Akkerman, Onno W.

Alffenaar, Jan-Willem C.

Bolhuis, Mathieu S.

de Lange, Wiel C. M.

Sturkenboom, Marieke G. G.

van der Werf, Tjip S.

PubMed

ARTS repository - University of Groningen

   University of GroningenAdequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help OptimizeTuberculosis Treatment for the FutureSturkenboom, Marieke G. G.; Akkerman, Onno W.; Bolhuis, Mathieu S.; de Lange, Wiel C.M.; van der Werf, Tjip S.; Alffenaar, Jan-Willem C.Published in:Antimicrobial Agents and ChemotherapyDOI:10.1128/AAC.05173-14IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Sturkenboom, M. G. G., Akkerman, O. W., Bolhuis, M. S., de Lange, W. C. M., van der Werf, T. S., &Alffenaar, J-W. C. (2015). Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will HelpOptimize Tuberculosis Treatment for the Future. Antimicrobial Agents and Chemotherapy, 59(4), 2474-2474. https://doi.org/10.1128/AAC.05173-14CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Adequate Design of Pharmacokinetic-Pharmacodynamic Studies WillHelp Optimize Tuberculosis Treatment for the FutureMarieke G. G. Sturkenboom,a Onno W. Akkerman,b,c Mathieu S. Bolhuis,a Wiel C. M. de Lange,b,c Tjip S. van der Werf,b,dJan-Willem C. AlffenaaraUniversity of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlandsa; University ofGroningen, University Medical Center Groningen, Pulmonary Diseases and Tuberculosis, Groningen, The Netherlandsb; University of Groningen, University MedicalCenter Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlandsc; University of Groningen, University Medical Center Groningen, Department of InternalMedicine, Groningen, The NetherlandsdWe read with interest the paper by Requena-Méndez and col-leagues, who aimed to evaluate plasma concentrations ofisoniazid administered daily and twice weekly (1). The samplingstrategy to assess the area under the concentration-time curve(AUC) consisted of obtaining two plasma samples at 2 and 6 h (C2and C6, respectively) after intake of the drugs. In addition, themaximum concentration of the drug in serum (Cmax) was definedas the higher of either the C2 or the C6 concentration. They con-cluded that low isoniazid exposure (the AUC from 0 to 6 h) or alow Cmax was not associated with poorer clinical outcomes.The authors summarized several limitations of their study. It ismost likely that the design of their pharmacokinetic study (i.e., C2and C6 monitoring) explains why they failed to find such an asso-ciation. They chose C2 and C6 monitoring because of logisticalreasons. Although this approach has been used frequently in thepast, this sampling strategy is suited neither for capturing the Cmaxnor for accurately predicting the AUC of isoniazid. Earlier, Prahland colleagues showed that currently used target values for C2 arenot predictive of treatment efficacy and need to be redefined (2).Due to the large pharmacokinetic variability of isoniazid, the trueCmax will be captured only by intensive pharmacokinetic sampling(3). In addition, estimation of the isoniazid AUC using two sam-ples (C2 and C6) does not qualify to be placed among the best-performing optimal sampling strategies for isoniazid (4). Obtain-ing a full pharmacokinetic curve and using a validated limitedsampling strategy are the only two strategies of accurately predict-ing the AUC. A more practical approach would include a thirdsample at 4 h after drug intake (4). To overcome practical compli-cations like sample stability, dried blood spot monitoring can