Eur J Clin Pharmacol

DOI 10.1007/s00228-016-2132-z

PHARMACOKINETICS AND DISPOSITION

Anti-tuberculosis drug concentrations in tuberculosis patients

with and without diabetes mellitus
A K Hemanth Kumar 1 & V Chandrasekaran 1 & T Kannan 1 & A Lakshmi Murali 2 &
J Lavanya 3 & V Sudha 1 & Soumya Swaminathan 1 & Geetha Ramachandran 1

Received: 14 June 2016 / Accepted: 9 September 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract absorption/faster elimination of INH and PZA in the

Purpose The aim of the study was to compare plasma con-
centrations of rifampicin (RMP), isoniazid (INH) and
pyrazinamide (PZA) between tuberculosis (TB) patients with
and without diabetes mellitus (DM).
Methods Two-hour post-dosing concentrations of RMP, INH
and PZA were determined in adult TB patients that were stud-
ied with (n = 452) and without DM (n = 1460), treated with a
thrice-weekly regimen in India. Drug concentrations were es-
timated by HPLC.
Results The median (IQR) INH [6.6 (3.910.0) and 7.8 (4.6
11.3)] and PZA [31.0 (22.338.0) and 34.1 (24.642.7)] mi-
crogram per milliliter concentrations were significantly lower
in diabetic than non-diabetic TB patients (p < 0.001 for both
drugs). Blood glucose was negatively correlated with plasma
INH (r = 0.09, p < 0.001) and PZA (r = 0.092, p < 0.001).
Multiple linear regression analysis showed RMP, INH and
PZA concentrations were influenced by age and drug doses,
INH and PZA by DM, RMP by alcohol use and PZA by
gender and category of ATT. DM reduced INH and PZA con-
centrations by 0.8 and 3.0 g/ml, respectively.
Conclusions TB patients with DM had lower INH and
PZA concentrations. Negative correlation between blood
glucose and drug concentrations suggests delayed
* Geetha Ramachandran
geethar@nirt.res.in; geetha202@rediffmail.com
1
Department of Biochemistry and Clinical Pharmacology, National
Institute for Research in Tuberculosis, Mayor Sathyamoorthy Road,
Chetpet, Chennai 600 031, India
2
State TB Officer, Chennai, Tamil Nadu, India
3
District TB Officer, Chennai, India
presence of elevated glucose.
Keywords Tuberculosis . Anti-tuberculosis drug
concentrations . Revised National Tuberculosis Control
Programme . Diabetes mellitus
Introduction
Tuberculosis (TB) has increasingly become a problem in de-
veloping countries, and diabetes mellitus (DM) has emerged
as a growing worldwide chronic health condition, as a conse-
quence of increases in obesity, changing patterns of diet and
physical activity [14]. There is growing evidence that DM is
an important risk factor for TB and could affect disease pre-
sentation and treatment response [5]. Furthermore, TB might
induce glucose intolerance and worsen glycaemic control in
people with DM. In a setting of the increasing overlap of
populations at risk of both diseases, the combination of TB
and DM represents a worldwide health threat.
A few studies have shown that diabetic patients were more
likely to develop multidrug-resistant TB than those without
DM [6, 7]. Although the scientific mechanism by which DM
would lead to preferential acquisition of multidrug-resistant
TB is unclear, the role of sub-optimal drug concentrations
cannot be ruled out. In fact, some studies have observed lower
concentrations of rifampicin (RMP) and isoniazid (INH) in
patients with TB + DM than those with TB [8, 9].
The aim of the present study was to compare 2-h plasma
concentrations of RMP, INH and pyrazinamide (PZA) be-
tween TB patients with and without DM being treated with
thrice-weekly anti-TB regimens in India. We also identified
factors that influenced drug concentrations.

