Treatment responses in multidrug-resistant tuberculosis in Germany

Heyckendorf, Jan; Leth, Frank van; Avsar, Korkut; Glattki, Georg; Günther, Gunar; Kalsdorf, Barbara; Müller, Marius; Olaru, Ioana D.; Rolling, Thierry; Salzer, Helmut J. F.; Schuhmann, Maren; Terhalle, Elena; Lange, Christoph

doi:10.5588/ijtld.17.0741

Cited by 9 publications

(11 citation statements)

References 28 publications

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“…The four-month conversion rate is higher than the study conducted in Latvia (60%). 28 The two-month culture conversion rate in this study was 46.9% which is much lower than the study conducted in Seoul (90.1%) 42 China (65.2%) 47 and Germany (61%), 43 but higher than reported finding from Chinese study (33.3%). 38 The difference in the culture conversion rate among different study sites might be related to a difference in treatment protocol followed in different sites, the difference in the study population, type of drug resistance, and the difference in the quality of reported data.…”

Section: Discussioncontrasting

confidence: 72%

“…37 The present study reported a shorter median time to culture conversion compared to studies conducted in China (159 days), 38 USA (93 days), 39 Delhi (91 days), 40 London (91 days). 41 The median time to culture conversion in the present study is longer than the study conducted in Seoul (19 days), 42 Germany (39 days), 43 and India (35 days). 44 The discrepancy in the median time to sputum culture conversion could be due to the reporting system of the time to conversion.…”

Section: Discussioncontrasting

confidence: 52%

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<p>Predictors of Time to Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients in Oromia Region Hospitals, Ethiopia</p>

Tekalegn

Woldeyohannes

Assefa

et al. 2020

IDR

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Purpose: Multi-drug-resistant tuberculosis occurs when the tuberculosis bacteria develop resistance to at least the two most effective first-line anti-tuberculosis drugs, isoniazid and rifampicin. Sputum culture conversion is one of the indicators to monitor patients' prognosis throughout the treatment. Hence, this study aimed to assess time to culture conversion and its determinants among drug-resistant tuberculosis patients. Patients and Methods: A total of 228 drug-resistant tuberculosis patients in selected hospitals in Oromia region, Ethiopia, were included in this study. Descriptive statistics like median time to sputum smear and culture conversion were computed. Bivariate and multivariate Cox proportional hazard models were used to identify the independent predictors of time to culture conversion. The adjusted hazard ratio (AHR) with 95% confidence interval (CI) was used to report the strength of association. Statistical significance was declared at p <0.05. Results: The median age of the study participants was 28 years with inter-quartile range of (IQR) of 22-32 years, and 60% of the patients were male. The median time to culture conversion was 61 days (IQR: 34-92 days). The proportion of sputum culture conversion at 2nd, 4th, and 6th months of treatment initiation was 47%, 82.5%, and 89%, respectively. The final adjusted multivariate Cox proportional hazard model revealed that patients with massive effusion on chest radiographic finding had a 60%-decreased culture conversion time (AHR: 0.4, 95% CI: 0.1-0.9). Patients with abnormalities without cavitations (AHR: 0.5, 95% CI: 0.2-0.9) and those with uninterpreted findings (AHR: 0.3 95% CI: 0.1-0.5) had delayed culture conversion time. Conclusion: Chest radiographic findings such as massive effusion, abnormalities without cavitations, and uninterpreted findings were found to be predictors of time to sputum culture conversion. Patients with such characteristics have prolonged culture conversion time. Hence, they may need special attention during the treatment.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussioncontrasting

confidence: 52%

<p>Predictors of Time to Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients in Oromia Region Hospitals, Ethiopia</p>

Tekalegn

Woldeyohannes

Assefa

et al. 2020

IDR

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“…All patients enrolled into these cohorts had culture confirmed pulmonary tuberculosis ( Table 1, Figure 1 ) ( 14, 15 ). In detail, fifty patients with drug-susceptible tuberculosis were enrolled into the drug-susceptible German Identification Cohort (DS-GIC) and 30 MDR tuberculosis patients to the multidrug-resistant German Identification Cohort (MDR-GIC).…”