behelpful (5).Requena-Mendez et al. suggested that weight-based twice-weekly dosing is still a suitable alternative. We argue that theirstudy was not designed and lacked the power to relate this strategyto treatment outcome. Conclusions on treatment outcome maybe further complicated by the fact that data regarding drug sus-ceptibility were not available (1, 6). The earlier meta-analysis onthis subject showed that microbiological failure was more fre-quent with the intermittent dosing schedules (7). Indeed, inter-mittent dosing should no longer be recommended (8).Only a well-designed sampling schedule and information ondrug intake and drug susceptibility in combination with long-term follow-up will provide relevant data that may help to opti-mize tuberculosis (TB) treatment.REFERENCES1. Requena-Mendez A, Davies G, Waterhouse D, Ardrey A, Jave O, Lopez-Romero SL, Ward SA, Moore DA. 2014. Effect of dosage, co-morbiditiesand food on pharmacokinetics of isoniazid in Peruvian TB patients. Anti-microb Agents Chemother 58:7164 –7170. http://dx.doi.org/10.1128/AAC.03258-14.2. Prahl JB, Johansen IS, Cohen AS, Frimodt-Moller N, Andersen AB. 2014.Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Che-mother 69:2841–2847. http://dx.doi.org/10.1093/jac/dku210.3. Pasipanodya JG, Srivastava S, Gumbo T. 2015. Comment on: clinicalsignificance of 2 h plasma concentrations of first-line anti-tuberculosisdrugs: a prospective observational study. J Antimicrob Chemother 70:320 –321. http://dx.doi.org/10.1093/jac/dku345.4. Magis-Escurra C, Later-Nijland HM, Alffenaar JW, Broeders J, BurgerDM, van Crevel R, Boeree MJ, Donders AR, van Altena R, van der WerfTS, Aarnoutse RE. 2014. Population pharmacokinetics and limited sam-pling strategy for first-line tuberculosis drugs and moxifloxacin. Int J An-timicrob Agents 44:229 –234. http://dx.doi.org/10.1016/j.ijantimicag.2014.04.019.5. Vu DH, Alffenaar JW, Edelbroek PM, Brouwers JR, Uges DR. 2011. Dried bloodspots: a new tool for tuberculosis treatment optimization. Curr Pharm Des 17:2931–2939. http://dx.doi.org/10.2174/138161211797470174.6. Gumbo T, Louie A, Liu W, Brown D, Ambrose PG, Bhavnani SM,Drusano GL. 2007. Isoniazid bactericidal activity and resistance emer-gence: integrating pharmacodynamics and pharmacogenomics to predictefficacy in different ethnic populations. Antimicrob Agents Chemother 51:2329 –2336. http://dx.doi.org/10.1128/AAC.00185-07.7. Pasipanodya JG, Srivastava S, Gumbo T. 2012. Meta-analysis of clinicalstudies supports the pharmacokinetic variability hypothesis for acquireddrug resistance and failure of antituberculosis therapy. Clin Infect Dis 55:169 –177. http://dx.doi.org/10.1093/cid/cis353.8. World Health Organization. 2010. Treatment of tuberculosis guidelines,4th ed. World Health Organization, Geneva, Switzerland.Citation Sturkenboom MGG, Akkerman OW, Bolhuis MS, de Lange WCM, van derWerf TS, Alffenaar J-WC. 2015. Adequate design of pharmacokinetic-pharmacodynamic studies will help optimize tuberculosis treatment for thefuture. Antimicrob Agents Chemother 59:2474. doi:10.1128/AAC.05173-14.Address correspondence to Jan-Willem C. Alffenaar, j.w.c.alffenaar@umcg.nl.For the author reply, see doi:10.1128/AAC.05182-14.Copyright © 2015, American Society for Microbiology. All Rights Reserved.doi:10.1128/AAC.05173-14LETTER TO THE EDITOR2474 aac.asm.org April 2015 Volume 59 Number 4Antimicrobial Agents and Chemotherapy on July 19, 2015 by University of Groningenhttp://aac.asm.org/Downloaded from 

