Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis.

Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

Pharmacokinetics of ertapenem in patients with multidrug-resistant tuberculosis.

Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for the treatment of MDR- and XDR-TB because its relatively long half-life enables once-daily dosing.A retrospective study was performed for all patients with suspected MDR-TB at the Tuberculosis Center Beatrixoord of the University Medical Center Groningen (Haren, the Netherlands) who received ertapenem as part of their treatment regimen between December 1, 2010 and March 1, 2013. Safety and pharmacokinetics were evaluated.18 patients were treated with 1000 mg ertapenem for a mean (range) of 77 (5-210) days. Sputum smear and culture were converted in all patients. Drug exposure was evaluated in 12 patients. The mean (range) area under the concentration-time curve up to 24 h was 544.9 (309-1130) h·mg·L(-1) The mean (range) maximum observed plasma concentration was 127.5 (73.9-277.9) mg·L(-1)In general, ertapenem treatment was well tolerated during MDR-TB treatment and showed a favourable pharmacokinetic/pharmacodynamic profile in MDR-TB patients. We conclude that ertapenem is a highly promising drug for the treatment of MDR-TB that warrants further investigation.

Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.

Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis.

Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.

Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB.

Clinical experience on meropenem-clavulanate to treat tuberculosis (TB) is anecdotal (according to case reports on 10 patients). The aim of our case-control study was to evaluate the contribution of meropenem-clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases after 3 months of second-line treatment. 37 cases with MDR-/XDR-TB were prescribed meropenem-clavulanate (3 g daily dose) in addition to a linezolid-containing regimen (dosage range 300-1200 mg·day(-1)), designed according to international guidelines, which was prescribed to 61 controls. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of sputum-smear positive and of re-treatment cases). The group of cases yielded a higher proportion of sputum-smear converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and culture converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of culture converters than controls (p=0.03). One case had to withdraw from meropenem-clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem-clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.

Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis.

Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0-24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg·kg(-1) of SXT (range 6.1-6.8 mg·kg(-1)) once daily for a median treatment period of 381 days (range 129-465 days). In two patients, the dose was escalated to 960 mg. The free AUC0-24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment.

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients.

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug-drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid. Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated. Linezolid exposure increased by a median (interquartile range) of 44% (23-102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events. In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug-drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size.

Weight loss during tuberculosis treatment is an important risk factor for drug-induced hepatotoxicity.

The objective of this study was to determine the association between weight loss and drug-induced hepatotoxicity (DIH). A retrospective observational study of 192 active tuberculosis (TB) patients consecutively admitted in a tertiary referral TB centre in the Netherlands was conducted. The outcome measure for DIH was defined as hepatotoxicity necessitating interruption of anti-TB drugs. Multivariate logistic regression analysis on interruption of anti-TB drugs was performed, with age, sex, nutritional status, TB disease severity, drug resistance, comorbidity including baseline liver function tests, anti-TB drug regimen, co-medication and addictions as independent risk factors. Anti-TB drugs were interrupted in thirty-one patients (16·1%). The most important risk factor was weight loss of 2 kg or more within 4 weeks during TB treatment (OR 211, 95% CI 36·0, 1232). Other independent risk factors were infection with hepatitis C (OR 19·6, 95% CI 2·4, 164), age over 60 years (OR 18·5, 95% CI 2·3, 151) and multi-drug-resistant TB (OR 8·2, 95% CI 1·3, 53·6). This study shows that weight loss during TB treatment was the most important risk factor for DIH necessitating interruption of anti-TB drugs. Causes of weight loss during TB treatment and the association between weight change and hepatotoxicity need further investigation.

Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis.

BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug monitoring is not feasible in most settings. Developing a limited-sampling strategy based on population pharmacokinetics (PK) may help to overcome this problem. METHODS: Steady-state plasma concentrations after the administration of 400 mg of MFX once daily were determined in 21 patients with TB, using a validated liquid chromatography-tandem mass spectrometry method. A one-compartment population model was generated and crossvalidated. Monte Carlo data simulation (n=1000) was used to calculate limited-sampling strategies. The correlation between predicted MFX AUC0-24h (area under the concentration-time curve 0 to 24 hours) and observed AUC0-24h was investigated by Bland-Altman analysis. Finally, the predictive performance of the final model was tested prospectively using MFX profiles from patients with TB receiving 400, 600, or 800 mg once daily. RESULTS: Median minimum inhibitory concentration of Mycobacterium tuberculosis isolates was 0.25 mg/L (interquartile range: 0.25-0.5 mg/L). The geometric mean AUC0-24h was 24.5 mg·h/L (range: 8.5-72.2 mg·h/L), which resulted in a geometric mean AUC0-24h/minimum inhibitory concentration ratio of 72 (range: 21-321). PK analysis, based on PK profiles of 400 mg of MFX once daily, resulted in a crossvalidated population PK model with the following parameters: apparent clearance (Cl) 18.5±8.6 L/h per 1.85 m, Vd 3.0±0.7 L/kg corrected lean body mass, Ka 1.15±1.16 h, and F was fixed at 1. After the Monte Carlo simulation, the best predicting strategy for MFX AUC0-24h for practical use was based on MFX concentrations 4 and 14 hours postdosing (r=0.90, prediction bias=-1.5%, and root mean square error=15%). CONCLUSIONS: MFX AUC0-24h in patients with TB can be predicted with acceptable accuracy for clinical management, using limited sampling. AUC0-24h prediction based on 2 samples, 4 and 14 hours postdose, can be used to individualize treatment.

