In Vitro Susceptibility of Mycobacterium tuberculosis to Amikacin, Kanamycin, and Capreomycin.

Amikacin, kanamycin, and capreomycin are among the most important second-line drugs for multidrug-resistant tuberculosis. Although amikacin and kanamycin are administered at the same dose and show the same pharmacokinetics, they have different WHO breakpoints, suggesting that the two drugs have different MICs. The aim of this study was to investigate possible differences in MICs between the aminoglycosides and capreomycin. Using the direct concentration method, a range of concentrations of amikacin, kanamycin, and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0, and 64.0 mg/liter) were tested against 57 clinical Mycobacterium tuberculosis strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days. At 2 mg/liter, 48 strains (84%) were inhibited by amikacin and only 5 strains (9%) were inhibited by kanamycin (P < 0.05, Wilcoxon signed-rank test). The median MICs of amikacin, kanamycin, and capreomycin were 2, 4, and 8 mg/liter, respectively. No difference in amikacin, kanamycin, and capreomycin MIC distributions was observed between multidrug-resistant strains and fully susceptible strains. The results indicate that amikacin is more active than kanamycin and capreomycin against M. tuberculosis with the absolute concentration method. Determination of the impact of this difference on clinical outcomes in daily practice requires a prospective study, including pharmacokinetic and pharmacodynamic evaluations.

'Happy the man, who, studying nature's laws, Thro' known effects can trace the secret cause.' Do we have enough pieces to solve the pyrazinamide puzzle?

A low pH was assumed to be required for the activity of pyrazinoic acid (the active form of pyrazinamide) against Mycobacterium tuberculosis, but recently activity has been demonstrated at neutral pH. Renewed interest in pyrazinamide has led to an increasing number of potential targets and the suspicion that pyrazinamide is a 'dirty drug'. However, it is our opinion that the recent demonstration that pyrazinoic acid is active against PanD provides an alternative explanation for the secret of pyrazinamide's unusual activity. In this article we propose that PanD is the primary target of pyrazinoic acid but expression of pyrazinoic acid susceptibility requires an intact stress response. As the mycobacterial stress response requires the interaction of a number of genes, disruption of any could result in an inability to enter the susceptible phenotype. We believe this model can explain most of the recent observations of the seemingly diverse spectrum of activity of pyrazinamide.

Reduced Chance of Hearing Loss Associated with Therapeutic Drug Monitoring of Aminoglycosides in the Treatment of Multidrug-Resistant Tuberculosis.

Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our tuberculosis center, we used therapeutic drug monitoring (TDM) targeting preset pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto)toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of tuberculosis (TB) patients treated with amikacin or kanamycin in the period from 2000 to 2012. Patients with culture-confirmed multiresistant or extensively drug-resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including maximum concentration (Cmax), Cmin, and audiometry data, were extracted from the patients' medical charts. A total of 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratios obtained from 57 patients were 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg of body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg, a correlation was found between the dose per kg of body weight during daily dosing and the extent of hearing loss in dB at 8,000 Hz. These findings suggest that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CLm), 1.57 ± 3.71 liters/h; volume of distribution (V), 0.30 ± 0.05 liters · kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.).

Emerging drugs and alternative possibilities in the treatment of tuberculosis.

INTRODUCTION: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB. AREAS COVERED: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB. EXPERT OPINION: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment. The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation. Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.

Revisiting susceptibility testing in MDR-TB by a standardized quantitative phenotypic assessment in a European multicentre study.