Methods
A prospective study was undertaken in adult patients that were
recruited with either pulmonary or extra pulmonary TB receiv-
ing anti-TB treatment (ATT) in the Revised National TB
Control Programme (RNTCP) treatment centres in the
Chennai Corporation during October 2013 to September 2015.
Patients were recruited from eight TB units across the city of
Chennai. Diagnosis and treatment were according to RNTCP
guidelines [10]. Patients received either category I or category II
treatment. Category I treatment consisted of a 6-month thrice-
weekly regimen with RMP, INH, PZA and ethambutol (EMB)
for 2 months, followed by RMP and INH for 4 months [10].
Category II treatment consisted of a thrice-weekly 8-month reg-
imen with streptomycin, INH, RMP, PZA and EMB for
2 months, followed by INH, RMP, PZA and EMB for 1 month
and INH, RMP and EMB for the remaining 5 months. The drug
doses were RMP 450 mg (600 mg for those 60 kg body
weight), INH 600 mg, EMB 1200 mg, PZA 1500 mg and strep-
tomycin 0.75 g. The drugs were administered as single drugs;
fixed dose combinations were not used.
Patients were eligible to take part in this study if they met
the following study criteria: (i) aged 18 years or above, (ii)
body weight not less than 30 kg, (iii) received at least 2 weeks
of ATT regularly, (iv) not very sick or moribund, (v) willing to
participate and give informed written consent and (vi) agree-
ing to come to the same DOT centre until completion of the
study. Patients with extrapulmonary forms of TB requiring
treatment with steroids were not included. None of the patients
had TB of the pancreas. The study commenced after obtaining
approval from the Institutional Ethics Committee of the
National Institute for Research in Tuberculosis (NIRT) and
the study followed the Declaration of Helsinki.
A structured questionnaire was used to elicit patient details.
Any patient with a known history of DM, with or without
random blood glucose 200 mg/dl on the study day, was con-
sidered diabetic. Information regarding the diabetic drugs tak-
en by the patients was noted where ever available. Sub-
optimal cut-off values were taken as <8 g/ml for RMP,
<3 g/ml for INH and <20 g/ml for PZA [11].
Study procedures
Patients, who were diagnosed with TB, were referred to the study
investigatorbythemedicalofficersatthe TBunits. Thepurposeof
the study and procedures were explained to those patients who
suited the study criteria. Patients who were willing to participate
were recruited after obtaining informed written consent. The
study was conducted at the respective TB units at a steady state,
after patients had received a minimum of seven doses of ATT. On
the study day, the anti-TB drugs were administered under direct
supervision and about 3 ml blood was collected at 2 h post-dosing.
Eur J Clin Pharmacol
This blood was distributed into heparinised, oxalate-fluoride,
plain and EDTA vacutainer tubes, which were used to estimate
RMP, INH and PZA concentrations, blood glucose, liver and
renal function tests and routine haematological tests, respectively.
The time of food intake by the patients was noted.
Drug estimations
Blood collected in the heparin vacutainer tube was centrifuged
immediately and plasma was separated. Ascorbic acid solution
was added to plasma to prevent oxidation of RMP. The plasma
samples were stored at -20 C until analysis. All drug estimations
wereundertakenwithina weekofsample collection.Plasma INH,
PZA and RMP concentrations were determined by high-
performance liquid chromatography (Shimadzu Corporation,
Kyoto, Japan) using validated methods. Plasma RMP was ex-
tracted using acetonitrile and analysis performed using C18 col-
umn at 254 nm. The retention time of RMP was 1.7 min [12].
Plasma INH and PZA were estimated simultaneously by extrac-
tion using para-hydrobenzaldehyde and trifluoroacetic acid.
Analysis was performed using a C8 column at 267 nm. The reten-
tion times of PZA and INH were 3 and 5.5 min, respectively [13].
The methods were highly specific with no interfering peaks at the
retention times of the drugs. The between and within run varia-
tions for all the drugs were below 10 %. The lower limits of
quantification for RMP, INH and PZA were 0.25, 0.25 and
1.25 g/ml, respectively.
Blood glucose was determined immediately in an automat-
ed chemistry analyser (Olympus AU400, Japan).
Statistical evaluation
Analysis of data was performed using SPSS, version 20.0
(IBM, USA). Data was expressed as median and inter-
quartile range. Mann-Whitney U test was performed to study
the differences in the baseline variables and plasma drug con-
centrations between the diabetic and non-diabetic TB groups
of patients. Pearsons correlation test was done to study the
correlation between drug levels and blood glucose. The chi-
squared test was used to compare proportions. The multiple
linear regression analysis by the stepwise method was per-
formed to identify factors influencing drug concentrations. A
p value <0.05 was taken as significant.
Sample size calculation
This was calculated based on the study of Babalik et al. [9],
which reported a mean (SD) PZA concentration of 23.4 (2.0)
and 25.9 (1.4) g/ml in TB patients with and without DM.
Assuming 90 % power, 95 % confidence level, true difference
Eur J Clin Pharmacol