Limited sampling strategies for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis.

INTRODUCTION: Linezolid is a potential drug for the treatment of multidrug-resistant tuberculosis but its use is limited because of severe adverse effects such as anemia, thrombocytopenia, and peripheral neuropathy. This study aimed to develop a model for the prediction of linezolid area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12h) by limited sampling strategy to enable individualized dosing. PATIENTS AND METHODS: Fourteen patients with multidrug-resistant tuberculosis received linezolid twice daily as part of their antituberculosis treatment. Linezolid concentrations were determined at steady state by high-performance liquid chromatography tandem mass spectrometry before and at 1, 2, 4, 8, and 12 hours after dosing. Linezolid AUC0-12h population model and limited sampling models were calculated with MWPharm software. The correlation between predicted linezolid AUC0-12h and observed linezolid AUC0-12h was investigated by Bland-Altman analysis. RESULTS: A total of 26 pharmacokinetic profiles were obtained. The median AUC0-12h was 51.8 (interquartile range, 41.8-65.9) mg*h/L at 300 mg and 123.8 (interquartile range, 100.9-152.5) mg*h/L at 600 mg, both twice daily. The most relevant model clinically for prediction of linezolid AUC0-12h used a linezolid trough concentration (r = 0.91, prediction bias = -2.9% and root mean square error = 15%). DISCUSSION: The difference between choosing a trough concentration and two to three samples increased the correlation from 0.90 to 0.95 but appeared not clinically relevant because it did not result in different dosing advice. CONCLUSION: This study showed that linezolid AUC0-12h in patients with multidrug-resistant tuberculosis could be predicted accurately by a minimal sampling strategy and could be used to individualize the dose.

[Dysphagia in a young woman from Somalia]. / Dysfagie bij jonge vrouw uit Somalië

BACKGROUND: Multidrug-resistant tuberculosis is increasing worldwide. The determination of possible resistance is essential for adequate treatment. Tuberculosis is common amongst immigrants from Somalia and extra-pulmonary localisation is often seen. CASE DESCRIPTION: A 21-year-old woman from Somalia presented with progressive dysphagia and severe weight loss. Endoscopy revealed two ulcers in the mid-oesophagus. A chest x-ray showed enlarged lymph nodes in the right hilar and mediastinal regions. The Ziehl-Neelsen stain and PCR for mycobacteria were negative. Sputum samples and oesophageal biopsies were cultured. Quadruple tuberculostatic therapy was started empirically. After five weeks, a sputum culture grew Mycobacterium tuberculosis, which was resistant to rifampicin and isoniazid. She was treated with second-line anti-tuberculous therapy and eventually recovered. CONCLUSION: Tuberculosis can manifest in many ways. It is important to obtain patient material for culture; not only to confirm the diagnosis but also for the determination of possible resistance which is necessary for adequate therapy.

Immunology in tuberculosis: challenges in monitoring of disease activity and identifying correlates of protection.

Humans have always lived with tubercle bacilli. Host susceptibility both inherited and acquired determines whether an individual infected with Mycobacterium tuberculosis will eventually fall ill and develop tuberculosis (TB). After infection with M. tuberculosis, a latent TB infection may ensue reflected by immune recognition of specific antigenic epitopes expressed by M. tuberculosis the Region of Difference 1 proteins ESAT-6 and CFP-10 leading to interferon gamma release in vitro. Multi-Drug-Resistant TB has emerged as an enormous infectious threat in certain regions in the world, and the Acquired immunodeficiency by co-infection with HIV has accelerated the TB epidemic even further. A paradoxical response or Immune Response Inflammatory Syndrome in the context of treatment of HIV co-infection - is an increased inflammatory reaction during effective reduction in the bacterial load. This should be differentiated from treatment failure. A huge challenge is to develop novel markers that can differentiate paradoxical responses from treatment failure. We discuss the role of protection of vaccines especially BCG, iron metabolism and the role of vitamin D.

[Practice guideline prevention, diagnosis and treatment of tuberculosis in patients with an HIV infection]. / Richtlijn preventie, diagnose en behandeling van tuberculose bij patiënten met een hiv-infectie.

An interdisciplinary workgroup from the National Committee for Practical Tuberculosis Control in the Netherlands has written an evidence-based practice guideline on the prevention, diagnosis, and treatment of HIV-infected patients with active tuberculosis or latent tuberculosis infection. The diagnosis and treatment of tuberculosis are effectively the same in patients with or without an HIV infection. The diagnosis is more complex in a patient with an HIV infection due to the effect of the immunodeficiency on diagnostic parameters. Concomitant treatment of tuberculosis and HIV is complicated by drug interactions and overlapping adverse effects. In patients with tuberculosis and an HIV infection, the tuberculosis is preferably treated before antiretroviral therapy is started. The nurse or nurse practitioner in the organisation where the tuberculosis is diagnosed is responsible for supporting the HIV patient with tuberculosis.