OBJECTIVES: Treatment outcome of MDR-TB is critically dependent on the proper use of second-line drugs as per the result of in vitro drug susceptibility testing (DST). We aimed to establish a standardized DST procedure based on quantitative determination of drug resistance and compared the results with those of genotypes associated with drug resistance. METHODS: The protocol, based on MGIT 960 and the TB eXiST software, was evaluated in nine European reference laboratories. Resistance detection at a screening drug concentration was followed by determination of resistance levels and estimation of the resistance proportion. Mutations in 14 gene regions were investigated using established techniques. RESULTS: A total of 139 Mycobacterium tuberculosis isolates from patients with MDR-TB and resistance beyond MDR-TB were tested for 13 antituberculous drugs: isoniazid, rifampicin, rifabutin, ethambutol, pyrazinamide, streptomycin, para-aminosalicylic acid, ethionamide, amikacin, capreomycin, ofloxacin, moxifloxacin and linezolid. Concordance between phenotypic and genotypic resistance was >80%, except for ethambutol. Time to results was short (median 10 days). High-level resistance, which precludes the therapeutic use of an antituberculous drug, was observed in 49% of the isolates. The finding of a low or intermediate resistance level in 16% and 35% of the isolates, respectively, may help in designing an efficient personalized regimen for the treatment of MDR-TB patients. CONCLUSIONS: The automated DST procedure permits accurate and rapid quantitative resistance profiling of first- and second-line antituberculous drugs. Prospective validation is warranted to determine the impact on patient care.

Molecular epidemiology of tuberculosis in Cambodian children.

SUMMARY We analysed Mycobacterium tuberculosis strains from children, hospitalized from January 2004 to July 2008 in the largest paediatric hospital complex in Cambodia. Specimens were tested for drug susceptibility and genotypes. From the 260 children, 161 strains were available. The East African-Indian genotype family was the most common (59.0%), increasing in frequency with distance from the Phnom Penh area, while the frequency of the Beijing genotype family strains decreased. The drug resistance pattern showed a similar geographical gradient: lowest in the northwest (4.6%), intermediate in the central (17.1%), and highest in the southeastern (30.8%) parts of the country. Three children (1.9%) had multidrug-resistant tuberculosis. The Beijing genotype and streptomycin resistance were significantly associated (P < 0.001). As tuberculosis in children reflects recent transmission patterns in the community, multidrug resistance levels inform about the current quality of the tuberculosis programme.

The microbiological quality of water in fish spas with Garra rufa fish, the Netherlands, October to November 2012.

In fish spas, clients may submerge their hands, feet or whole body in basins with Garra rufa fish, for dead skin removal. Skin infections may result from using these spas, transmitted from fish to clients, through either fish or water, or from client to client. The microbiological water quality was determined in 24 fish spas in 16 companies in the Netherlands through analysis of a single water sample per fish spa. Water samples were tested for the presence of Aeromonas spp., Vibrio spp.,Pseudomonas aeruginosa, nontuberculous mycobacteria,and faecal indicator bacteria by using standard culture methods. The majority of the examined fish spas contained Aeromonas spp. (n = 24), P. aeruginosa(n = 18), Vibrio spp. (n = 16) including V. cholerae non-O1/O139 and V. vulnificus, and several rapid growing Mycobacterium spp. (n = 23) including M. fortuitum, M.conceptionense, M. abscessus and M. chelonae. Faecal contamination of the fish spa water was low. Based on the detected concentrations of Aeromonas spp., Vibriospp., and P. aeruginosa, the detected Mycobacteriumspp., and the health implications of these bacteria, the health risk from using fish spas is considered limited for healthy people with an intact skin and no underlying disease.

Molecular surveillance of multi- and extensively drug-resistant tuberculosis transmission in the European Union from 2003 to 2011.

The European Centre for Disease Prevention and Control (ECDC) initiated a project on the molecular surveillance of multi- and extensively drug-resistant tuberculosis (MDR-/XDR-TB) transmission in the European Union (EU) in the period from 2009 to 2011. In total, 2,092 variable number of tandem repeat (VNTR) patterns of MDR-/XDR-TB Mycobacterium tuberculosis isolates were collected, originating from 24 different countries in the period 2003 to 2011. Of the collected VNTR patterns, 45% (n=941) could be assigned to one of the 79 European multiple-country molecular fingerprint clusters and 50% of those (n=470) belonged to one extremely large cluster caused by Beijing strains of one genotype. We conclude that international transmission of MDR-/XDR-TB plays an important role in the EU, especially in the eastern part, and is significantly related to the spread of one strain or clone of the Beijing genotype. Implementation of international cluster investigation in EU countries should reveal underlying factors of transmission, and show how TB control can be improved regarding case finding, contact tracing, infection control and treatment in order to prevent further spread of MDR-/XDR-TB in the EU.

