Multidrug-Resistant Tuberculosis During Pregnancy: Two Case Reports and Review of the Literature

The GeneXpert MTB/RIF molecular assay of sputum samples detected Mycobacterium tuberculosis at a low bacillary load and identified rifampicin resistance, and direct sputum smear examinations were negative, whereas sputum culture was positive.

The clinical examination found an acute hypoxemic respiratory distress, her peripheral oxygen saturation was 85% on room air, her heart rate was 100 beats per minute, and her respiratory rate was 24 breaths per minute and her body weight was 60 kg. Chest  examination revealed faint crackles, while the remainder of the physical examination was unremarkable. Supplemental oxygen therapy was initiated.

Initial laboratory investigations revealed an anemia with an hemoglobin level of 10.3 g/dL, an erythrocyte sedimentation rate (ESR) of 72 mm/h at the first hour. Initial liver function tests (ASAT, ALAT, ALP, GGT) were within normal limits. Serological tests for hepatitis B and C, HIV, TPHA and VDRL were negative. Abdominal ultrasonography was unremarkable and confirmed an ongoing pregnancy at approximately 24 weeks of amenorrhea. Baseline audiometry was normal.

Hain Genotype line probe assay testing revealed gyrA mutations (mutations 3C and 3D), consistent with fluoroquinolone resistance. Susceptibility to kanamycin and other aminoglycosides was reported.

Taken together, these findings supported a diagnosis of rifampicin and fluoroquinolone-resistant pulmonary tuberculosis, associated with cerebral lesions radiologically suggestive of tuberculomas.

Given the severity of the patient’s clinical condition, the case was discussed at a specialized multidisciplinary meeting. The consensus recommendation was to promptly initiate an appropriate antituberculosis treatment regimen.

Initial treatment with RHZE, combined with vitamin B6, associated with a six-week course of oral corticosteroids was initiated. Regarding the neurological manifestations, specialist consultation favored a diagnosis of cerebral tuberculomas and recommended treatment with levetiracetam for three months, followed by reassessment.

After one month of treatment, given the lack of clinical improvement, the case was discussed in a multidisciplinary team meeting, and the decision was made to initiate a treatment regimen comprising kanamycin, linezolid, clofazimine, isoniazid, cycloserine, ethambutol, ethionamide, and vitamin B6.

However, follow-up liver function tests revealed significant hepatocellular injury, with ASAT levels of 349 IU/L, ALAT levels of 457 IU/L, and GGT levels of 253 IU/L. Antituberculosis treatment was discontinued 1 month after. Following discussion at a pharmacovigilance meeting, the liver injury was considered likely to be drug-induced, with isoniazid and/or pyrazinamide suspected as potential causative agents. Isoniazid was considered the more likely culprit based on the temporal relationship and the doses administered.

Following treatment discontinuation, transaminase levels progressively returned to normal in 15 days, and the case was re-discussed at a multidisciplinary team meeting, the decision was made to resume treatment while excluding isoniazid and pyrazinamide. Treatment was therefore reintroduced after 1 week, with a regimen comprising kanamycin, linezolid, clofazimine, cycloserine, ethambutol, ethionamide, and vitamin B6. Follow-up liver function tests after treatment reintroduction remained satisfactory.

From an obstetric perspective, a gynecological consultation recommended considering delivery at 34 weeks of gestation, depending on maternal and fetal outcomes. Ultimately, the pregnancy was continued under multidisciplinary monitoring. The patient delivered at term a live-born male infant weighing 1700 g, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The tuberculin skin test (Mantoux test) and gastric aspirate examination performed in the newborn were negative for acid-fast bacilli. Histopathological examination of the placenta was unremarkable, with no evidence of tuberculous involvement. No obvious congenital malformations were observed. During the postpartum period, the patient was in good general condition, with a body weight of 64 kg. Liver function tests were within normal limits and 2 direct sputum smear examinations were negative.

Given the drug-resistance profile and the need to optimize the treatment regimen in the postpartum period, bedaquiline was initiated. From a respiratory standpoint, the patient reported clinical improvement. Regarding the neurological manifestations, follow-up brain MRI revealed persistent lesions. Neurological consultation recommended continuation of the ongoing treatment regimen. Evaluation of the infant at 3 months of age revealed no clinical evidence of tuberculosis.

