Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis.

Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Diagnosis, treatment and transmission of rifampicin-resistant TB in the Netherlands, 2010-2019.

BACKGROUND: New tools for diagnosis and treatment of rifampicin-resistant (RR-) and multidrug-resistant (MDR-) TB have become available in the last decade, including better tests confirming transmission.OBJECTIVE: To analyse transmission risks of MDR/RR-TB in the Netherlands.METHODS: Analysis of national data of patients with MDR/RR-TB notified in 2010-2019, including contact investigation and genotyping data.RESULTS: Patients with MDR/RR-TB (n = 121) were more often female (adjusted odds ratio [aOR] 1.5), foreign-born, previously treated for TB (aOR 5.2) and co-infected with HIV (aOR 2.3) than patients with no MDR/RR-TB. Treatment outcomes were satisfactory, with at least 79% completing treatment. After additional whole-genome sequencing (WGS), five molecular clusters of 16 patients remained. Patients in three clusters could not be epidemiologically linked and were unlikely to have been infected in the Netherlands. The remaining eight (6.6%) patients with MDR/RR-TB belonged to two clusters, and were likely the result of transmission in the Netherlands. Among close contacts of patients with smear-positive pulmonary MDR/RR-TB, 13.4% (n = 38) had TB infection and 1.1% (n = 3) had TB disease. Only six contacts with TB infection were treated with a quinolone-based preventive treatment regimen.CONCLUSION: MDR/RR-TB is effectively controlled in the Netherlands. Preventive treatment options could be considered more frequently in contacts clearly infected by an index patient with MDR-TB.

A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The Netherlands.

BACKGROUND: The frequency of clinical isolation of non-tuberculous mycobacteria (NTM) in the Netherlands is increasing, but its clinical relevance is often uncertain. OBJECTIVE: To assess the frequency and clinical relevance of isolation of NTM in four associated hospitals in a single region in the Netherlands. METHODS: Medical files of all patients from whom NTM were isolated between January 1999 and January 2005 were reviewed retrospectively. Diagnostic criteria for non-tuberculous mycobacterial disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. RESULTS: 232 patients were found, from whom NTM were isolated from the respiratory tract in 91% of cases. Patients were mostly white men, with an average age of 60 years and pre-existing pulmonary disease. Fifty-three of 212 patients (25%) with pulmonary isolates met the ATS diagnostic criteria for pulmonary NTM disease; this percentage differed by species. Most patients were treated with rifampicin, ethambutol and clarithromycin. Treatment outcome for pulmonary NTM disease was suboptimal but differed by species: overall, improvement was seen in 67% of treated patients, but in only 50% of those with pulmonary M avium disease. Lymphadenitis was the most common extrapulmonary disease type. CONCLUSIONS: Twenty-five per cent of all patients with pulmonary NTM isolates met the ATS criteria. Clinical relevance differs by species. NTM isolation increases over time. Species distribution differs from that of neighbouring countries and the M avium complex isolates have traits different from those reported in the USA. Adherence to diagnostic and treatment guidelines can be improved.

Clinical relevance of Mycobacterium malmoense isolation in The Netherlands.

Uncertainty exists about the clinical relevance of Mycobacterium malmoense isolation, especially in pulmonary samples. We therefore determined clinical relevance, treatment and outcome of M. malmoense isolation in The Netherlands. A retrospective medical file study was conducted for all patients in The Netherlands from whom Mycobacterium malmoense had been isolated between January 2002 and January 2006. Diagnostic criteria for nontuberculous mycobacterial (NTM) disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. Treatment was compared with guidelines published by the British Thoracic Society. In total, 51 patients were found from whom M. malmoense was isolated. Of these, 40 (78%) patients had pulmonary isolates and 32 (80%) of them met the ATS diagnostic criteria. Cavitary disease was most common (n = 28; 88%). Patients with pulmonary disease were mostly males, with an average age of 56 yrs and pre-existing chronic obstructive pulmonary disease. Cervical lymphadenitis was the most common extrapulmonary disease type. Adherence to treatment guidelines was poor. A good clinical response to treatment was observed in 70% and 73% of patients treated for pulmonary and extrapulmonary disease, respectively. In conclusion, M. malmoense is a clinically highly relevant NTM in The Netherlands causing serious pulmonary morbidity. Adherence to treatment guidelines is not satisfactory.

