TUBERCULOSIS 0272-5231/97 $0.00 + .

20

USING THERAPEUTIC DRUG

MONITORING TO DOSE THE
ANTIMYCOBACTERIAL DRUGS
Charles A. Peloquin, PharmD

Therapeutic drug monitoring (TDM) is the
process of adjusting drug doses based on se-
rum concentration data? TDM, also known
as applied pharmacokinetics, allows the clinician
to quantify the relationships among drug
doses, serum concentrations, and therapeutic
responses in patients. It also allows the clini-
cian to avoid concentration-related toxicities.
The use of TDM with antimycobacterial
drugs allows for better control of treatment,
particularly in patients with drug-resistant
mycobacterial infections and in those with
comorbid conditions, such as end-stage renal
disease or acquired immunodeficiency syn-
drome (AIDS).This article focuses on the clin-
ical aspects of TDM. A companion article
published in Clinics in Laboratory M e d i ~ i n e ' ~
provides additional details regarding the
technical aspects of providing a TDM service.
By necessity, portions of these two manu-
scripts are similar.
ANTIMYCOBACTERIAL DRUGS
Isoniazid (INH), rifampin, pyrazinamide,
ethionamide, streptomycin, para-aminosali-
cylic acid (PAS), cycloserine, ethambutol, and
Parts of this article have previously appeared in the
Sept. 1996 (163),Clinics in Laboratory Medicine.
capreomycin are the only drugs approved by
the US Food and Drug Administration (FDA)
for the treatment of tuberculosis.16Amikacin,
kanamycin, ciprofloxacin, ofloxacin, and clo-
fazimine are other drugs that have been used
successfully for tuberculosis but lack FDA ap-
proval for that use. Rifabutin, clarithromycin,
and azithromycin appear to be better suited
for Mycobacterium avium complex (MAC) in-
fection, based on current information. As new
macrolides, quinolones, and rifamycins are
developed, their potential use for the treat-
ment of mycobacterial infections should be
investigated.
Published studies on tuberculosis drugs are
not evenly distributed across the list of avail-
able agents. Most were either pharmacokinet-
ics studies in healthy volunteers or treatment
studies in patients with drug-susceptible tu-
berculosis. Few studies were conducted with
the second-line tuberculosis drugs against
multidrug-resistant tuberculosis (MDR-TB).
As a result, there are significant gaps in our
knowledge, and the optimal use of TDM for
mycobacterial infections is currently under
study. Serum concentrations provide ob-
jective information regarding how selected
doses are meeting therapeutic goals. This
allows the clinician to make informed deci-
sions when individualizing drug doses. Bear

From the Infectious Disease Pharmacokinetics Laboratory, National Jewish Center for Immunology and Respiratory
Medicine; and the Department of Pharmacy and Medicine, University of Colorado Health Sciences Center, Denver,
Co1orado

CLINICS IN CHEST MEDICINE

VOLUME 18 * NUMBER 1 * MARCH 1997 79

80 PELOQUIN

in mind that drug therapy is the only aspect
of a mycobacterial infection within our con-
trol. Everything else is predetermined, includ-
ing the patient's demographic information,
his or her extent and duration of disease,
the causative organism, its drug-susceptibility
pattern, and so forth. Because infections
caused by MDR-TB or MAC are so difficult
to cure, the better we are able to control drug
therapy, the better our patients should do.8
PHARMACOKINETIC PARAMETERS
The most frequently described pharmacoki-
netic parameters are the maximum serum
concentration (C,,,), the time at which it oc-
curs (T,,,), and the speed with which the
drug leaves the body (apparent elimination
half-life). For most orally administered tuber-
culosis drugs, T, occurs around 2 hours
after the dose, so that generally is when we
collect "peak" serum concentrations. Addi-
tional parameters include the dispersion of
the drug in the body (volume of distribution)
and the removal of the drug from the body
(clearance). Various methods calculate those
parameters from serum-concentration-versus-
time data. A graph display of the serum-
concentration-versus-time data reveals a
curve, and an area under that curve (AUC)
can be calculated (Fig. l).17 Parameter esti-
mates summarize the movement of drugs
through the body, allowing clinicians to pre-
dict, measure, adjust, and control drug ther-
apy (Tables 1, 2).19
PHARMACODYNAMIC PARAMETERS
The interaction of a drug with a microor-
ganism can be described by the minimal in-
hibitory concentration (MIC), minimal bacte-
ricidal concentration (MBC), and the kinetics
of inhibition or killing (time-kill curve^).^ One
can study these in vitro (agar or broth), in
macrophage models, and, potentially, in ani-
mal models or in humans. Pharmacodynam-
ics ("drug action") relates the achievable se-
rum or tissue concentrations of a drug to the
amount needed to inhibit or kill the organism
(MIC or MBC). Pharmacodynamic parame-
ters include the C,,, : MIC ratio, the time
above the MIC, and the AUC above the MIC
(see Fig. 1).
Verbist and have described the
mechanisms of action of the antimycobacte-
rial drugs. Although our knowledge is incom-
plete, it does form a basis for understanding
the pharmacodynamics of the drugs. In vitro
studies using bactericidal agents against aero-
bic bacteria have suggested optimal dosing
strategies. For cell-wall-active agents (penicil-
lins, cephalosporins), the duration that con-
centrations remain above the MIC (time >
MIC) should be maximized.'l For agents that
attack intracellular targets (aminoglycosides,
quinolones), the C,,, : MIC ratio or, perhaps,