Extent and origin of resistance to antituberculosis drugs in the Netherlands, 1993 to 2011.

The elimination of tuberculosis (TB) is threatened by an apparent increase in the level of resistance in Mycobacterium tuberculosis. In the Netherlands, where the majority of TB patients are migrants, resistance may also be increasing. We conducted a retrospective study, using 18,294 M. tuberculosis isolates from TB cases notified between 1993 and 2011. We investigated the trends in antituberculosis drug resistance, focusing on the country of birth of the patients and whether resistance had developed during treatment or was the result of transmission of resistant M. tuberculosis strains. For both scenarios, we determined whether this had happened in or outside the Netherlands. Antituberculosis drug resistance was found in 13% of all cases analysed and showed an increasing trend among patients who had been born in the Netherlands (p<0.001) and a decreasing trend among foreign-born (p=0.02) over the study period. Since 2005, the proportion of M. tuberculosis resistant strains among all strains tested has increased in both groups (p=0.03 and p=0.01, respectively). Overall, we found a significantly increasing trend when excluding streptomycin resistance (p<0.001). The trend was most markedly increased for isoniazid resistance (p = 0.01). Although resistance was mainly due to transmission of resistant strains, mostly outside the Netherlands or before 1993 (when DNA fingerprinting was not systematically performed), in some cases (n=45), resistance was acquired in the Netherlands. We conclude that antituberculosis drug resistance is increasing in the Netherlands, mostly related to migration from high TB-incidence countries, but also to domestic acquisition.

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.

Experiences from 4 Years of Organization of an External Quality Assessment for Mycobacterium tuberculosis Whole-Genome Sequencing in the European Union/European Economic Area.

Here, we report the development and key features of the first external quality assessment (EQA) scheme for Mycobacterium tuberculosis whole-genome sequencing (WGS). The results of four rounds (2017 to 2020) of implementation within the European tuberculosis reference laboratories network (ERLTB-Net-2) are presented and discussed. EQA panels comprising 10 genomic DNAs were distributed to ERLTB-Net 2 laboratories volunteering to participate in this exercise. Since 2018, five FASTQ files were added to better assess the dry WGS processes, and in 2020, three of the five files were replaced by synthetic files (providing additional flexibility for the mutations included in the panels). Ten National tuberculosis reference laboratories participated in all four EQA rounds, and seven participated in at least one. High-confidence resistance mutations were correctly identified by all laboratories, but challenges remained with respect to the identification of mixed loci and interpretation of rare mutations. M. tuberculosis genotyping and clustering analysis was >90% accurate for pure samples with the main challenges being related to the analysis of mixed genotypes and DNA FASTQ files. The development and implementation of this WGS EQA scheme has contributed to the continuous improvement in performance of participating laboratories in M. tuberculosis WGS and data analysis. This scheme can serve as a model of comprehensive quality assessment for M. tuberculosis WGS that can be replicated in different settings worldwide. IMPORTANCE The wider availability of whole-genome sequencing (WGS) coupled to new developments in bioinformatic tools and databases to interpret Mycobacterium tuberculosis complex WGS data has accelerated the adoption of this method for the routine prediction of antimycobacterial drug resistance and genotyping, thus necessitating the establishment of a comprehensive external quality control system. Here, we report 4 years of development and results from such a panel.

ZIEHL-NEELSEN MICROSCOPY IN THE DIAGNOSIS OF TUBERCULOSIS IN SETTINGS OF HIGH HUMAN IMMUNODEFICIENCY VIRUS PREVALENCE.