Clinical relevance of Mycobacterium simiae in pulmonary samples.

The aim of the present study was to determine the clinical relevance of Mycobacterium simiae isolation from clinical samples. The medical files of patients in the Netherlands from whom M. simiae was isolated between 1999 and 2006 were reviewed in order to assess frequency and clinical relevance. Clinical relevance was defined as fulfilment of the diagnostic criteria of the American Thoracic Society. From the files, 28 patients were identified, of whom six (21%) met the American Thoracic Society diagnostic criteria. A slight (54%) female predominance was observed, which is uncommon for nontuberculous mycobacteria isolation. Fulfilment of the diagnostic criteria and initiation of treatment were not in agreement; treatment results were poor. Only a minority of clinical M. simiae isolates are clinically relevant and, applying the American Thoracic Society diagnostic criteria, the number of true infections is overestimated. Physicians in the Netherlands do not always use these criteria in daily practice, resulting in both over- and underdiagnosis of M. simiae infection. Further studies are required in order to improve diagnostic criteria and treatment regimens.

Second-line drug resistance in multidrug-resistant tuberculosis cases of various origins in the Netherlands.

SETTING: The Netherlands. OBJECTIVE: To investigate the frequency of resistance to second-line drugs among multidrug-resistant tuberculosis (MDR-TB) cases and its correlation with patients' geographic origin. DESIGN: Retrospective laboratory database study of multidrug-resistant Mycobacterium tuberculosis complex strains isolated in the Netherlands between January 1993 and October 2007. RESULTS: We found 153 patients with MDR-TB, of whom 18 (12%) were native Dutch. Complete second-line drug susceptibility testing was performed for 131 MDR-TB patients. Resistance to second-line drugs was noted in primary samples of 28 (21%) MDR-TB patients. Resistance to a single second-line drug was most frequent (24/28 [86%]; 9 to prothionamide [PTH], 6 to para-aminosalicylic acid, 4 to amikacin [AMK], 4 to ciprofloxacin and 1 to cycloserine). Four MDR-TB patients had strains resistant to multiple second-line drugs; two were extensively drug-resistant M. bovis. In MDR-TB patients of European and Central Asian origin, resistance to second-line drugs was most frequent and involved the widest range of drugs. PTH resistance was frequent among African and American MDR-TB patients, while AMK resistance was frequent among South-East Asians. CONCLUSION: Resistance to second-line drugs is infrequent among MDR-TB patients in the Netherlands. Most second-line drug resistance is recorded among immigrants, with substantial differences in second-line drug resistance in MDR-TB patients originating from different geographical areas.

The rising incidence and clinical relevance of Mycobacterium malmoense: a review of the literature.

The incidence of Mycobacterium malmoense infections compared to other non-tuberculous mycobacteria (NTM) has increased since 1980, especially in northern Europe. Based on various epidemiological and clinical reports outside northern Europe, there is a wide distribution of these infections. Infections with M. malmoense cause pulmonary disease comparable with tuberculosis (TB). The main extra-pulmonary disease type is paediatric cervical lymphadenitis. M. malmoense isolates are clinically significant in about 70-80% of patients. Like other NTM infections, M. malmoense is often found in patients with chronic obstructive pulmonary disease (COPD) and may cause serious morbidity and mortality when inadequately treated. The best treatment consists of a 2-year regimen with rifampicin and ethambutol. The literature on infections with M. malmoense is reviewed with respect to epidemiology, clinical presentation, treatment and outcome.

[Characteristics and treatment of tuberculosis patients in Dekkerswald, 2000-2005]. / Kenmerken en behandeling van tuberculosepatiënten in Dekkerswald, 2000-2005.