E
a
2.0

1.5
In
.r

I
a-

I \
C max

I
- - -..,,.
MIL
1
x
v
z
0
1.0

E
zw
y 0.5

8
0
0 4 8 12 16 20 24
TIME (hr)
Figure 1. Hypothetical serum concentration versus time cutve, displaying the maximum serum
concentration (Cm& the area under the curve (AUC), and the relationship of these parameters to
the minimal inhibitory concentration (MIC). CONC = concentration. (From Peloquin CA: Antimicro-
bial therapy. In Bittar EE (ed): Principles of Medical Biology. Greenwich, CT, Jai Press Inc.,
in press.)
Table 1. PHARMACOKINETIC PARAMETERS OF THE ANTIMYCOBACTERIAL DRUGS
~~

Volume of
Serum Cmax Serum Tmex Normal Serum CSF Distribution
Drug Name (CLs/mL) (hours) Half-life Penetration (%) Protein Binding (ml)
Amikacin (AK) 35-45 0.5-1.5(IM) 2-4h 20-40 est. 040% est. 0.2-0.3
65-80* End infusion (IV)
Aminosalicylic acid (PAS) 20-60 4-8 (granules) 0.5-2 h 10-50 50-73% (15% in 0.8-3.8 est.
(granules) some reports)
Azithromycin (AZI) 0.3-0.5 2 1-5 days Not known 50% 25-1 00
Capreomycin (CM) 35-45 1-2 (IM) 2-4h 20-40 est. Not known 0.2-0.3
End infusion (IV) Est. low
Ciprofloxacin (CIP) 4-6 targeted 1-2 3-5h 4-1 0 20-40Yo 2-3
Clarithromycin (CUR) 2-7 2-3 3-5 h saturable elim. Not known 72% 2.5-4
Clofazimine (CFZ) 0.5-2 2-1 2 Biphasic: Not known Not known Not known
a: 10 days Est. poor Est. very large
b: several weeks
Cycloserine (CSN) 20-35 2-4 10-12 h 50-80 Not known 0.2-0.35est.
0% est.
Ethambutol (EMB) 2-6 2-3 Biphasic: 5-65est. &30% est. 1.6-3.8
a: 4-5 h Variable, also binds RBC
b: 10-15 inflammation
Ethionamide (ETA) 1 -5 1-2.5 2-4 h 20-1 00 est. Not known 30% est. 1.5-4est.
lsoniazid (INH) 3-6 0.75-2 Polymorphic: 20-1 00 10 est. estimated 0.6-1 est.
fast: 1.5-2 h
slow: 3.5-4h
Kanamycin (KM) 35-45 0.5-1.5(IM) 2-4 h 20-40 est. 0 4 0 % est. 0.2-0.3
65-80 End infusion (IV)
Ofloxacin (OFLOX) 6-12 targeted 1 -2 5-8 h 30-90 8-30% 1-2.5
Pyrazinamide (PZA) 20-60 1-2 9-11 h 50-1 00 Not known 0.6-0.7est
Rifabutin (RBN) 0.3-0.9 2-4 20-25 h (steady state) 30-70 70-90 8-9
Rifampin (RIF) 8-24 2 2-4 h 5-20 est. 60-80 est. 0.6-1 est.
Variable,
inflammation
Streptomycin (SM) 35-45 0.5-1.5(IM) 2-4 h 20-40 est. 20-57 est. 0.2-0.3
65-80* End infusion (IV)
Thiacetazone (Tbl) 0.9-2.4 2-4 12-20 h Not known Not known 1-2 est.

= High-dose protocol dosing.