OBJECTIVE: To determine the accuracy of Ziehl-Neelsen microscopy in the diagnosis of TB in setings of high HIV prevalence. DESIGN: Cross-sectional descriptive study. SETTING: Hospitals serving areas of high human immunodeficiency virus prevalence in western Kenya. The study was conducted between September 2007 and September 2009. RESULTS: In total, 341/872(39.1%) of the TB suspects were positive in ZN, 53.1% (181/341) of them culture positive. Only 3.8% (20/531) of the ZN smear negatives were culture positive. Of the 695 suspects evaluated for both Mycobacterium and HIV infection, 255 (36.7%) were ZN smear positive, 42.7% of them HIV positive. Out of the 440 ZN smear negatives, 37% were HIV positive. Similarly, 168 suspects were culture positive, 46.4% of them HIV positive. The HIV infection did not significantly reduce ZN smear positivity rate (P = 0.42) and culture sensitivity (P = 0.09). The ZN sensitivity and specificity were 88.1% and 79.7%, respectively. The predictive values were 58.0 (PPV), and 95.5% (NPV), respectively. However, the area under the ROC curve was 0.84, with 95% CI between 0.80-0.87 and P < 0.001). The ZN smear microscopy had a lesser ability to distinguish between TB and non-TB cases compared to culture. CONCLUSION: ZN microscopy causes a significant over-diagnosis of TB in settings of high HIV/AIDS prevalence. There is need for further studies on this subject taking into consideration the various confounding factors.

The impact of diabetes mellitus on pulmonary TB.

OBJECTIVE: To compare the clinical characteristics and laboratory results of pulmonary TB (PTB) patients with and without diabetes mellitus (DM) and the relationship between haemoglobin A1C (HbA1c) concentration and mycobacterial load at county level area in Sichuan Province, China. METHODS: A retrospective study was performed from January 2018 to July 2019 inJianyang People's Hospital, Sichuan Province. Clinical characteristics and laboratory results of newly diagnosed TB patients were collected. Univariable and multivariable logistic regression analyses were performed. The Kruskal-Wallis test was used to compare HbA1c level and mycobacterial load. RESULTS: The final sample included 415 patients with TB, of whom 45 were diagnosed with DM (10.8%). Uni-variable logistic regression showed that PTB patients with concomitant DM were more likely to present with haemoptysis, positive acid-fast bacilli (AFB) smear, cavity, higher erythrocyte sedimentation rate (ESR), higher serum C-reactive protein (CRP), lower serum albumin (ALB), or higher fasting blood glucose (FBG). Multivariate logistic regression analyses showed that AFB smear positivity (OR 15.81, 95% CI 3.09-80.95) and FBG (OR 1.88, 95% CI 1.53-2.31) were independent risk factors of DMPTB. The mycobacterial load was heaviest when the HbA1c was 7.9 mmol/L (95% CI 7.35-11.1) and declined along with HbA1c rising up. But it has not been significantly associated with HbA1c. CONCLUSIONS: Patients with PTB over 45 years old, with haemoptysis, positive AFB, cavity, higher ESR, higher CRP, lower ALB or higher FBG are more likely to present with concomitant DM. Patients with PTB with these factors need to be targeted for DM screening. The mycobacterial load has not been significantly associated with HbA1c.

