Clinical Infectious Diseases
CORRESPONDENCE
Therapeutic Drug Monitoring
in Tuberculosis: Practical
Application for Physicians
TO THE EDITOR—We studied with great in-
terest the novel treatment guidelines for
drug-susceptible tuberculosis [1]. The
authors mention situations where thera-
peutic drug monitoring (TDM) may be
useful: drug malabsorption, drug under-
dosing, and drug–drug interactions.
Limited availability in low-resource set-
tings, sample stability, and costs meant
that TDM was not advocated for drug-
susceptible tuberculosis [2] but endorsed
for multidrug-resistant tuberculosis [3].
Nahid and colleagues emphasize that no
prospective randomized controlled trials
(RCTs) are available to define the role of
TDM in tuberculosis treatment [1].
Indeed, an RCT may define in which
subpopulations TDM has the most im-
pact and allow quantification of that im-
pact to support additional cost analyses.
Yet, the pharmaceutical industry would
generally decline support of a trial with-
out a new drug regimen, and public fund-
ing remains competitive and focused on
regimens that may shorten total treat-
ment duration. Short of a new trial, do
we not already have sufficient evidence
that shows that drug exposure to, for ex-
ample, isoniazid is relevant for outcome
[4]? Early bactericidal activity studies
show a clear association between dose
(ie, exposure) and reduction in bacterial
load [5]. An RCT demonstrated that
dose selection based on N-acetyltransfer-
ase polymorphism resulted in less treat-
ment failure in rapid acetylators and
fewer adverse drug events in poor acetyla-
tors [6]. Although not tested, this makes a
strong case for TDM. The guidelines
mention that low drug exposure did
not translate into poor outcome in some
studies. Yet in these studies, TDM was
used only after patients have manifested
slow response to therapy where equiva-
lence in outcome could instead be
interpreted as an actual benefit conferred
by TDM in preventing the more rare
events of relapse or acquired drug resis-
tance. Moreover, optimal assessment of
drug exposure should always be related
to a patient’s actual Mycobacterium tu-
berculosis minimum inhibitory concen-
tration (MIC), and the time that TDM
focuses only on drug exposure has passed
[7]. Commercially available MIC plates
are accurate and operationally acceptable
[8]. But could we expect widespread im-
plementation of TDM by 2 serum samples
collected at 2 and 6 hours after drug intake
and sent frozen to a certified laboratory?
Likely not, as such a shipment is often
not feasible. However, dried blood spot
analysis (DBSA) is a game-changing alter-
native [9]. Sample collection is now easier
using a drop of blood from a fingerprick
collected on a card, which can be shipped
at ambient temperature by mail. Indeed,
we agree with authors that the benefit of
TDM may be higher in patients with mal-
absorption, human immunodeficiency
virus coinfection, diabetes, or delayed spu-
tum culture conversion. However, we favor
operational studies using DBSA to assess
the application of early TDM in those sub-
populations. TDM should be considered a
useful tool in supporting clinical decision
making. DBSA renders TDM feasible
in many situations [10]. We expect such
work will ultimately change the perception
that TDM is only for specialized centers in
low-prevalence settings, and instead con-
sidered as an important tool in the global
fight against tuberculosis.
Note
Potential conflicts of interest. All authors:
No reported conflicts. All authors have submitted
the ICMJE Form for Disclosure of Potential Con-
flicts of Interest. Conflicts that the editors consid-
er relevant to the content of the manuscript have
been disclosed.
Jan-Willem C. Alffenaar,1 Simon Tiberi,3
Roger K. Verbeeck,4 Scott K. Heysell,5 and
Martin P. Grobusch2
1
Department of Clinical Pharmacy and Pharmacology,
University Medical Center Groningen, University of Groningen,
and 2Center of Tropical Medicine and Travel Medicine,
Department of Infectious Diseases, Division of Internal
Medicine, Academic Medical Center, University of
Amsterdam, The Netherlands; 3Division of Infection, Barts
Health NHS Trust, London, United Kingdom; 4School of
Pharmacy, University of Namibia, Windhoek; and 5Division of
Infectious Diseases and International Health, Department of
Medicine, University of Virginia, Charlottesville
References
1. Nahid P, Dorman S, Alipanah N, et al. Official
American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases Society
of America clinical practice guidelines: treatment of
drug-susceptible tuberculosis. Clin Infect Dis 2016;
63:e147–95.
2. van der Burgt EP, Sturkenboom MGG, Bolhuis MS,
et al. End TB with precision treatment! Eur Respir J
2016; 47:680–2.
3. Lange C, Abubakar I, Alffenaar J-WC, et al. Manage-
ment of patients with multidrug-resistant/extensively
drug-resistant tuberculosis in Europe: a TBNET con-
sensus statement. Eur Respir J 2014; 44:23–63.
4. Pasipanodya JG, McIlleron H, Burger A, Wash PA,
Smith P, Gumbo T. Serum drug concentrations pre-
dictive of pulmonary tuberculosis outcomes. J Infect
Dis 2013; 208:1464–73.
5. Donald PR, Sirgel FA, Venter A, et al. The influence
of human N-acetyltransferase genotype on the early
bactericidal activity of isoniazid. Clin Infect Dis
2004; 39:1425–30.
6. Azuma J, Ohno M, Kubota R, et al. NAT2 genotype
guided regimen reduces isoniazid-induced liver in-
jury and early treatment failure in the 6-month
four-drug standard treatment of tuberculosis: a ran-
domized controlled trial for pharmacogenetics-
based therapy. Eur J Clin Pharmacol 2013;
69:1091–101.
7. Zuur MA, Bolhuis MS, Anthony R, et al. Current
status and opportunities for therapeutic drug mon-
itoring in the treatment of tuberculosis. Expert Opin
Drug Metab Toxicol 2016; 12:509–21.
8. Heysell SK, Pholwat S, Mpagama SG, et al. Sensititre
MycoTB plate compared to Bactec MGIT 960 for first-
and second-line antituberculosis drug susceptibility
testing in Tanzania: a call to operationalize MICs.
Antimicrob Agents Chemother 2015; 59:7104–8.
9. Vu DH, Alffenaar JWC, Edelbroek PM, Brouwers
JRBJ, Uges DRA. Dried blood spots: a new tool for
tuberculosis treatment optimization. Curr Pharm
Des 2011; 17:2931–9.
10. Ghimire S, Bolhuis MS, Sturkenboom MGG, et al.
Incorporating therapeutic drug monitoring into
the World Health Organization hierarchy of tuber-
culosis diagnostics. Eur Respir J 2016; 47:1867–9.
Correspondence: J.-W. C. Alffenaar, University of Groningen,
University Medical Center Groningen, Department of Hospital
and Clinical Pharmacy, PO Box 30.001, 9700 RB Groningen, The
Netherlands (j.w.c.alffenaar@umcg.nl).
Clinical Infectious Diseases®
© The Author 2016. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail journals.permissions@oup.com.
DOI: 10.1093/cid/ciw677
CORRESPONDENCE • CID • 1