Therapeutic drug monitoring was performed on patients with slow response to tuberculosis treatment. The study found that most patients had lower than expected drug levels of isoniazid and rifampin at peak serum concentration. Diabetes was a risk factor for low rifampin levels. Dose adjustments based on drug monitoring led to expected drug levels in the majority of patients and shortened treatment duration. The study supports the role of therapeutic drug monitoring, especially for rifampin, in managing slow response to tuberculosis treatment.

1. Therapeutic Drug Monitoring for Slow
Response to Tuberculosis Treatment in a State
Control Program, Virginia, USA
Presented by
Nagi AbdallaCenters for disease prevention and control

2. CONTENTS
• Introduction
– Abstract
– About Tuberculosis
– About TDM
– Aims
• Methods
– Patients
– TDM
– Data analysis
• Results
– Initial C2hr levels
– Risk Factors for Low Isoniazid or Rifampin Levels
– Follow-up C2hr Levels after Dose Adjustment
– Treatment Outcomes
• Discussion-Conclusion
• Summary

3. INTRODUCTION

4. Abstract
• Therapeutic drug monitoring may be useful in
tuberculosis management, but programmatic
implementation is understudied.
• Type of study: retrospective cohort study
• Objective:
– determine prevalence of lower than expected levels of
Anti-Tb drugs measured at time of estimated peak
serum concentration
– Effect of debilitating diseases (DM) on drug response
– Effect of dose adjustment

5. About Tuberculosis
• 1.4 million deaths occurred in 2008 alone..
• delayed diagnosis and ineffective or in-complete treatment..
• With appropriate therapy; cure rate exceeds 95%
• Effect of slow response:
– prolonged infection
– extended treatment duration
– acquired drug resistance
– recurrence of TB after treatment.
• Causes of slow response:
– Malabsorption
– inaccurate dosing
– altered metabolism
– drug–drug interactions

6. About TDM
• A useful tool to uncover the causes of slow response
• Still considered optional in the TB management guide
line and a few TB control programs has access to TDM,
so best implementation methods are still to be studied
• other issues:
– Variation of definition of slow response
– Proper selection of drugs for TDM varies
– Still difficult to implement TDM in the general population
• Benefits:
– Proper monitoring in patients with other debilitating
diseases
– Application in early course of slow response patients may
prevent further complications and may shortens treatment
duration.

7. • Identification of slow response patients:
>30 days from the start of treatment the patient has
>2 of the following findings:
– sputum smear positive for acid-fast bacilli
– no improvement in TB-specific symptoms including:
• fever, cough, weight loss, and/or night sweats;
– no improvement in chest radiograph lesions previously
identified as consistent with TB.

8. Aim of this study
• Perform a retrospective cohort study among patients
slow to respond to pulmonary TB treatment to
determine the prevalence of lower than expected levels
of isoniazid, rifampin, ethambutol, and pyrazinamide
measured at the time of estimated peak serum
concentration (Cmax)
• Secondary objectives:
– investigation of risk factors for levels below the expected
range
– evaluation of the mean change and likelihood of achieving a
level within the expected range after dose adjustment
– comparison of outcomes between persons with slow
responses with those with low and expected levels

9. METHODS

10. Patients
• Selection:
– All patients who were >18 years of age
– had confirmed Mycobacterium tuberculosis cultures
– started TB therapy treated for pulmonary TB and extra-
pulmonary TB and who began a regimen of iso-niazid,
rifampin, ethambutol, and pyrazinamide.
• Exclusions of this study:
– resistance to ≥1 first-line medication.
– Patients were also excluded if they had TDM performed
for reasons other than slow response.
• Full medical history and information were collected
from the patients

11. TDM
• daily dose of TB medications in the morning while
fasting and then observed for 2 hours (fasting)
• At 2 hours after medication administration, venous
blood was collected and serum was separated before
transport on dry ice to the regional referral laboratory
• (C2hr) were used to estimated (Cmax) and were
determined by using:
– HPLC (for isoniazid and rifampin)
– GC-MS (for ethambutol and pyrazinamide).
• Expected C2hr ranges were provided and were consistent
with published normal values

