Measurement of Anti-TB Drugs in Lung Tissue From Patients Having Surgery to Treat Tuberculosis

It takes 6 to 24 months of intensive combination therapy to cure tuberculosis (TB) with
antibiotics that have proven activity in vitro. In contrast, many pulmonary infectious
diseases can be cured following single drug treatment with similar drugs for only one to a
few weeks. We hypothesize that the unusual complexity of TB lesions and the degree of
sequestration of TB bacilli within these lesions may limit access of the drugs to their site
of action, leading to treatment failure, long treatment duration and the emergence of drug
resistance. To test the hypothesis that drug maldistribution into lesions impacts on
treatment duration and failure, we propose to examine the lesion-specific penetration
properties of 5 standard anti-TB drugs in the lungs of subjects selected for lung surgery.
The study is designed to understand what lesion types are the most difficult to penetrate.
This aspect of TB drug pharmacokinetics has been largely neglected so far, probably owing to
the lack of adequate technology and the limited availability of human TB lesion samples.
Fifteen patients who elect lung resection surgery will be asked to participate in the study.
Consented subjects will receive 4-5 first and second line anti-TB drugs concomitantly at 1
of 5 pre-determined times prior to surgery. At the time of resection, drug levels will be
measured in plasma, in uninvolved lung tissue and in lesions using standard analytical
methods as well as imaging Mass Spectrometry (MS) where drug concentration gradients can be
visualized across tissue sections. The major aim of this study is to determine actual
concentrations and permeability coefficients of the 5 study drugs in various lesion types
contained within subjects surgically removed lung tissue. Data analysis will also provide
the relative exposure of each drug in plasma versus lung tissue and lesion. If conclusive,
the results may be taken into consideration when selecting drug doses and dosing regimens.
Additionally, images generated by standard of care (SOC) High Resolution Computed Tomography
(HRCT), and Dynamic MRI for each subject will provide information regarding lesion structure
and anatomy, lesional blood flow and microvascular function. Lesion-specific correlations
will be established between CT radiology and drug pharmacokinetic (PK) to identify which
histopathologic lesion types may be particularly difficult to sterilize and to evaluate the
potential impact of drug penetration on treatment outcome. The long term goal of this study
is to identify the factors behind poor lesion penetration, so that new agents can be
optimized with better penetration properties to target harder-to-sterilize lesion' types.

- INCLUSION CRITERIA:

1. Males and females age 20 and above

2. Selected for lung resection due to anti-tuberculous treatment failure, multidrug
resistant disease, or other reason determined by the treating physician

3. Radiographic evidence of tuberculous disease of the lung(s)

4. If already on an aminoglycoside, ability and willingness to substitute this
aminoglycoside with KM for the one study dose

5. Willingness to receive MRI scan and marker and Gadolinium injection

6. Willingness to have samples stored

7. Ability and willingness to give written or oral informed consent

EXCLUSION CRITERIA:

1. Subjects less than 20 years of age

2. Women of childbearing potential who are pregnant, breast feeding, or unwilling to
avoid pregnancy (i.e., the use of appropriate contraception including oral and
subcutaneous implantable hormonal contraceptives, condoms, diaphragm, intrauterine
device (IUD), or abstinence from sexual intercourse) [Note: Prospective female
participants of childbearing potential must have negative pregnancy test (urine)
within 48 hours prior to study entry.]

3. Allergy or hypersensitivity to any of the 5 study drugs, any aminoglycoside, or
rifamycin (those allergic to fluoroquinolones will not receive MXF).

4. Those with severe gout

5. Severe claustrophobia or Gadolinium hypersensitivity (tbc)

6. Renal, hepatic, auditory and/or vestibular impairment.

1. Serum creatinine greater than 2.0 mg/dL (renal)

2. Aspartate aminotransferase (AST or SGOT) greater than 100 IU/L (LFTs)

3. Alanine aminotransferase (ALT or SGPT) greater than 100 IU/L (LFTs)

4. Total bilirubin greater than 2.0 mg/dL (LFTs)

7. The use of any of Rifampicin (RIF), Rifapentine or Rifabutin within 30 days prior to
the study

8. HIV infection, determined by a positive HIV test performed with the past 6 months

9. The use of any of the following drugs within 30 days prior to study:

1. Systemic cancer chemotherapy

2. Systemic corticosteroids (oral or IV only) with the following

exceptions (i.e.the following are NOT exclusion criteria): intranasal, topical,
and inhaled corticosteroids, a short course (10 days or less) of corticosteroids
for a non-chronic condition completed at least 2 weeks prior to enrollment in
this study

3. Systemic IND agents other than Linezolid

4. Antiretroviral medications

5. Growth factors

10. The need for ongoing therapy with warfarin, phenytoin, lithium cholestrymine,
levodopa, cimetidine, disulfiram, ergot derivatives, fosphenytoin, carbamazepine,
cyclosporine, tacrolimus, sirolimus, amiodarone or Phenobarbital (If a potential
subject is on one of these medications but it is being stopped per standard of care,
to be eligible for the study the drug must be stopped at least one day prior to
receiving study drug. A longer washout period is not necessary.) The only exception
to this is amiodarone; because of amiodarone s long half-life and potential for QT
prolongation, it should be stopped at least 60 days prior to receiving study drugs.