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Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help Optimize Tuberculosis Treatment for the Future

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   University of GroningenAdequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help OptimizeTuberculosis Treatment for the FutureSturkenboom, Marieke G. G.; Akkerman, Onno W.; Bolhuis, Mathieu S.; de Lange, Wiel C.M.; van der Werf, Tjip S.; Alffenaar, Jan-Willem C.Published in:Antimicrobial Agents and ChemotherapyDOI:10.1128/AAC.05173-14IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Sturkenboom, M. G. G., Akkerman, O. W., Bolhuis, M. S., de Lange, W. C. M., van der Werf, T. S., &Alffenaar, J-W. C. (2015). Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will HelpOptimize Tuberculosis Treatment for the Future. Antimicrobial Agents and Chemotherapy, 59(4), 2474-2474. https://doi.org/10.1128/AAC.05173-14CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Adequate Design of Pharmacokinetic-Pharmacodynamic Studies WillHelp Optimize Tuberculosis Treatment for the FutureMarieke G. G. Sturkenboom,a Onno W. Akkerman,b,c Mathieu S. Bolhuis,a Wiel C. M. de Lange,b,c Tjip S. van der Werf,b,dJan-Willem C. AlffenaaraUniversity of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlandsa; University ofGroningen, University Medical Center Groningen, Pulmonary Diseases and Tuberculosis, Groningen, The Netherlandsb; University of Groningen, University MedicalCenter Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlandsc; University of Groningen, University Medical Center Groningen, Department of InternalMedicine, Groningen, The NetherlandsdWe read with interest the paper by Requena-Méndez and col-leagues, who aimed to evaluate plasma concentrations ofisoniazid administered daily and twice weekly (1). The samplingstrategy to assess the area under the concentration-time curve(AUC) consisted of obtaining two plasma samples at 2 and 6 h (C2and C6, respectively) after intake of the drugs. In addition, themaximum concentration of the drug in serum (Cmax) was definedas the higher of either the C2 or the C6 concentration. They con-cluded that low isoniazid exposure (the AUC from 0 to 6 h) or alow Cmax was not associated with poorer clinical outcomes.The authors summarized several limitations of their study. It ismost likely that the design of their pharmacokinetic study (i.e., C2and C6 monitoring) explains why they failed to find such an asso-ciation. They chose C2 and C6 monitoring because of logisticalreasons. Although this approach has been used frequently in thepast, this sampling strategy is suited neither for capturing theCmaxnor for accurately predicting the AUC of isoniazid. Earlier, Prahland colleagues showed that currently used target values for C2 arenot predictive of treatment efficacy and need to be redefined (2).Due to the large pharmacokinetic variability of isoniazid, the trueCmax will be captured only by intensive pharmacokinetic sampling(3). In addition, estimation of the isoniazid AUC using two sam-ples (C2 and C6) does not qualify to be placed among the best-performing optimal sampling strategies for isoniazid (4). Obtain-ing a full pharmacokinetic curve and using a validated limitedsampling strategy are the only two strategies of accurately predict-ing the AUC. A more practical approach would include a thirdsample at 4 h after drug intake (4). To overcome practical compli-cations like sample stability, dried blood spot monitoring can behelpful (5).Requena-Mendez et al. suggested that weight-based twice-weekly dosing is still a suitable alternative. We argue that theirstudy was not designed and lacked the power to relate this strategyto treatment outcome. Conclusions on treatment outcome maybe further complicated by the fact that data regarding drug sus-ceptibility were not available (1, 6). The earlier meta-analysis onthis subject showed that microbiological failure was more fre-quent with the intermittent dosing schedules (7). Indeed, inter-mittent dosing should no longer be recommended (8).Only a well-designed sampling schedule and information ondrug intake and drug susceptibility in combination with long-term follow-up will provide relevant data that may help to opti-mize tuberculosis (TB) treatment.REFERENCES1. Requena-Mendez A, Davies G, Waterhouse D, Ardrey A, Jave O, Lopez-Romero SL, Ward SA, Moore DA. 2014. Effect of dosage, co-morbiditiesand food on pharmacokinetics of isoniazid in Peruvian TB patients. Anti-microb Agents Chemother 58:7164 –7170. http://dx.doi.org/10.1128/AAC.03258-14.2. Prahl JB, Johansen IS, Cohen AS, Frimodt-Moller N, Andersen AB. 2014.Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Che-mother 69:2841–2847. http://dx.doi.org/10.1093/jac/dku210.3. Pasipanodya JG, Srivastava S, Gumbo T. 2015. Comment on: clinicalsignificance of 2 h plasma concentrations of first-line anti-tuberculosisdrugs: a prospective observational study. J Antimicrob Chemother 70:320 –321. http://dx.doi.org/10.1093/jac/dku345.4. Magis-Escurra C, Later-Nijland HM, Alffenaar JW, Broeders J, BurgerDM, van Crevel R, Boeree MJ, Donders AR, van Altena R, van der WerfTS, Aarnoutse RE. 2014. Population pharmacokinetics and limited sam-pling strategy for first-line tuberculosis drugs and moxifloxacin. Int J An-timicrob Agents 44:229 –234. http://dx.doi.org/10.1016/j.ijantimicag.2014.04.019.5. VuDH,Alffenaar JW, EdelbroekPM,Brouwers JR,UgesDR. 2011. Dried bloodspots: a new tool for tuberculosis treatment optimization. Curr Pharm Des 17:2931–2939. http://dx.doi.org/10.2174/138161211797470174.6. Gumbo T, Louie A, Liu W, Brown D, Ambrose PG, Bhavnani SM,Drusano GL. 2007. Isoniazid bactericidal activity and resistance emer-gence: integrating pharmacodynamics and pharmacogenomics to predictefficacy in different ethnic populations. Antimicrob Agents Chemother 51:2329 –2336. http://dx.doi.org/10.1128/AAC.00185-07.7. Pasipanodya JG, Srivastava S, Gumbo T. 2012. Meta-analysis of clinicalstudies supports the pharmacokinetic variability hypothesis for acquireddrug resistance and failure of antituberculosis therapy. Clin Infect Dis 55:169 –177. http://dx.doi.org/10.1093/cid/cis353.8. World Health Organization. 2010. Treatment of tuberculosis guidelines,4th ed. World Health Organization, Geneva, Switzerland.Citation Sturkenboom MGG, Akkerman OW, Bolhuis MS, de Lange WCM, van derWerf TS, Alffenaar J-WC. 2015. Adequate design of pharmacokinetic-pharmacodynamic studies will help optimize tuberculosis treatment for thefuture. Antimicrob Agents Chemother 59:2474. doi:10.1128/AAC.05173-14.Address correspondence to Jan-Willem C. Alffenaar, j.w.c.alffenaar@umcg.nl.For the author reply, see doi:10.1128/AAC.05182-14.Copyright © 2015, American Society for Microbiology. All Rights Reserved.doi:10.1128/AAC.05173-14LETTER TO THE EDITOR2474 aac.asm.org April 2015 Volume 59 Number 4Antimicrobial Agents and Chemotherapy on July 19, 2015 by University of Groningenhttp://aac.asm.org/Downloaded from 

