Simon Tiberi

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.

First case of extensively drug-resistant tuberculosis treated with both delamanid and bedaquiline

The European Respiratory Journal has recently discussed delamanid and bedaquiline and their use in difficult-to-treat cases affected by multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant (XDR-TB) [1–4]. The use of delamanid or bedaquiline is particularly important when four active drugs cannot be identified and included in a regimen, as per World Health Organization (WHO) guidelines [1–6]. Recently a debate has been initiated around the report of a severe, almost untreatable, XDR-TB case who could not access both new drugs simultaneously [7–10] due to concerns about possible additive toxicity (cardiotoxicity), as well as the lack of evidence and specific guidance on their combined use [10–13]. Report of the first case, concerns and challenges of treatment of severe XDR-TB with both delamanid and bedaquiline http://ow.ly/WzeB3004Cmo

Effectiveness and safety of meropenem/ clavulanate-containing regimens in the treatment of MDR- and XDR-TB

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases. Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6–9) versus 5 (4–6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49–156) days. No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment). The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases. Meropenem/clavulanate is effective and safe to treat MDR- and XDR-TB in comparison with controls http://ow.ly/XG75j

Bedaquiline in MDR/XDR-TB cases: first experience on compassionate use

To the Editor: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are recognised as global emerging public health priorities [1, 2], with 310 000 MDR-TB cases notified to the World Health Organization (WHO) in 2011, 9% of them being XDR. MDR/XDR-TB testify to the failure of National TB Programmes to use available first- and second-line drugs correctly [3], and generate clinical dilemmas for clinicians managing these difficult-to-treat cases. The chances of achieving treatment success, or even sputum smear and culture conversion, are largely suboptimal in these cases [1, 2]. In the largest MDR-TB cohort ever analysed [1, 2], the proportion of cases treated successfully was 54%, with 8% failing or relapsing, 15% dying and 23% defaulting. In the XDR-TB subgroup, 40% achieved treatment success, 22% failed treatment or relapsed, 15% died, and 16% defaulted. The reason for this is simple: treatment of MDR/XDR-TB is expensive [4], more toxic [5, 6], and, as of today, takes up to 2 years of therapy according to current WHO guidelines [3]. The therapeutic armamentarium is limited in XDR-TB cases, where, by definition, the strains of Mycobacterium tuberculosis are resistant to the two most powerful anti-TB drugs (rifampicin and isoniazid, defining MDR-TB) plus any fluoroquinolones and to at least one second-line injectable (amikacin, capreomycin and kanamycin). The remaining treatment options available are the “old” bacteriostatic drugs and the not well-known WHO group 5 drugs [3, 5–7]. The real …

Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience

Treatment of multidrug-resistant (MDR) tuberculosis (TB) (defined as resistance to at least isoniazid and rifampicin, two core first-line drugs for TB treatment) and extensively drug-resistant (XDR)-TB (defined as resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs amikacin, capreomycin or kanamycin) are a challenge for both clinicians and public health specialists [1–5]. Treatment outcomes of difficult-to-treat MDR-TB cases (e.g. those with an extensive resistance pattern) are still unsatisfactory, adverse events frequent and severe, and the necessary drugs expensive [6]. Ertapenem may be useful for MDR/XDR-TB to simplify administration of carbapenem when the patient is at home http://ow.ly/Snx69

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92–280) days and exposed to bedaquiline for 168 (86–180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively). Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30–60) days and 60 (33–90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions. Bedaquiline is safe and effective in treating MDR- and XDR-TB patients http://ow.ly/6MWK30adHkw

