Clinical Relevance of Rifampicin-Moxifloxacin Interaction in Isoniazid-Resistant/Intolerant Tuberculosis Patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB center investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or -intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or -intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e., area under the concentration-time curve (AUC0-24h), and attainment of AUC0-24h/MIC > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC0-24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC0-24h/MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC0-24h/MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

Corticosteroid therapy for the management of paradoxical inflammatory reaction in patients with pulmonary tuberculosis.

BACKGROUND: Paradoxical reaction after the initiation of tuberculosis treatment is defined as increased inflammation following effective antimycobacterial treatment. This is a phenomenon that can severely complicate a patient's recovery, potentially leading to further morbidity and residual deficits. Paradoxical reaction remains poorly understood regarding its pathophysiology and management. Only a limited number of reports look critically at the available therapeutic options, with evidence of the efficacy of prednisolone therapy being primarily limited to extrapulmonary PR only. CASE: We describe two HIV negative patients who were admitted to our department with pulmonary tuberculosis, presenting with inflammatory patterns attributable to PR and their response to adjunctive steroid therapy. DISCUSSION AND CONCLUSIONS: The presented cases further highlight the need for immunological studies and randomized trials for corticosteroid therapy are needed to better understand this phenomenon as well as provide an evidence-base for anti-inflammatory treatment. Furthermore, by means of this case series, we are also able to highlight the potential variability in the symptomatology of the lesser known PR phenomenon, in which we observed a hypotensive shock-like syndrome not previously described in literature.

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/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB.

The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of ≥0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L.

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.

Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.

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.

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.

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.

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

BACKGROUND: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. METHODS AND FINDINGS: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). CONCLUSIONS: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.