University of Groningen Research Database

  
 University of Groningen
Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help Optimize
Tuberculosis Treatment for the Future
Sturkenboom, Marieke G. G.; Akkerman, Onno; Bolhuis, Mathieu; de Lange, Wilhelmus; van
der Werf, Tjip S. ; Alffenaar, Johannes
Published in:
Antimicrobial Agents and Chemotherapy
DOI:
10.1128/AAC.05173-14
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2015
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Sturkenboom, M. G. G., Akkerman, O. W., Bolhuis, M. S., de Lange, W. C. M., van der Werf, T. S., &
Alffenaar, J-W. C. (2015). Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help
Optimize Tuberculosis Treatment for the Future. Antimicrobial Agents and Chemotherapy, 59(4), 2474-
2474. DOI: 10.1128/AAC.05173-14
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 11-02-2018
Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will
Help Optimize Tuberculosis Treatment for the Future
Marieke G. G. Sturkenboom,a Onno W. Akkerman,b,c Mathieu S. Bolhuis,a Wiel C. M. de Lange,b,c Tjip S. van der Werf,b,d
Jan-Willem C. Alffenaara
University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlandsa; University of
Groningen, University Medical Center Groningen, Pulmonary Diseases and Tuberculosis, Groningen, The Netherlandsb; University of Groningen, University Medical
Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlandsc; University of Groningen, University Medical Center Groningen, Department of Internal
Medicine, Groningen, The Netherlandsd
We read with interest the paper by Requena-Méndez and col-leagues, who aimed to evaluate plasma concentrations of
isoniazid administered daily and twice weekly (1). The sampling
strategy to assess the area under the concentration-time curve
(AUC) consisted of obtaining two plasma samples at 2 and 6 h (C2
and C6, respectively) after intake of the drugs. In addition, the
maximum concentration of the drug in serum (Cmax) was defined
as the higher of either the C2 or the C6 concentration. They con-
cluded that low isoniazid exposure (the AUC from 0 to 6 h) or a
low Cmax was not associated with poorer clinical outcomes.
The authors summarized several limitations of their study. It is
most likely that the design of their pharmacokinetic study (i.e., C2
and C6 monitoring) explains why they failed to find such an asso-
ciation. They chose C2 and C6 monitoring because of logistical
reasons. Although this approach has been used frequently in the
past, this sampling strategy is suited neither for capturing theCmax
nor for accurately predicting the AUC of isoniazid. Earlier, Prahl
and colleagues showed that currently used target values for C2 are
not predictive of treatment efficacy and need to be redefined (2).
Due to the large pharmacokinetic variability of isoniazid, the true
Cmax will be captured only by intensive pharmacokinetic sampling
(3). In addition, estimation of the isoniazid AUC using two sam-
ples (C2 and C6) does not qualify to be placed among the best-
performing optimal sampling strategies for isoniazid (4). Obtain-
ing a full pharmacokinetic curve and using a validated limited
sampling strategy are the only two strategies of accurately predict-
ing the AUC. A more practical approach would include a third
sample at 4 h after drug intake (4). To overcome practical compli-
cations like sample stability, dried blood spot monitoring can be
helpful (5).
Requena-Mendez et al. suggested that weight-based twice-
weekly dosing is still a suitable alternative. We argue that their
study was not designed and lacked the power to relate this strategy
