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A result is received from the laboratory on a 38 year old male patient. It is the results of phenotypic drug susceptibility testing (DST) on a cultured M. tuberculosis isolate from a lymph node aspirate taken ten months previously. This reports XDR-TB (resistance to rifampicin, isoniazid, ofloxacin, and kanamycin). The patient is contacted and brought for review. He reports previous TB history as shown below:
On review he is asymptomatic with no evidence of lymph node disease. He reports that the lymph node swelling was in his neck in 2010 and TB treatment was started on clinical grounds, treatment was then stopped some time later (exact timing not clear) because it was not working.
He is HIV-infected and has been on ART for three years. His current regimen is TDF/3TC/EFV, the latest viral load is <40 copies/ml and CD4+ cell count 197 cells/ul.
Chest X-ray is performed which shows left lower zone and right lateral pleural opacification, consistent with previous TB disease. Sputum culture is sent and a decision is made to monitor his clinical condition.
Two months later he returns complaining of swelling of the right hand. On examination he has soft tissue swelling of the dorsal aspect of the first web space. Pus is aspirated and sent for TB culture & DST. The sputum culture sent previously has been reported as negative.
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The culture from the aspirate is positive for M. tuberculosis. The Genotype MTBDRplus assay is performed on the culture isolate and is reported as resistant to rifampicin but sensitive to isoniazid.
Interpretation
The Genotype MTBDRplus assay is an example of a line probe assay (LPA). This allows the simultaneous detection of M. tuberculosis complex and the most common mutations in the rpoB, katG and inhA genes. Line probe technology involves DNA extraction, DNA amplification by polymerase chain reaction (PCR) and hybridization of PCR products with oligonucleotide probes embedded in a strip. Subsequent colorimetric change as a result of hybridization allows discrimination between wild-type and mutant strains. Mutations are identified by lack of binding to wild-type probes combined with binding to a specific mutation probe (Figure 1).
In this case rifampicin monoresistance has been identified with the LPA. However, there is also the previous growth of XDR-TB from a lymph node aspirate to consider. It remains possible that the current isolate could be XDR-TB (or MDR-TB). The Genotype MTBDRplus assay has suboptimal sensitivity for INH resistance as not all mutations associated with INH resistance are incorporated in the assay.
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Treatment recommendation
The patient has active extrapulmonary TB disease, which seems on the current evidence to be confined to soft tissue disease. This certainly warrants antituberculous chemotherapy.
One option would be to wait for full phenotypic DST results on the current isolate to inform selection of an individualised drug regimen. However, that risks progression of soft tissue TB disease and possible dissemination to other sites.
The second option would to treat as rifampicin monoresistance, with a standardised regimen consisting of isoniazid, kanamycin, moxifloxacin, pyrazinamide, ethionamide, and terizidone. However, that risks suboptimal therapy and amplification of drug resistance if the isolate is confirmed as XDR-TB.
The third option is to take into account the previous growth of XDR-TB and to institute an XDR regimen such as capreomycin, moxifloxacin, ethionamide, terizidone, PAS, and clofazimine.
Evidence to inform which of these strategies is best is extremely limited. There is also limited information regarding penetration of second-line anti-TB drugs into different tissues, so the efficacy of selected drugs in different forms of extrapulmonary TB is relatively poorly understood.
Case resolution
The patient was commenced on a standardised regimen consisting of isoniazid, kanamycin, ofloxacin, pyrazinamide, ethionamide, and terizidone. Sputum cultures were negative. Phenotypic DST on the isolated cultured from the aspirate revealed monoresistance to rifampicin, with phenotypic susceptibility to isoniazid, ofloxacin, and kanamycin. The soft tissue swelling reduced significantly in the first month of treatment and his drug regimen including isoniazid was continued.
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I. The burden of drug resistance in extrapulmonary TB has not been well characterised. Case series from uMzinyathi district in KwaZulu-Natal have suggested relatively high prevalence of XDR-TB from pleural and lymph node aspirates (7/21 or 33.3% of culture-positive isolates were XDR) and also from blood cultures (20/41 or 48.8% of culture-positive isolates were XDR). However, these series had inherent bias as aspirates were more likely to be performed when there was pre-existing concern about drug resistance. In addition this sub-district continues to have different epidemiology of drug resistance than elsewhere so the results may not be representative. There is some preliminary evidence that the Xpert MTB/RIF assay can be performed with extrapulmonary specimens and it is hoped this may bring some new understanding to the epidemiology of drug resistance in EPTB.
II. It is important to remember always to treat the patient and not the laboratory result. In this case, at the time the initial laboratory result (showing XDR-TB) was received, there was no strong evidence of active TB disease. Instituting treatment with the inherent risks of toxicity would not have been in the best interests of the patient. Full reassessment of the patient for active disease and then close follow-up and monitoring of symptoms and signs is appropriate. Ultimately the strain isolated from the soft tissue disease had a different susceptibility pattern and an appropriate treatment regimen has been instituted.
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Disclaimer:
Although every attempt has been made to ensure that the information in this book is accurate and up-to-date, the authors and publishers accept no responsibility for any loss or damage resulting from use of the information herein.
It is the responsibility of the individual clinician or health care worker to abide by national and local guidelines and protocols regarding management of HIV and TB. Information regarding drug indications and dosages should be checked with the national or local formulary, or with the pharmaceutical package insert.
None of the authors has declared any competing financial interests with regards to any material discussed within the HIV and TB Drug Resistance and Clinical Management Case Book.
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