Section: Resultsmentioning

confidence: 99%

A 22-gene transcriptomic model indicating individual therapy durations in multidrug-resistant tuberculosis

Heyckendorf

Marwitz

Reimann

et al. 2020

Preprint

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Emerging multidrug-resistant tuberculosis is a major global health challenge. The World Health Organization currently recommends treatment durations of 9-18 months or more for patients with multidrug-resistant tuberculosis. We identified and validated a host-RNA signature to serve as a biomarker for individualized therapy durations for patients with multidrug-resistant tuberculosis. Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained one year after end-of-therapy. A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints. Fifty patients with drug-susceptible tuberculosis and 30 patients with multidrug-resistant tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with drug-susceptible tuberculosis and 32 patients with multidrug-resistant tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with multidrug-resistant tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model accurately predicted clinical outcomes for patients in the DS-GVC (AUC=0.937 [95%CI:0.899-0.976]) and suggested that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%, p<0.001), and the MDR-RVC (mean reduction of 161.0 days, 23.4%, p=0.001). Biomarker-guided management may substantially shorten the duration of therapy for many patients with multidrug-resistant tuberculosis.

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“…Commercially available PCR based test systems such as the GeneXpert MTB/RIF ultra (Cepheid, Sunnyvale, Ca., USA) are very sensitive with regard to the detection of Mtb, but are most probably not suitable for therapy response assessment due to extended mycobacterial DNA stability even after the death of the bacteria (46,47). However, PCR based methods are able to predict drugresistance for most anti-TB agents, which is not possible based on lipids (48). Currently, culture remains the gold standard for the diagnosis of TB and the assessment of bacterial burden despite being slow.…”

Section: Perspectives For Mycobacterial Derived Lipid Biomarker In CLmentioning

confidence: 99%

Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determineMycobacterium tuberculosisbacterial burden

Brandenburg

Heyckendorf

Waldow

et al. 2021

Preprint

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It is estimated that approximately one-fourth of the world′s population is infected with strains of the Mycobacterium tuberculosis complex (MTBC), the causative agents of tuberculosis (TB). In this study, we present rationally developed molecular markers for bacterial burden, which are derived from mycobacterial phospholipids. Using lipidomic approaches, we show that tuberculostearic acid (TSA)-containing phosphatidylinositols (PI) are present in all clinically relevant MTBC lineages investigated. For the major abundant lipid PI 16:0-19:0 (TSA), a detection limit equivalent to 102 colony forming units (CFU) was determined for bacterial cultures and approximately 103 for cell culture systems. We further developed a mass spectrometry based targeted lipid assay, which - in contrast to bacterial quantification on solid medium - can be performed within several hours including sample preparation. Translation of this indirect and culture-free detection approach allowed the determination of pathogen loads in infected murine macrophages, human neutrophils and murine lung tissue. We show that marker lipids inferred from the mycobacterial PIs are increased in peripheral blood mononuclear cells (PBMCs) of TB patients beyond the lipid metabolic background in comparison to healthy controls. In a small cohort of drug-susceptible TB patients elevated levels of these marker molecules were detected at therapy start and declined following successful anti-tuberculosis treatment. The concentration of TSA-containing PIs can be used as correlate for reliable and rapid quantification of Mycobacterium tuberculosis (Mtb) burden in experimental in vitro model systems and may also provide a clinically relevant tool for monitoring TB therapy.

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Treatment responses in multidrug-resistant tuberculosis in Germany

Cited by 9 publications

References 28 publications

<p>Predictors of Time to Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients in Oromia Region Hospitals, Ethiopia</p>

<p>Predictors of Time to Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients in Oromia Region Hospitals, Ethiopia</p>

A 22-gene transcriptomic model indicating individual therapy durations in multidrug-resistant tuberculosis

Tuberculostearic acid (TSA)-containing phosphatidylinositols as reliable marker to determineMycobacterium tuberculosisbacterial burden

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