Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart
  • Log out

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions

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

Simon Tiberi, Lia D'Ambrosio, Saverio De Lorenzo, Pietro Viggiani, Rosella Centis, Giovanni Sotgiu, Jan Wilem C. Alffenaar, Giovanni Battista Migliori
European Respiratory Journal 2016 47: 333-336; DOI: 10.1183/13993003.01278-2015
Simon Tiberi
1Division of Infection, Barts Healthcare NHS Trust, London, UK
7These authors contributed equally
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lia D'Ambrosio
2Public Health Consulting Group, Lugano, Switzerland
3WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate, Italy
7These authors contributed equally
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Saverio De Lorenzo
4Eugenio Morelli MDR-TB Reference Hospital, AOVV, Sondalo, Italy
7These authors contributed equally
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pietro Viggiani
4Eugenio Morelli MDR-TB Reference Hospital, AOVV, Sondalo, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rosella Centis
3WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giovanni Sotgiu
5Clinical Epidemiology and Medical Statistics Unit, Dept of Biomedical Sciences, University of Sassari – Research, Medical Education and Professional Development Unit, AOU Sassari, Sassari, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jan Wilem C. Alffenaar
6University of Groningen, University Medical Center Groningen, Dept of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giovanni Battista Migliori
3WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: giovannibattista.migliori@fsm.it
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Ertapenem may be useful for MDR/XDR-TB to simplify administration of carbapenem when the patient is at home http://ow.ly/Snx69

To the Editor:

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].

A previous proof-of-concept study from our group has suggested that meropenem clavulanate is potentially useful in the treatment of these cases and is also well tolerated [7]. In vitro and pharmacological data suggest that ertapenem, a newer carbapenem compound, is potentially active against Mycobacterium tuberculosis, its longer half-life allowing single daily parenteral administration (rather than thrice-daily administration of meropenem) and advantageous homecare or day-hospital management [8, 9].

Clinical information necessary to study safety, tolerability and efficacy of ertapenem was retrospectively collected on all MDR-TB cases treated at the E. Morelli Hospital (the TB reference centre for Italy) between 2008 and 2015. Carbapenems were used in MDR-TB patients lacking active drugs in their regimen. Meropenem (3 g three times daily) or imipenem (500 mg four times a day) was given during hospital stay and if limited drug options switched to ertapenem (1 g once daily) for easier home-care or day-hospital administration.

Regimens to treat MDR/XDR-TB cases were tailored to drug susceptibility testing (DST) results according to World Health Organization (WHO) recommendations [2] to design an Optimised Background Regimen (OBR), using fluoroquinolones, injectable agents and other second-line oral agents co-administered with linezolid and carbapenems in heavily resistant/drug-intolerant individuals. A team composed of three external investigators reviewed and agreed on each clinical record reporting on the use of carbapenems in the study period, in collaboration with local specialists.

The database was developed to be consistent with that used in previous studies [7, 10, 11]. The protocol and outcome definitions were compatible with those used to study the largest MDR-TB cohort available [3, 4].

A patient who completed treatment as recommended by the national policy without evidence of failure and was consistently culture-negative with at least three or more consecutive cultures taken at least 30 days apart after the intensive phase was defined as cured. Treatment failure was defined as treatment terminated or need for a permanent regimen change of at least two anti-TB drugs because of: 1) lack of conversion by the end of the intensive phase; 2) bacteriological reversion in the continuation phase after conversion to negative; 3) evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs; or 4) adverse drug reactions [1].

Sputum conversion was defined as two consecutive negative sputum smears in patients who were sputum smear-positive at diagnosis. Time to culture conversion was defined as time from treatment start to the date of the first of two consecutive negative cultures [7, 10].

Approval for collection of study data was provided by the ethical committee of the coordinating centre in Tradate, Italy [7, 10, 11], in compliance with national regulations and organisational requirements for protection of human subjects. All data were coded and individual identifiers were available only to treating physicians.

Safety and tolerability outcomes included major and minor adverse events. Any adverse reaction resulting in temporary or permanent discontinuation of a drug was defined as major, while a minor adverse event required only dose adjustment and/or addition of concomitant treatment [7, 10]. Efficacy end-points included time to sputum smear and culture conversions, and treatment outcomes [7, 10].