OBJECTIVE: To describe the patient population in Dekkerswald, Nijmegen, one of two tuberculosis (TB) centres in The Netherlands. DESIGN: Descriptive, retrospective study. METHOD: Examination of medical records for all TB patients hospitalised between 2000 and 2005, including demographic, social, clinical and follow-up data. RESULTS: Data from 166 patients were analysed. Tertiary referrals accounted for 98% of all hospitalisations. Most patients (68%) were referred for clinical reasons, and 32% were referred for social reasons. Drug resistance was encountered in 23% of patients; 9% had multidrug-resistant TB. Ten percent of patients were seropositive for HIV. Toxicity and side-effects of treatment often led to changes in treatment (40%). Patients had pulmonary TB (59%), extrapulmonary TB (23%) or both (17%). Overall, 141 patients (85%) completed treatment. The TB-related mortality rate was 5%. CONCLUSION: In Dekkerswald, there is a selected patient population that is characterised by drug-resistance, comorbidity, side-effects, extrapulmonary disease and social issues. Due to the low prevalence of TB in The Netherlands, knowledge and experience regarding complex types of TB are limited. Centralisation of patient care is important to preserve and optimise this expertise.

Aetiology and presentation of HIV/AIDS-associated pulmonary infections in patients presenting for bronchoscopy at a referral hospital in northern Tanzania.

OBJECTIVES: To determine the aetiological agents of pulmonary infections in HIV-infected Tanzanians and to correlate the causative agents with clinical, radiographic features, and mortality. DESIGN: A prospective study. SETTING: Kilimanjaro Christian Medical Centre (KCMC), Tanzania. SUBJECTS: Bronchoalveolar lavage fluid (BAL) were obtained from 120 HIV infected patients with pulmonary infections. BAL for causative agents was analysed and correlated with clinical and radiographic features, and one-month outcome. RESULTS: Causative agents were identified in 71 (59.2%) patients and in 16 of these patients, multiple agents were found. Common bacteria were identified in 35 (29.2%) patients, Mycobacterium tuberculosis in 28 (23.3%), Human Herpes Virus 8 (HHV8) in 12 (10%), Pneumocystis jiroveci in nine (7.5%) and fungi in five (4.2%) patients. Median CD4 T cell count of the patients with identified causes was 47 cells/microl (IQR 14-91) and in the 49 patients with undetermined aetiology was 100 cells/ microl (IQR 36-188; p = 0.01). Micronodular chest radiographic lesions were associated with presence of M. tuberculosis (p = 0.002). The one-month mortality was 20 (16.7%). The highest mortality was associated with HHV8 (41.7%) and M. tuberculosis (32.1%). Mortality in patients with undetermined aetiology was 11.3%. No death occurred in patients with PCP. CONCLUSION: In this population of severely immunosuppressed HIV-infected patients with pulmonary infection a variety of causative agents was identified. Micronodular radiographic lesions were indicative of TB. High mortality was associated with M. tuberculosis or HHV8. No death occurred in patients with P. jiroveci infection.

Ebola, fragile health systems and tuberculosis care: a call for pre-emptive action and operational research.

The Ebola outbreak that started in late 2013 is by far the largest and most sustained in history. It occurred in a part of the world where pre-existing health systems were already fragile, and these deteriorated further during the epidemic due to a large number of health worker deaths; temporary or permanent closure of health facilities; non-payment of health workers; intrinsic fear of contracting or being stigmatised by Ebola among the population, which negatively influenced health-seeking behaviour; enforced quarantine of Ebola-affected communities, restricting the access of vulnerable individuals to health facilities; and late response by the international community. There are also reports of drug and consumable stockouts due to deficiencies in the procurement and supply chain as a result of overriding Ebola-related priorities. Providing tuberculosis (TB) care and achieving favourable treatment outcomes require a fully functioning health system, accurate patient tracking and high patient adherence to treatment. Furthermore, as Ebola is easily transmitted through body fluids, the use of needles-essential for TB diagnosis and treatment-needs to be avoided during an outbreak. We highlight ways in which a sustained Ebola outbreak could jeopardise TB activities and suggest pre-emptive preventive measures while awaiting operational research evidence.

Molecular drug susceptibility testing in the Netherlands: performance of the MTBDRplus and MTBDRsl assays.

