation
LZD
20 mg/mL suspension
20 mg/kg daily orally
DLM
25 mg dispersible
tablet
25 mg twice daily orally
TRD
250 mg capsule
dispersed in 10 mL
WFI (25 mg/mL)
suspension
20 mg/kg daily orally
PAS granules
PAS sodium salt
(equal to 4 g PAS
acid) sachet
250 mg/kg daily orally 200 mg/kg daily orally
CFZ
50 mg dispersible
tablet
5 mg/ kg daily orally
TB = tuberculosis; Ultra = Xpert MTB/RIF Ultra (Cepheid, USA); LPA = GenoType MTBDRplus version 2.0 line probe assay (Hain Lifescience, Germany); LZD = linezolid;
DLM = delamanid; TRD = terizidone; PAS = para-aminosalicylic acid; CFZ = clofazimine; WFI = water for injection.
AJTCCM VOL. 31 NO. 2 2025 75
ORIGINAL RESEARCH: BRIEF REPORT
as for studies on preventive strategies for mitigating mother-to-child
transmission of TB.
e authors obtained written informed consent to publish this
article from the infant’s legal guardian (his mother).
Declaration. RP serves on the editorial board of AJTCCM, but had no
involvement in the handling of this manuscript.
Acknowledgements. None.
Author contributions. VS: conceptualisation, case history collection,
manuscript dra preparation. MW, FH: case history collection. RP, KL,
KN, KSSH: manuscript editing. All authors read and approved the nal
manuscript.
Funding.None.
Conicts of interest.None.
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https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-
reports/global-tuberculosis-report-2023 (accessed 10 June 2024).
2. World Health Organization. Meeting report of the WHO expert consultation on the
denition of extensively drug-resistant tuberculosis. 27-29 October 2020. Geneva:
WHO, 2020. https://www.who.int/publications/i/item/9789240018662 (accessed
10June 2024).
3. Shenoi A, Kavitha A. Perinatal tuberculosis. Pediatr Infect Dis 2019;1(1):30-33.
https://doi.org/10.5005/jp-journals-10081-1107
4. Singh M, Kothur K, Dayal D, Kusuma S. Perinatal tuberculosis: A case series. J Trop
Pediatr 2007;53(2):135-138. https://doi.org/10.1093/tropej/fml074
5. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: Congenital
tuberculosis. N Engl J Med 1994;330(15):1051-1054. https://doi.org/10.1056/
NEJM199404143301505
6. World Health Organization. WHO consolidated guidelines on tuberculosis. Module5:
Management of tuberculosis in children and adolescents. Geneva: WHO, 2022.
https://www.who.int/publications/i/item/9789240046764 (accessed 12 June 2024).
7. National Department of Health, South Africa. Clinical management of rifampicin-
resistant tuberculosis: Updated clinical reference guide. Pretoria: NDoH, 2023. https://
knowledgehub.health.gov.za/elibrary/clinical-management-rifampicin-resistant-
tubercolosis (accessed 12 June 2024).
8. World Health Organization. WHO consolidated guidelines on tuberculosis. Module1:
Prevention – tuberculosis preventive treatment. Geneva: WHO, 2024. https://www.
who.int/publications/i/item/9789240096196 (accessed 13 September 2024).
9. Boast A, How JA, Lau C, etal. Pre-extensively drug-resistant congenital tuberculosis
in an extremely premature baby. Clin Infect Dis 2024;78(1):149-153. https://doi.
org/10.1093/cid/ciad540
10. Espiritu N, Aguirre L, Jave O, Sanchez L, Kirwan DE, Gilman RH. Congenital
transmission of multidrug-resistant tuberculosis. Am J Trop Med Hyg
2014;91(1):92-95. https://doi.org/10.4269/ajtmh.13-0002
Received 24 June 2024. Accepted 11 November 2024. Published 2 June 2025.
Table1. Summary of drug therapy and microbiological TB ndings of the case patient during the course of treatment
Pre-treatment Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Month 10 Month 11 Month 12 Month 13 Month 14 Month 15
TB results 15 Feb 2022
Ultra positive
Rifampicin resistant
TB culture:
No growth aer
42days
16 Feb 2022
Ultra positive
Rifampicin resistant
LPA (clinical
specimen)
unsuccessful
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
Contaminated
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
TB culture:
No growth
aer 42 days
Patient weight (kg) 3.36 3.6 3.6 3.6 4.7 5.4 5.7 6.1 6.0 6.5 6.6 6.7 8.0 7.5 8 7.5
Drug and formulation
LZD
20 mg/mL suspension
20 mg/kg daily orally
DLM
25 mg dispersible
tablet
25 mg twice daily orally
TRD
250 mg capsule
dispersed in 10 mL
WFI (25 mg/mL)
suspension
20 mg/kg daily orally
PAS granules
PAS sodium salt
(equal to 4 g PAS
acid) sachet
250 mg/kg daily orally 200 mg/kg daily orally
CFZ
50 mg dispersible
tablet
5 mg/ kg daily orally
TB = tuberculosis; Ultra = Xpert MTB/RIF Ultra (Cepheid, USA); LPA = GenoType MTBDRplus version 2.0 line probe assay (Hain Lifescience, Germany); LZD = linezolid;
DLM = delamanid; TRD = terizidone; PAS = para-aminosalicylic acid; CFZ = clofazimine; WFI = water for injection.