DST for all first- and second-line anti-TB drugs was performed by the Reference Laboratory in Sondalo, Italy, which participates in the WHO-approved external quality-assured programme [1, 2, 7, 10]. In Sondalo, sputum smear examinations are performed weekly until negative and then monthly. Cultures are performed monthly [7, 10].

The main results are summarised in table 1. Five cases (two females and three males) of pulmonary TB with a mean age of 35.5 years were treated with ertapenem. All were HIV seronegative, previously treated for TB for >30 days (average 2.5 times) and reporting treatment failure. At diagnosis, the cases were sputum smear and culture positive with bilateral cavities on chest radiography. Resistance patterns were severe, with documented resistance to at least four out of the five first-line drugs and to several core second-line anti-TB drugs (average 9.2 resistances per case). Two cases were XDR and three pre-XDR (e.g. either resistance to fluoroquinolones (one case) or to second-line injectables (two cases)), as clinicians are used to calling them. Four cases were immigrants from countries with high MDR-TB prevalence (Moldova, Romania and Ukraine).

View this table:
  • View inline
  • View popup
TABLE 1

Clinical characteristics of five patients with multidrug-resistant/extensively drug-resistant tuberculosis (TB) treated with ertapenem in Sondalo, Italy

Three cases achieved cure, one completed treatment without meeting the criteria for cure (no expectoration), and one failed to convert his sputum smear and culture, and died after 114 days of hospital admission. Meropenem or imipenem exposure was, on average, 34.4 days (table 1), while that of ertapenem was 431.4 days (median 540 days, range 20–690 days). The average exposure to linezolid was 590.5 days at the mean dose of 975 mg·day−1 (with a single, minor, gastrointestinal adverse event described in case 4). The adoption of TDM (Therapeutic Drug Monitoring) allowed optimisation of the dose and reduction of the adverse events with this drug [11, 12].

All carbapenem drugs were well tolerated and never required interruption or dose adjustment. Of note, due to its complexity, case 1 required bedaquiline (under compassionate use) to ensure a sufficient number of active drugs [13].

In the three out of five patients converting and for whom a time to bacteriological conversion was available (patient 2 died shortly within a month of the start of treatment and patient 3 did not expectorate after discharge), the average time to achieve bacteriological conversion was 47.7 days for sputum smear and 60 days for culture.

This study represents the first clinical report, to our knowledge, on the use of ertapenem to treat MDR- and XDR-TB, with the specific role of simplifying the administration of the carbapenem when the patient is at home. The small sample size and the retrospective nature of the study limit the possibility of generalising its results. However, the good tolerability and the positive outcomes achieved in the majority of the cases suggest continuing studying the clinical potential of carbapenems against MDR- and XDR-TB. With this in mind, an international consortium, ECSG (European Carbapenems Study Group), was created to further study meropenem, imipenem and ertapenem, and to investigate their role when added to OBR to treat MDR- and XDR-TB cases.

The clinical management of these cases is extremely expensive. Diel et al. [6] estimated a cost, in Europe, of €6 466 124 to treat 136 XDR-TB cases, which is equivalent to €88.05 per day just to purchase drugs. The cost is very conservative. In fact, the long exposure to both linezolid and carbapenems (plus bedaquiline in case 1) in these extremely severe cases generated very high costs for drugs, to be added to the other costs related to hospital stay (on the order of 100 days per case).

The time necessary to achieve bacteriological conversion is long, and a portion of these cases (one out of five in our study), unfortunately, remain infectious till death. Although the absolute numbers are small [1, 6], even low TB incidence countries continue to face almost untreatable TB cases [14] without necessarily having the capacity to prevent secondary infections and, therefore, future cases sustained by potentially lethal strains [15].

A coordinated action is necessary at the European level to strengthen public health services (within National TB Programmes, where still in place) to prevent MDR-TB, while continuing the search for new drugs and the research on the potentialities of existing molecules with proven activity against M. tuberculosis.

Footnotes

  • Conflict of interest: None declared.