of 2.0 g/ml and accounting for 20 % missing data, the min-
imum required sample size was 375. Since we observed the
ratio of TB + DM to TB patients to be 1:5 in a previous study
[14], the sample size was fixed to be 1875.
Results
A total of 1912 TB patients were recruited to the study (patient
details in Table 1). Among them, 452 patients (24 %) fitted the
study definition of DM. The diabetic and non-diabetic groups of
TB patients significantly differed in age, BMI, distribution of
gender, type of disease, milligram per kilogram doses of RMP,
INH and PZA and smear status. Blood glucose was significantly
higher in TB + DM patients than those with TB. Serum creati-
nine significantly differed between the two groups of patients.
Among the 452 TB + DM patients, 73 were newly diag-
nosed of DM, based on the blood glucose values estimated on
the study day. The remaining 379 patients were on diabetic
medications; of them, 145 and 234 patients respectively had

Table 1 Baseline patient details

Factors All patients TB patients DM + TB patients p value
(n = 1912) (n = 1460) (n = 452)

Age (years) 38 (2750) 34 (2546) 48 (4055) <0.001

Sex
Male 1291 (67.5 %) 959 (65.7 %) 332 (73.5 %) 0.002
Female 621 (32.5 %) 501 (34.3 %) 120 (26.5 %)
BMI (kg/sqm) 18.7 (16.421.6) 18.2 (16.021.0) 20.4 (18.023.2) <0.001
Type of TB
Pulmonary 1241 (64.9 %) 865 (59.2 %) 376 (83.2 %) <0.001
Extra pulmonary 671 (35.1 %) 595 (40.8 %) 76 (16.8 %)
Type of ATT
Category I 1659 (86.8 %) 1257 (86.1 %) 402 (88.9 %) 0.131
Category II 253 (13.2 %) 203 (13.9 %) 50 (11.1 %)
Dosing (mg/kg)
RMP 9.6 (8.710.7) 10.0 (8.811.3) 9.0 (8.310.0) <0.001
INH 12.5 (10.914.3) 13.0 (11.115.0) 11.3 (10.012.8) <0.001
PZA 31.3 (27.331.3) 32.6 (27.837.5) 28.3 (25.031.9) <0.001
Smoking
Yes 612 (32 %) 469 (32.1 %) 143 (31.6 %) 0.863
No 1300 (68 %) 991 (67.9 %) 309 (68.4 %)
Alcohol use
Yes 742 (38.8 %) 551 (37.7 %) 191 (42.3 %) 0.087
No 1170 (61.2 %) 909 (62.3 %) 261 (57.7 %)
Smear statusa
Positive 887 (60.7 %) 600 (56.7 %) 287 (71.4 %) <0.001
Negative 574 (39.3 %) 459 (43.3 %) 115 (28.6 %)
INH susceptibility patternb
Sensitive 834 (94 %) 561 (93.7 %) 273 (94.8 %) 0.131
Resistant 53 (6 %) 38 (6.3 %) 15 (5.2 %)
HIV co-infection
Negative 1881 (99 %) 1433 (98.8 %) 448 (99.6 %) 0.276
Positive 19 (1 %) 17 (1.2 %) 2 (0.4 %)
Blood glucose (mg/dl) 96.0 (84.0127.0) 91.0 (81.5103.0) 263.5 (176.0365.0) <0.001
Creatinine (mg/dl) 0.7 (0.60.9) 0.7 (0.60.9) 0.8 (0.70.9) 0.007
ALT (U/lit) 13 (1019) 13 (1019) 14 (1119) 0.085