to treatment outcome. Conclusions on treatment outcome may
be further complicated by the fact that data regarding drug sus-
ceptibility were not available (1, 6). The earlier meta-analysis on
this subject showed that microbiological failure was more fre-
quent with the intermittent dosing schedules (7). Indeed, inter-
mittent dosing should no longer be recommended (8).
Only a well-designed sampling schedule and information on
drug intake and drug susceptibility in combination with long-
term follow-up will provide relevant data that may help to opti-
mize tuberculosis (TB) treatment.
REFERENCES
1. Requena-Mendez A, Davies G, Waterhouse D, Ardrey A, Jave O, Lopez-
Romero SL, Ward SA, Moore DA. 2014. Effect of dosage, co-morbidities
and food on pharmacokinetics of isoniazid in Peruvian TB patients. Anti-
microb Agents Chemother 58:7164 –7170. http://dx.doi.org/10.1128/AAC
.03258-14.
2. Prahl JB, Johansen IS, Cohen AS, Frimodt-Moller N, Andersen AB. 2014.
Clinical significance of 2 h plasma concentrations of first-line anti-
tuberculosis drugs: a prospective observational study. J Antimicrob Che-
mother 69:2841–2847. http://dx.doi.org/10.1093/jac/dku210.
3. Pasipanodya JG, Srivastava S, Gumbo T. 2015. Comment on: clinical
significance of 2 h plasma concentrations of first-line anti-tuberculosis
drugs: a prospective observational study. J Antimicrob Chemother 70:320 –
321. http://dx.doi.org/10.1093/jac/dku345.
4. Magis-Escurra C, Later-Nijland HM, Alffenaar JW, Broeders J, Burger
DM, van Crevel R, Boeree MJ, Donders AR, van Altena R, van der Werf
TS, Aarnoutse RE. 2014. Population pharmacokinetics and limited sam-
pling strategy for first-line tuberculosis drugs and moxifloxacin. Int J An-
timicrob Agents 44:229 –234. http://dx.doi.org/10.1016/j.ijantimicag.2014
.04.019.
5. VuDH,Alffenaar JW, EdelbroekPM,Brouwers JR,UgesDR. 2011. Dried blood
spots: a new tool for tuberculosis treatment optimization. Curr Pharm Des 17:
2931–2939. http://dx.doi.org/10.2174/138161211797470174.
6. Gumbo T, Louie A, Liu W, Brown D, Ambrose PG, Bhavnani SM,
Drusano GL. 2007. Isoniazid bactericidal activity and resistance emer-
gence: integrating pharmacodynamics and pharmacogenomics to predict
efficacy in different ethnic populations. Antimicrob Agents Chemother 51:
2329 –2336. http://dx.doi.org/10.1128/AAC.00185-07.
7. Pasipanodya JG, Srivastava S, Gumbo T. 2012. Meta-analysis of clinical
studies supports the pharmacokinetic variability hypothesis for acquired
drug resistance and failure of antituberculosis therapy. Clin Infect Dis 55:
169 –177. http://dx.doi.org/10.1093/cid/cis353.
8. World Health Organization. 2010. Treatment of tuberculosis guidelines,
4th ed. World Health Organization, Geneva, Switzerland.
Citation Sturkenboom MGG, Akkerman OW, Bolhuis MS, de Lange WCM, van der
Werf TS, Alffenaar J-WC. 2015. Adequate design of pharmacokinetic-
pharmacodynamic studies will help optimize tuberculosis treatment for the
future. Antimicrob Agents Chemother 59:2474. doi:10.1128/AAC.05173-14.
Address correspondence to Jan-Willem C. Alffenaar, j.w.c.alffenaar@umcg.nl.
For the author reply, see doi:10.1128/AAC.05182-14.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.05173-14
LETTER TO THE EDITOR
2474 aac.asm.org April 2015 Volume 59 Number 4Antimicrobial Agents and Chemotherapy
 o
n
 July 19, 2015 by University of G
roningen
http://aac.asm
.org/
D
ow
nloaded from
 


Adequate Design of Pharmacokinetic-Pharmacodynamic Studies Will Help Optimize Tuberculosis Treatment for the Future

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