BACKGROUND: The performance of molecular drug susceptibility testing in countries with a low prevalence of drug resistance, such as the Netherlands, has not been adequately studied. OBJECTIVE: To evaluate the diagnostic accuracy of the GenoType(®) MTBDRplus and MTBDRsl assays to detect resistance to first- and second-line anti-tuberculosis drugs in the context of a nationwide screening programme in the Netherlands. RESULTS: The MTBDRplus assay had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 99%, 80% and 100% for detecting rifampicin resistance. The sensitivity, specificity, PPV and NPV of either a katG or inhA mutation for detecting isoniazid resistance were 88%, 100%, 100% and 99%. The MTBDRsl assay had a sensitivity, specificity, PPV and NPV of 100%, 99%, 83%, and 100% for detecting moxifloxacin resistance; 62%, 71%, 58% and 74%, respectively, for detecting ethambutol resistance; 86%, 99%, 86% and 99% for detecting amikacin resistance; and 50%, 96%, 71% and 91% for detecting capreomycin resistance. CONCLUSION: The MTBDRplus and MTBDRsl assays may aid in decision making in tuberculosis treatment in low-level drug resistance settings and should preferably be used to exclude resistance.

Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009.

SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, integrated, well-resourced TB service where all patients are offered culture-confirmed diagnosis by a central reference laboratory. OBJECTIVE: To assess the treatment outcomes of MDR-TB patients over a period of 10 years in The Netherlands. DESIGN: Demographic, clinical and microbiological features of all patients with MDR-TB who started treatment in 2000-2009 in the Netherlands were analysed from national registry and patient records. RESULTS: Characteristics of the 113 MDR-TB patients were as follows: male/female ratio 1.57, 96% foreign born, median age 29 years, 96 (85%) pulmonary TB, 56 (50%) smear-positive, 14 (12%) human immunodeficiency virus (HIV) co-infected. Of the 104 (92%) patients who started MDR-TB treatment, 86% had a successful outcome using a median of six active drugs; eight underwent pulmonary surgery. HIV negativity was associated with successful outcome (adjusted OR 2.1, 95%CI 1.1-3.8). CONCLUSION: High success rates for MDR-TB treatment were achieved with close collaboration of all stakeholders, reaching the targets set for drug-susceptible TB. HIV remained an independent risk factor for unsuccessful treatment outcome.

Traditional healers and pulmonary tuberculosis in Malawi.

SETTING: Queen Elizabeth Central Hospital (QECH) and Blantyre district, Malawi. OBJECTIVE: To investigate the use that tuberculosis (TB) patients in Malawi make of traditional healers and traditional medicine. DESIGN: A questionnaire study was carried out on 89 smear-positive pulmonary TB patients admitted to QECH. Seven traditional healers in Blantyre were also interviewed about their knowledge, attitudes and practice of patients whom they considered to have TB. RESULTS: Of the 89 patients, 33 (37%) visited a traditional healer before seeking regular medical care. Patients spent a median length of 4 weeks with the traditional healer. During this time, 24 patients did not improve or deteriorated while on traditional treatment. No patient was referred to the medical services by the traditional healer. All traditional healers claimed to know about TB. Four said they would refer a patient to hospital if their treatment was not curative. In 1995, six traditional healers claimed to have cured 116 patients with TB. CONCLUSION: It is important to involve traditional healers in the educational activities of the National TB Control Programme. These healers need to be taught to recognise and refer patients with TB, whom they should not treat, but at the same time be encouraged to administer safe treatments for conditions which are more amenable to their practice.

The diagnosis of smear-negative pulmonary tuberculosis: the practice of sputum smear examination in Malawi.

SETTING: Forty hospitals in Malawi (3 central, 22 district and 15 mission) performing smear microscopy and registering tuberculosis patients. OBJECTIVE: To determine, in patients aged 15 years or above, 1) the proportion with smear-negative pulmonary tuberculosis (PTB) who had sputum smears examined, 2) the number of sputum smears examined per patient, and 3) the proportion of patients registered with smear-positive and smear-negative PTB. DESIGN: Data collection during three 6-month periods, from January 1997 to June 1998, using tuberculosis registers, laboratory sputum registers and quarterly reports. RESULTS: Of 6301 smear-negative PTB patients, 84% had sputum smears examined, the rate increasing from 76% in January-June 1997, to 85% in July-December 1997, to 89% in January-June 1998. Of patients who submitted sputum (where the number of smears was recorded), 99% had two or more smears examined and 93% had three smears examined. In district and mission hospitals performance improved over time, while in central hospitals results were more variable. During the same 18-month period 21 422 patients aged 15 years or more were registered with PTB: 59% with smear-positive PTB and 41% with smear-negative PTB; this pattern was similar in each 6-month period. CONCLUSION: The study suggests that it is reasonable to aim for a target of 90% or more of smear-negative PTB patients having sputum smears examined.