BMI body mass index, ATT anti-TB treatment, RMP rifampicin, INH isoniazid, PZA pyrazinamide, DM diabetes
mellitus, ALT alanine transaminase
a
Sputum not collected in some patients with extra pulmonary TB
b
Drug susceptibility testing done in only culture positive specimens

blood glucose < and 200 mg/dl on the study day. Of the 379
patients who had a known history of DM, details of diabetic
medications were available in 324 patients; this mainly com-
prised of metformin alone (n = 10), sulphonyl urea alone
(n = 7), metformin and sulphonyl urea (n = 174), insulin alone
(n = 111) and insulin with oral drugs (n = 22).
The median (IQR) plasma RMP, INH and PZA concentrations
in TB patients with and without DM were 2.3 (0.65.0) and 2.3
(0.74.9), 6.6 (3.910.0) and 7.8 (4.611.3) and 31.0 (22.338.0)
and 34.1 (24.642.7) g/ml, respectively. Patients with TB + DM
had significantly lower plasma INH and PZA concentrations than
those with TB (p < 0.001 for both drugs) (Fig. 1).
There existed a significant negative correlation between
blood glucose and plasma INH (r = 0.09, p < 0.001) and
PZA (r = 0.092, p < 0.001).
The proportion of patients with 2-h RMP (<8 g/ml), INH
(<3 g/ml) and PZA (<20 g/ml) below normal in TB patients
with and without DM was 92 and 91 %, 17 and 16 % and 19
and 17 %, respectively; none of the differences were statisti-
cally significant.
Of the 889 patients who were smear positive at baseline,
smear results at 2 months were available in 795 patients.
Among them, 722 and 73 patients respectively were smear neg-
ative and positive at 2 months. The proportion of patients re-
maining smear positive at 2 months did not significantly differ
between TB and TB + DM patients (9.0 vs 9.5 %, p = 0.797).
The multiple linear regression by the stepwise method was
performed to identify the factors influencing RMP, INH and
PZA concentrations. After adjusting for each of the factors
such as age, gender, smoking, alcohol, diabetes, category of
ATT, BMI, HIV co-infection, disease type, baseline smear
status, milligram per kilogram drug dose and baseline INH
susceptibility pattern, it was observed that age and milligram
per kilogram drug doses influenced all the three drug concen-
trations. In addition, RMP concentrations were influenced by
alcohol use, INH by DM and PZA by gender, DM and
2nd Hour Drug Concentration (g/ml)
95.00
85.00
75.00
65.00
55.00
45.00
0.935 < 0.001
35.00
25.00
15.00
5.00
-5.00
TB+DM TB TB+DM
RMP
RIF INH
Fig. 1 Two-hour drug concentrations in TB patients with and without
diabetes mellitus. The central line of the box plot denotes median and the
lower and upper lines denote 25 and 75 percentiles. The vertical bars
denote minimum and maximum values. RMP rifampicin, INH isoniazid,
PZA pyrazinamide
Eur J Clin Pharmacol
category of ATT (Table 2). DM was associated with reduced
INH and PZA concentrations.
Discussion
It has been reported that DM has an adverse impact on TB
treatment outcome, reduces cure rate and enhances the risk of
relapse and emergence of drug resistance [1517]. It has also
been shown that DM is associated with slow response, and
plasma concentrations of anti-TB drugs are likely to be below
the expected therapeutic ranges among patients with TB + DM.
Plasma concentrations of RMP have also been reported to de-
cline in some [8, 9] but not all [18, 19] studies in TB + DM
patients. However, available data are inconclusive with regard to
whether DM affects serum therapeutic levels of anti-TB drugs.
The present study conducted in TB patients with and without
DM compared 2-h post-dosing concentrations of key first-line
anti-TB drugs, namely, RMP, INH and PZA. We did not ob-
serve any difference in RMP levels between patients with TB
and TB + DM. While this finding is in line with some studies
[18, 19], it disagrees with that of the other studies [8, 9]. The
reasons for the variability in these results could be related to
disease severity, nutritional status, extent of protein binding,
drug dosages, dosing schedule, pharmacogenetics or other fac-
tors. In India, ATT is thrice weekly during the entire treatment
duration and doses are not body weight based (except RMP).
This is probably one of the first report on plasma INH and
PZA concentrations being significantly lower in those with
TB + DM than those with TB. Babalik et al. had observed
2-h plasma INH levels to be lower in patients with TB + DM
than those with TB [9]. The reasons for low INH and PZA
concentrations in patients with TB + DM are more likely due
to lower milligram per kilogram doses received by TB + DM
patients, although malabsorption of drugs because of diabetic
enteropathy cannot be ruled out. It would be interesting to
examine if pharmacokinetic drug-drug interactions existed be-
< 0.001 tween INH/PZA and anti-diabetic medications. It would also
be worthwhile to understand whether transport of INH and
PZA in the body is glucose mediated, which could lead to
faster elimination of drugs from the blood. In fact, a negative
correlation between blood glucose and drug concentrations
observed in this study supports this hypothesis. Furthermore,
a study in rats has shown that the absorption of INH was
reduced by 50 % when administered with glucose [20].
Although we observed lower plasma INH and PZA con-