This case highlights the therapeutic challenges of fluoroquinolone-resistant tuberculosis during pregnancy, particularly in the presence of neurological involvement and drug-induced hepatotoxicity, and underscores the importance of individualized, multidisciplinary management.

Case 2 : A 24-year-old woman with a six-year smoking history. She was being followed for bacteriologically confirmed pulmonary tuberculosis since 4 months. Her clinical course during initial antituberculosis treatment was characterized by a negative bacteriological results at the second month followed by a positive result at the fourth month. Xpert MTB/RIF testing detected Mycobacterium tuberculosis and rifampicin resistance. Molecular drug susceptibility testing using the Hain assay revealed fluoroquinolone resistance associated with a gyrA gene mutation (mutation 3c), while susceptibility to kanamycin was retained.

On admission, the patient presents a performance status score of 0. She was afebrile, with a body temperature of 37°C, and an oxygen saturation of 96% on room air. Her blood pressure was 90/50 mmHg, heart rate was 78 beats/min, respiratory rate was 20 breaths/min, and body weight was 59 kg. Chest examination revealed mild wheezing, with no other significant clinical abnormalities.

Chest radiography revealed diffuse, ill-defined bilateral reticulomicronodular opacities, predominantly involving the middle lung zones (Figure 3). Initial laboratory investigations showed an hemoglobin level of 11.1 g/dl, and an erythrocyte sedimentation rate of 24 mm/h at the first hour. Renal and hepatic function were preserved. Serological tests for HIV, hepatitis B, hepatitis C, and syphilis (TPHA-VDRL) were negative. Abdominal ultrasonography, ophthalmological examination, and audiometry normal findings.

Following multidisciplinary discussion, an extended antituberculosis regimen tailored to the drug-resistance profile was selected. The regimen included kanamycin, ethionamide, cycloserine, ethambutol, pyrazinamide, linezolid, para-aminosalicylic acid (PAS), and isoniazid, together with vitamin B6 supplementation.

Follow-up chest radiography, after 2 months, showed initial radiological improvement, whereas bacteriological monitoring yielded discordant results: smear microscopy was negative in one specimen but remained positive (1+) in other specimen. During follow-up, the patient developed knee arthralgia, prompting an adjustment of the pyrazinamide dosage, as well as amenorrhea. The serum β-human chorionic gonadotropin (β-hCG) testing was positive, with a level of 50,107 mIU/mL. Pelvic ultrasonography confirmed an ongoing pregnancy estimated at 15 weeks of gestation despite contraceptives measures.

After thorough discussion with the patient and counseling regarding the potential risks and expected benefits, she repeatedly expressed her wish to continue the pregnancy to term. Accordingly, joint follow-up by the pulmonology and obstetrics and gynecology teams was recommended, including regular fetal morphological ultrasonographic examinations.

At the 5 months of pregnancy, regarding microbiological findings, sputum smear microscopy remained positive (1+), but became negative on the six month, suggesting a favorable bacteriological response to treatment. From a respiratory standpoint, the patient reported clinical improvement, with a reduction of productive cough, resolution of fever and night sweats, she experienced a 6 kg weight gain during treatment. Gynecological follow-up was also scheduled.

The patient spontaneously went into labor at 37 weeks of amenorrhea and delivered a live male infant weighing 1.5 kg, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The tuberculin skin test (Mantoux test) and gastric aspirate examination performed in the newborn were negative for acid-fast bacilli. Placental histopathological examination was unremarkable, with no evidence of tuberculous involvement. No obvious congenital malformations were observed.

Evaluation of the infant at 3 months of age revealed no clinical evidence of tuberculosis infection. During the postpartum period, the mother continued her second-line antituberculosis treatment, including injectable kanamycin.

After 18 months of second-line antituberculosis treatment, the patient's clinical and laboratory outcomes were favorable. Chest radiography demonstrated radiological improvement at the end of treatment (Figure 4).