Faster for less: the new "shorter" regimen for multidrug-resistant tuberculosis

Multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are growing clinical and public health concerns, with an estimated worldwide incidence and mortality of 480 000 and 190 000 cases, respectively (2014) [1]. The World Health Organization (WHO) End TB Strategy reiterates the MDR-/XDR-TB threat and the solutions to control the epidemic [2]. Unfortunately, large proportions of patients with resistant TB do not have access to adequate diagnostics and treatment yet, while treatment success rates remain suboptimal (as demonstrated in the largest retrospective cohort of MDR-TB patients, i.e., TB caused by Mycobacterium tuberculosis isolates resistant to at least isoniazid and rifampicin) and decrease further with resistance patterns beyond XDR-TB [3]. Evaluation of drug resistances is needed to identify candidates for the shorter regimen in MDR-TB hot spots http://ow.ly/wZV33022VXt

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases. 84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60–428) versus 85 (49–156) days, respectively. Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only. Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients. Meropenem/clavulanate is safe and more effective than imipenem/clavulanate in treating MDR and XDR-TB patients http://ow.ly/Z4S2o

WHO recommendations on shorter treatment of multidrug-resistant tuberculosis.

2486 www.thelancet.com Vol 387 June 18, 2016 Tuberculosis is now the world’s commonest cause of death from infectious disease. The ominous spread of multidrug-resistant (MDR) and extensively drugresistant (XDR) tuberculosis, and the scarce treatment options available, are priority global health issues. With a global estimate in 2014 of 450 000 cases of MDR and XDR tuberculosis causing 150 000 deaths, and the continuing spread, the WHO End TB Strategy highlights the threat that MDR and XDR tuberculosis pose to global public health security. Poor treatment success of available treatment regimens and evolution of Mycobacterium tuberculosis strains with resistance patterns beyond XDR tuberculosis pose major management challenges. Available treatment regimens have poor effi cacy, are toxic and expensive, and require lengthy treatment, compromising patient adherence and therapeutic drug monitoring. Furthermore, health-care providers fi nd it diffi cult to design eff ective regimens because of inadequate laboratory facilities for tuberculosis drug susceptibility testing (DST). The recent release by WHO of new recommendations aimed at speeding up tuberculosis DST using a rapid molecular MTBDRsl test and use of shorter MDR tuberculosis treatment regimens is a welcome, long-awaited development. The recommendations highlight the advantages of the new regimen (4–6 months of kanamycin acid, moxifl oxacin, protionamide, clofazimine, pyrazinamide and high-dose isoniazid and ethambutol followed by 5 months of moxifl oxacin, clofazimine, pyrazinamide, and ethambutol), and provide a fact sheet with the necessary explanations. The shorter duration (9 months) and its low cost (<US

Multidrug-resistant tuberculosis in Europe, 2010-2011.

1000) will go some way in improving the current dismal status quo. The regimen is recommended only for MDR tuberculosis cases not previously treated with, or resistant to, second-line anti-tuberculosis drugs. Although the new guidelines are welcomed, we have concerns about whether the shorter treatment regimen is likely to be eff ective in all geographical settings. The WHO recommendations are based on a multicentre study of 1200 patients, not geographically representative of all MDR and XDR tuberculosis endemic regions, and they might not be applicable in specifi c hotspots for MDR and XDR tuberculosis, such as countries of the former Soviet Union in which there are numerous previously treated cases. Thus, a cautious decision-making approach, based on DST, is essential. However, the short regimens have produced excellent outcomes under operational research conditions in some settings in which they benefi ted from preexisting knowledge of the local epidemiology of drug resistance and availability of rapid MTBDRsl testing to ensure DST for the key drugs composing the treatment regimen. Under these conditions, the WHOrecommended short MDR tuberculosis regimen could be very useful for some patients, as treatment duration is substantially reduced. Data show that the short regimen, previously called the Bangladesh regimen, might not be theoretically eff ective in certain settings. Our International Carbapenems Study Group recently did a multicentre, retrospective cohort study of 348 patients recruited in several clinical centres specialised in the management of MDR and XDR tuberculosis cases and located in eight countries in Europe and three countries in South America. Adults with a culture-confi rmed diagnosis of MDR tuberculosis were assessed according to meropenem-containing and imipenem-containing, WHO recommendations on shorter treatment of multidrug-resistant tuberculosis