12. Data Analysis
• Demographic and clinical characteristics were com-
pared with χ2 statistic or, for nonparametric data,
the Mann-Whitney U test.
• Risk factors were determined using Bivariate and
multivariate logistic regression analyses
• mean change in C2hr levels following dose
adjustment was determined using Paired Student t
tests.
• Daily doses were calculated for each drug
• Data were analyzed with SPSS 17 software

13. RESULTS

14. • 311 patients were included in the study, of whom
42 (14%) met criteria for slow response
• Of the 23 patients with initial smear-positive
sputum specimens, 17 (74%) had specimens that
remained smear positive
• The only significant predictor of slow response was
diabetes

16. Initial C2hr levels
26
39
42
20

17. Risk Factors for Low Isoniazid or Rifampin Levels

19. • small sample size precluded meaningful analysis of
risk factors for low ethambutol levels.
• Patients with diabetes were at significantly
increased risk of having a low rifampin level
• Patients who received isoniazid biweekly were less
likely to have low isoniazid levels than those who
received isoniazid daily, but this association was not
statistically significant in multivariate analysis
Other issues

20. Follow-up C2hr Levels after Dose Adjustment
• 18 patients with rifampin below expected range 
all increased from the initial to the follow-up level
– 16 (89%) had levels in the expected range
• 14 patients with daily-dosed INH below expected
range  increased levels in 12 patients
– 4 had levels in the expected range
• 4 (29%) patients had follow-up TDM for biweekly-
dosed isoniazid levels below the expected range 
all had increased levels

22. • Rifampin correction to the expected range was
more likely following the first dose adjustment than
were daily-dosed isoniazid levels below the
expected range (p = 0.01).
• There was no significant difference in the likelihood
of correction to the expected range between daily
and biweekly dosed isoniazid.
• No follow-up levels of ethambutol or pyrazinamide
were reported.
• There were no reported medication-related adverse
events following dose increase.

23. Treatment Outcomes
• 32 patients (76%) had complete outcomes
• 10 continued receiving treatment
• 3 died:
1. INH, rifampin, ehambutol, pyrazinamide (levels within
expected range)
2. INH, rifampin, ehambutol (levels within expected range)
3. INH, rifampin, ehambutol (levels below expected range)
• 2 moved out of the state (incomplete follow up)
• Median therapy completion time was 45 weeks
• No report for relapse over median of 14.5 months
• No resistance incidences while on treatment

24. DISCUSSION & CONCLUSION

25. Major findings
• In patients treated for Pulmonary TB and had slow
response  most of them had C2h levels of INH,
rifampin (and ethambutol in many) below the expect
range
• TDM strategy is useful for:
– Detecting low drug concentration levels
– Dose adjustment.
• Treatment duration in patients with lower than
expected levels of rifampin was shorter by 2 month
than in patients with normal levels (specific correlation
is unkown)  may benefit in treatment cost

26. • About 90% of patients with lower rifampin levels
achieved the target level after the first adjusted
dose  bactericidal activity↑
Rifampin could be the drug of choice in early TDM for
patients with failing TB therapy
• DM was significantly associated with slow response
anti-TB  ↓C2h
– (↓rifampin exposure, absorption??)
• Other factors may include: drug-drug interaction

27. Author’s recommendations
• Further investigation for TDM applicability in other
clinical settings and centers.
• Include other factors affecting PK in considerations:
– Pt weight-time of TDM-Livers cirrhosis- chronic kidney
disease…
• Consider other study limitations…
– (blood sampling time-C2h-C6h…etc)
– Inclusion of patients with normal response in TDM
• The big challenge: TDM cost vs. giving high dose for
pt. at risk

28. summary
• TDM for slow responding TB patients found in most
of them C2h below expected level of Rifampin and
INH (and in some ethambutol)
• TDM performed after dose adjustment found
expected levels suggesting a strong clinical
indication for TDM
• Rifampin could be a target drug for programmatic
TDM intervention
• Further prospective studies are need to evaluate
the benefit of TDM for Rifampin in various group of
TB slow responding patients.

29. Thank you for listening!
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