  • Received August 3, 2015.
  • Accepted August 26, 2015.
  • Copyright ©ERS 2016

References

  1. ↵
    World Health Organization. Global tuberculosis report 2014. WHO/HTM/TB2014.08. Geneva, World Health Organization, 2014.
  2. ↵
    1. Falzon D,
    2. Jaramillo E,
    3. Schünemann HJ, et al.
    WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011; 38: 516–528.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Falzon D,
    2. Gandhi N,
    3. Migliori GB, et al.
    Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 2013; 42: 156–168.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Migliori GB,
    2. Sotgiu G,
    3. Gandhi NR, et al.
    Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169–179.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Blasi F,
    2. Dara M,
    3. van der Werf MJ, et al.
    Supporting TB clinicians managing difficult cases: the ERS/WHO Consilium. Eur Respir J 2013; 41: 491–494.
    OpenUrlFREE Full Text
  6. ↵
    1. Diel R,
    2. Vandeputte J,
    3. de Vries G, et al.
    Costs of tuberculosis disease in the European Union: a systematic analysis and cost calculation. Eur Respir J 2014; 43: 554–565.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. De Lorenzo S,
    2. Alffenaar JW,
    3. Sotgiu G, et al.
    Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB. Eur Respir J 2013; 41: 1386–1392.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Cordillot M,
    2. Dubée V,
    3. Triboulet S, et al.
    In vitro cross-linking of Mycobacterium tuberculosis peptidoglycan by l,d-transpeptidases and inactivation of these enzymes by carbapenems. Antimicrob Agents Chemother 2013; 57: 5940–5945.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Tremblay LW,
    2. Fan F,
    3. Blanchard JS
    . Biochemical and structural characterization of Mycobacterium tuberculosis beta-lactamase with the carbapenems ertapenem and doripenem. Biochemistry 2010; 49: 3766–3773.
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    1. De Lorenzo S,
    2. Centis R,
    3. D'Ambrosio L, et al.
    On linezolid efficacy and tolerability. Eur Respir J 2012; 39: 770–772.
    OpenUrlFREE Full Text
  11. ↵
    1. Sotgiu G,
    2. Centis R,
    3. D'Ambrosio L, et al.
    Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012; 40: 1430–1442.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Srivastava S,
    2. Peloquin CA,
    3. Sotgiu G, et al.
    Therapeutic drug management: is it the future of multidrug-resistant tuberculosis treatment? Eur Respir J 2013; 42: 1449–1453.
    OpenUrlFREE Full Text
  13. ↵
    1. Tiberi S,
    2. De Lorenzo S,
    3. Centis R, et al.
    Bedaquiline in MDR/XDR-TB cases: first experience on compassionate use. Eur Respir J 2014; 43: 289–292.
    OpenUrlFREE Full Text
  14. ↵
    1. Esposito S,
    2. D'Ambrosio L,
    3. Tadolini M, et al.
    ERS/WHO Tuberculosis Consilium assistance with extensively drug-resistant tuberculosis management in a child: case study of compassionate delamanid use. Eur Respir J 2014; 44: 811–815.
    OpenUrlFREE Full Text
  15. ↵
    1. Sotgiu G,
    2. D'Ambrosio L,
    3. Centis R, et al.
    TB and M/XDR-TB infection control in European TB reference centres: the Achilles’ heel? Eur Respir J 2011; 38: 1221–1223.
    OpenUrlFREE Full Text
PreviousNext
Back to top
View this article with LENS
Vol 47 Issue 1 Table of Contents
European Respiratory Journal: 47 (1)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience
Simon Tiberi, Lia D'Ambrosio, Saverio De Lorenzo, Pietro Viggiani, Rosella Centis, Giovanni Sotgiu, Jan Wilem C. Alffenaar, Giovanni Battista Migliori
European Respiratory Journal Jan 2016, 47 (1) 333-336; DOI: 10.1183/13993003.01278-2015

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience
Simon Tiberi, Lia D'Ambrosio, Saverio De Lorenzo, Pietro Viggiani, Rosella Centis, Giovanni Sotgiu, Jan Wilem C. Alffenaar, Giovanni Battista Migliori
European Respiratory Journal Jan 2016, 47 (1) 333-336; DOI: 10.1183/13993003.01278-2015
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Respiratory infections and tuberculosis
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Agora

  • Airway immune responses to COVID-19 vaccination in COPD patients
  • Wider access to rifapentine-based regimens is needed for TB care globally
  • Normative multiple-breath washout data for children corrected for sensor error
Show more Agora

Research letters

  • Lessons from 2 years of use of the Post-COVID-19 Functional Status scale
  • Beta-blockade improves right ventricular diastolic function in exercising PAH
  • Trends in COVID-19-associated mortality in PH
Show more Research letters

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society