centrations in patients with TB + DM than those with TB, this
TB TB+DM TB
is unlikely to exert any therapeutic penalty. There was no
PZA
difference in the proportion of patients with drug concentra-
tions below the expected therapeutic range between TB and
TB + DM patient groups. Furthermore, the median INH and
PZA concentrations in both patient groups were well above
the expected concentrations. Hence, the differences observed
Eur J Clin Pharmacol
Table 2 Factors influencing the drug concentrations
RMP
Coefficient (95 % CI) p value
Age 0.019 (0.006 to 0.032) 0.005
Gender
Alcohol use 0.386 (0.751 to 0.022) 0.038
Diabetes
Category of ATT
Milligram per kilogram dose
RMP 0.209 (0.100 to 0.318) <0.001
INH 0.419 (0.293 to 0.545)
PZA
Factors such as age, gender, smoking, alcohol, diabetes, treatment category, body mass index, HIV co-infection, disease type, baseline smear status, dose
per weight and baseline INH susceptibility pattern were taken for linear regression analysis by the stepwise method
in INH and PZA levels between TB and TB + DM patients
may not be clinically significant. We chose the expected ther-
apeutic drug concentrations that have been widely followed,
though this remains a matter of debate. Our observation of
more than 90 % of diabetic and non-diabetic TB patients hav-
ing RMP below the therapeutic range is a matter of concern.
In this study, the proportion of patients being sputum smear
positive at 2 months did not significantly differ between diabetic
and non-diabetic TB patients. These findings are in support of
some studies which observed sputum clearance to be similar
between TB and TB + DM patients and that there appeared to
be no effect of DM on TB treatment outcome [21, 22]. It, how-
ever, contradicts the findings of other studies, which observed
delayed sputum conversion and high TB treatment failure rates
to be common in TB patients with DM [23], and also, DM
increased the risk of poor outcomes of TB therapy [2426].
Population pharmacokinetic modelling studies of RMP showed
that DM was strongly associated with the absorption and vol-
ume of distribution of RMP and suggested using high doses of
RMP in patients with TB and DM [27]. Drug concentrations
were, however, not examined in these studies. In a retrospective
study from Virginia, it was shown that DM was associated with
slow response to TB treatment [28]. We observed that DM
significantly influenced INH and PZA concentrations.
The study was limited by the fact that blood glucose was
estimated only on the study day. We did not perform glyco-
sylated haemoglobin which would have provided information
on the glycaemic control of diabetes. Since the study was
undertaken entirely under field/programme settings, it was
not possible to carry out more rigorous testing of their diabetic
condition. Another limitation was that the study was not con-
ducted under fasting condition. However, the time of food
intake on the study day was noted. It was observed that most
patients took their drugs within 30 to 60 min of food intake.
This was unlikely to impact the study findings.
INH PZA
Coefficient (95 % CI) p value Coefficient (95 % CI) p value
0.052 (0.028 to 0.075) <0.001 0.114 (0.058 to 0.170) <0.001
2.363 (4.036 to 0.689) 0.006
0.842 (0.028 to 0.128) 0.021 3.020 (4.756 to 1.284) <0.001
2.532 (4.525 to 0.540) 0.013
<0.001
0.536 (0.4220.650) <0.001
In conclusion, this study conducted in a fairly large number
of patients observed that 2-h plasma INH and PZA concentra-
tions were lower in patients with TB + DM than those with
TB. Though this was not found to be clinically significant, it
raises concerns over the optimal dosing of these medications.
Co-existence of DM influenced INH and PZA concentrations
after controlling for other factors. A negative correlation be-
tween blood glucose and drug concentrations is suggestive of
delayed absorption or faster elimination of INH and PZA in
the presence of higher glycaemia.
Acknowledgments The authors thank the patients who took part in the
study, staff of the clinical biochemistry laboratory for blood glucose esti-
mations, data entry operators, field investigators engaged in patient re-
cruitment, staff at the RNTCP treatment centres in the Chennai
Corporation and financial support by the United States Agency for
International Development through World Health Organisation,
SEARO, New Delhi, India.
Authors contributions GR designed the study and developed the pro-
tocol, AKH and GR conducted the study, GR obtained regulatory ap-
provals, AKH supervised drug estimations, VS carried out drug estima-
tions by HPLC, LM and JL recruited study patients, VC and TK per-
formed statistical analysis, GR drafted the manuscript and SS provided
critical inputs and overall guidance.
Compliance with ethical standards The study commenced after
obtaining approval from the Institutional Ethics Committee of the
National Institute for Research in Tuberculosis (NIRT).
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval All procedures performed in studies involving hu-
man participants were in accordance with the ethical standards of the
institutional and/or national research committee and with the 1964
Helsinki Declaration and its later amendments or comparable ethical
standards.