OBJECTIF: Comparer les caractéristiques cliniques et les résultats de laboratoire des patients atteints de TB pulmonaire (PTB) avec et sans diabète sucré (DM), et le lien entre le taux d'hémoglobine glyquée (HbA1c) et la charge mycobactérienne dans une zone de la province du Sichuan, Chine. MÉTHODES: Nous avons réalisé une étude rétrospective de janvier 2018 à juillet 2019 au Jianyang People's Hospital dans la province du Sichuan. Les caractéristiques cliniques et les résultats de laboratoire des patients ayant récemment reçu un diagnostic de TB ont été recueillis. Des analyses de régression logistique univariables et multivariables ont été réalisées. Le test de Kruskal-Wallis a été utilisé pour comparer le taux d'HbA1c avec la charge mycobactérienne. RÉSULTATS: L'échantillon final comprenait 415 patients atteints de TB, dont 45 avaient un diagnostic de DM (10,8%). La régression logistique univariable a démontré que les patients atteints de PTB étaient plus susceptibles de présenter un DM-PTB avec hémoptysie, une TB à microscopie positive, une TB cavitaire, une vitesse de sédimentation (ESR) plus élevée, un taux sérique de protéine C-réactive (CRP) plus élevé, un taux sérique d'albumine (ALB) plus bas ou une glycémie à jeun (FBG) plus élevée. Les analyses de régression logistique multivariables ont démontré que la microscopie positive (OR 15,81 ; IC 95% 3,09­80,95) et la FBG (OR 1,88 ; IC 95% 1,53­2,31) étaient des facteurs de risque indépendants de DM-PTB. La charge mycobactérienne était plus élevée lorsque le taux d'HbA1c était de 7,9 mmol/L (IC 95% 7,35­11,1) et baissait à mesure que le taux d'HbA1c augmentait. Aucune association significative avec le taux d'HbA1c n'a cependant été démontrée. CONCLUSIONS: Les patients atteints de PTB de plus de 45 ans, avec hémoptysie, microscopie positive, TB cavitaire, ESR élevée, CRP élevée, ALB basse ou FBG élevée sont plus susceptibles de présenter également un DM. Les patients atteints de PTB présentant ces facteurs de risque doivent faire l'objet d'un dépistage du DM. La charge mycobactérienne n'a pas été associée de manière significative avec le taux d'HbA1c.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480.

Susceptibility of clinical Mycobacterium tuberculosis isolates to PNU-100480 and linezolid was evaluated by the MGIT 960 system. The isolates had various susceptibilities to isoniazid (INH), rifampin, ethambutol, and streptomycin. The mean MIC for PNU-100480 was 3.2 times lower than that for linezolid. Therefore, PNU-100480 is a promising candidate to be developed further as an adjunct in the treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB).

Evaluation of moxifloxacin for the treatment of tuberculosis: 3 years of experience.

Moxifloxacin (MFX) is a powerful second-line anti-tuberculosis (TB) agent, but the optimal dose has not yet been established and long-term safety data are scarce. We retrospectively reviewed the medical charts of TB patients treated at the Tuberculosis Centre Beatrixoord, University Medical Centre Groningen (Haren, the Netherlands) receiving MFX 400 mg once daily as part of their TB treatment between January 1 2006 and January 1 2009. Safety data and drug-drug interactions were evaluated. Efficacy was predicted based on the area under the concentration-time curve up to 24 h post-dosage (AUC(0-24h))/minimal inhibitory concentration (MIC) ratio. 89 patients were treated with a median dose of 6.9 mg · kg(-1) MFX once daily for a median period of 74 days. Discontinuation of therapy occurred in only three patients due to gastrointestinal side-effects and hypersensitivity. Pharmacokinetic analysis showed an AUC(0-24h)/MIC ratio <100 in eight out of 16 patients. A large variation in protein binding affected the unbound AUC(0-24h) considerably. These data show that MFX treatment was well tolerated in 89 patients receiving a dose of 400 mg once daily for a prolonged period. Considering the variability in (un)bound AUC(0-24h)/MIC ratio, therapeutic drug monitoring is recommended in selected patients (i.e. rifampicin co-medication; MIC ≥ 0.25 mg · L(-1)) to assess optimal therapy.

Corrigendum to 'Should treatment of low-level rifampicin mono-resistant tuberculosis be different?' [JCTUBE 23 (2021) 100241].

[This corrects the article DOI: 10.1016/j.jctube.2021.100241.].

Should treatment of low-level rifampicin mono-resistant tuberculosis be different?

BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation. METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates. FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%. INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB. FUNDING: None.