References
1. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG,
Willett WC (2001) Diet, lifestyle, and the risk of type 2 diabetes
mellitus in women. New Engl J Med 345:790797
2. Van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB (2002)
Dietary patterns and risk for type 2 diabetes mellitus in US men.
Ann Intern Med 136:201209
3. Popkin BM (2008) Will Chinas nutrition transition overwhelm in
health care system and slow economic growth? Health Aff
(Milwood) 27:10641076
4. Mozaffarian D, Kamineni A, Carnethon M, Djousse L, Mukamal
KJ, Siscovick D (2009) Lifestyle risk factors and new-onset diabe-
tes mellitus in older adults: the cardiovascular health study. Arch
Intern Med 169:798807
5. Dooley KE, Chaisson RE (2009) Tuberculosis and diabetes
mellitus: convergence of two epidemics. Lancet Infect Dis 9:737
746
6. Bashar M, Alcabes P, Rom WN, Condos R (2001) Increased inci-
dence of multidrug-resistant tuberculosis in diabetic patients on the
Bellevue Chest Service, 1987 to 1997. Chest 120:15141519
7. Fishet-Hosch SP, Whitney E, McCormick JB, Crespo G, Smith B,
Rahbar MH, Restrepo BI (2008) Type 2 diabetes and multidrug-
resistant tuberculosis. Scand J Infect Dis 40:888893
8. Nijland HMJ, Ruslami R, Stalenhost JE, Alisjahbana B, Nelwan
RH, van der Ven AJ, Danusantoso H, Aarnoutse RE, van Crevel R
(2006) Exposure to rifampicin is strongly reduced in patients with
tuberculosis and type 2 diabetes. Clin Infect Dis 43:848854
9. Babalik A, Ulus IH, Bakirci N, Kuyuca T, Arpag H, Dagyildizi L,
Capaner E (2013) Plasma concentrations of isoniazid and rifampin
are decreased in adult pulmonary tuberculosis patients with diabetes
mellitus. Antimicrob Agents Chemother:57405742
10. Revised National TB Control Programme, Annual status report
(2011) Central TB Division, Government of India. TB India. 98
101
11. Abdullah A, Peloquin CA (2014) Therapeutic drug monitoring in
the treatment of tuberculosis: an update. Drugs 74:839854
12. Hemanth Kumar AK, Immanuel C, Ramachandran G, Chelvi KS,
Lalitha V, Prema G (2004) A validated high performance liquid
chromatography method for the determination of rifampicin and
desacetyl rifampicin in plasma and urine. Indian J Pharmacol 36:
231233
13. Hemanth Kumar AK, Sudha V, Ramachandran G (2012) Simple
and rapid liquid chromatography method for simultaneous determi-
nation of isoniazid and pyrazinamide in plasma. SAARC J TB
Lung diseases & HIV/AIDS 9:1318
14. Hemanth Kumar AK, Kannan T, Chandrasekaran V, Sudha V,
Vijayakumar A, Ramesh K, Lavanya J, Swaminathan S,
Ramachandran G (2016) Pharmacokinetics of thrice weekly rifam-
picin, isoniazid and pyrazinamide in adult tuberculosis patients in
India. Int J Tuberc Lung Dis 20(9):12361241
15. Singla R, Khan N, Al-Sharif N, Al-Sayegh MO, Shaikh MA,
Osman MM (2006) Influence of diabetes on manifestations and
treatment outcome of pulmonary TB patients. Int J Tuberc Lung
Dis 10:7479
Eur J Clin Pharmacol
16. Wang CS, Yang HC, Chen HC, Chuang SH, Chong IW, Hwang JJ,
Huang MS (2009) Impact of type 2 diabetes on manifestations and
treatment outcome of pulmonary tuberculosis. Epid Infect 137:
203210
17. Chang JT, Dou HY, Yen CL, Wu YH, Huang RM, Lin HJ, Su IJ,
Shieh CC (2011) Effect of type 2 diabetes mellitus on the clinical
severity and treatment outcome in patients with pulmonary tuber-
culosis: a potential role in the emergence of multi-drug resistance. J
Formos Med Assoc 110:372381
18. Ruslami R, Nijland HMJ, Adhiarta IGN, Kariadi HKS, Alisjahbana
B, Aarnoutse RE, van Crevel R (2010) Pharmacokinetics of antitu-
berculosis drugs in pulmonary tuberculosis patients with type 2
diabetes. Antimicrob Agents Chemother 54:10681074
19. Requena-Mendez A, Davies G, Ardrey A, Jave O, Lopez-Romero
SL, Ward SA, Moore DA (2012) Pharmacokinetics of rifampicin in
Peruvian tuberculosis patients with and without comorbid diabetes
or HIV. Antimicrob Agents Chemother 6:23572363
20. Matuski Y, Katakuse Y, Matsuura H, Kiwada H, Goromaru T
(1991) Effects of glucose and ascorbic acid on absorption and first
pass metabolism of isoniazid in rats. Chem Pharmaceut Bull
(Tokyo) 39:445448
21. Banu Rekha VV, Balasubramaninan R, Swaminathan S,
Ramachandran R, Rahman F, Sundaram V, Thyagarajan K,
Selvakumar N, Adhilakshmi AR, Iliyas S, Narayanan PR (2007)
Sputum conversion at the end of intensive phase of category-I
regimen in the treatment of pulmonary tuberculosis patients with
diabetes mellitus or HIV infection: an analysis of risk factors.
Indian J Med Res 126:452458
22. Balasubramanian R, Ramanathan U, Thyagarajan K,
Ramachandran R, Rajaram K, Bhaskar D, Shantharam Hariharan
RS, Narayanan PR (2007) Evaluation of an intermittent six-month
regimen in new pulmonary tuberculosis patients with diabetes
mellitus. Indian J Tub 54:168176
23. Viswanathan V, Vigneswari A, Selvan K, Satyavani K, Rajeswari
R, Kapur A (2014) Effect of diabetes on treatment outcome of
smear-positive pulmonary tuberculosisa report from South
India. J Diab Complic 28:162165
24. Alisjahbana B, Sahiratmadja E, Nelwan EJ, Purwa AM, Ahmad Y,
Ottenhoff TH, Nelwan RH, Parwati I, van der Meer JW, van Crevel
R (2007) The effect of type 2 diabetes mellitus on the presentation
and treatment response of pulmonary tuberculosis. Clin Infect Dis
45:428435
25. Dooley KE, Tang T, Golub JE, Dorman SE, Cronin W (2009)
Impact of diabetes mellitus on treatment outcomes of patients with
active tuberculosis. AmJTrop Med Hyg 80:634639
26. Zhang Q, Xiao H, Sugawara I (2009) Tuberculosis complicated by
diabetes mellitus at Shanghai Pulmonary Hospital, China. Jap J
Infect Dis 62:390391
27. Chang MJ, Chae J, Yun HY, Lee JI, Choi HD, Kim J, Park JS, Cho
YJ, Yoon HI, Lee CT, Shin WG, Lee JH (2015) Effects of type 2
diabetes mellitus on the population pharmacokinetics of rifampicin
in tuberculosis patients. Tuberculosis 95:5459
28. Heysell SK, Moore JL, Keller SJ, Houpt ER (2010) Therapeutic
drug monitoring for slow response to tuberculosis treatment in a
state control program, Virginia, USA. Emerg Infect Dis 16:1546
1553