,C = Maximum serum concentration; T, = the time at which ,C occurs; CSF = cerebrospinal fluid; est. = estimated; IM = intramuscularly; IV = intravenously.
Adapted from Peloquin CA, lseman MD: Antimycobacterial Agents. In Root RK (ed): Clinical Infectious Diseases: A Practical Approach. Oxford: Oxford University Press (in press); with permission
Qo
N

Table 2. PHARMACOKINETIC PARAMETERS OF THE ANTIMYCOBACTERIAL DRUGS

Renal Hepatic Active Metabolite
Drug Name Excretion (“A) Clearance (%) Metabolite Excretion Dose Renal Failure Dose Hepatic dis.
Amikacin (AK) >95 0 None None 12-15 mg/kg 3 x weekly Unchanged
Aminosalicylic acid 10 90 None Renal Unknown; avoid if poss. Not known
(PAS)
Azithromycin (MI) <10 >90 Nonrenal No Not known Unchanged Unchanged
Capreomycin (CM) >95 0 None None 12-15 rng/kg 3 x weekly Unchanged
Ciprofloxacin (CIP) 50-70 30-50 None Primarily renal Unchanged unless severe Unchanged unless
severe
Clarithromycin 20 80 Saturable 14-OH Primarily renal Unchanged Unchanged
(CLAR) clarithromycin
Clofazimine (CFZ) <1 Yes None Fecal Unchanged Unchanged
(% unknown)
Cycloserine (CSN) 70-1 00 Not known Not known Not known 25C-500 rng 3 x weekly Unchanged
Ethambutol (EMB) 80 20 None None 15-25 mg/kg 3 x weekly Unchanged
Ethionamide (ETA) 5 95 Yes: sulfoxide Nonrenal Unchanged Not known
lsoniazid (INH) Polymorphic: Polymorphic: None Renal (50-60%) Unchanged or reduced to Unchanged in most
Fast: 10 Fast: 90 & nonrenal every other day patients
Slow: 30 Slow: 70
Kanamycin (KM) >95 0 None None 12-15 mglkg 3 x weekly Unchanged
Ofloxacin (OFLOX) >90 <lo Not significant Primarily renal -800 mg 3 x weekly Unchanged
Pyrazinarnide (PZA) 5 95 None Renal 15-30 mg/kg 3 x weekly Not known
Rifabutin (RBN) 10 90 Yes: 25-0- Renal (35%) Unchanged in most patients Unchanged in most
deacetyl & nonrenal patients
Rifampin (RIF) 10 90 Yes: deacetyl Renal (20%) Unchanged in most patients Unchanged in most
& nonrenal patients
Streptomycin (SM) >95 0 None None 12-1 5 mg/kg 3 x weekly Unchanged
Thiacetazone (Tbl) <20 280 Not known Not known Not known; avoid if possible Not known; avoid if
possible

Adapted from Peloquin CA, lseman MD: Antirnycobacterial agents. In Root RK (ed): Clinical Infectious Diseases: A Practical Approach. Oxford, Oxford University Press (in press); with permission.
 USING THERAPEUTIC DRUG MONITORING TO DOSE THE ANTIMYCOBACTERIAL DRUGS
the portion of the AUC above the MIC should
be maximized.”
If these relationships hold true for the anti-
mycobacterial drugs, then cell-wall-active
agents like INH, ethionamide, cycloserine,
and ethambutol should be given in a way
that maintains their concentrations above the
MIC. The dosing of intracellular poisons like
rifampin, amikacin, kanamycin, ciprofloxacin,
ofloxacin, and capreomycin may be improved
by giving large doses intermittently. If these
relationships are tested prospectively, we can
refine our dosing strategies.
When selecting a drug’s dose and frequency,
one must consider concentration-related tox-
icities. High doses of rifampin given intermit-
tently, for instance, are likely to produce a
flu-like syndrome? Furthermore, bacterio-
static agents (possibly clofazimine, PAS, and
pyrazinamide) may require prolonged time
> MIC. Finally, not all pharmacodynamically
optimized regimens will be practical in the
clinical setting. It may be optimal to give
ethionamide six times daily, for example, but
that probably cannot be done with most pa-
tients. Compromises in the treatment plan
therefore may be necessary to meld ”optimal
doses” with ”practical doses.”
WHY TUBERCULOSIS DRUGS
SHOULD BE MONITORED
At the National Jewish Center for Immu-
nology and Respiratory Medicine (NJC), we
have been using TDM for patients with myco-
bacterial infections since 1989. The impetus
for developing this service was the repeated
observation by our clinicians that certain pa-
tients failed to respond to directly observed
therapy (DOT) that theoretically should have
been effective. These patients received drugs
selected on the basis of extensive in vitro
susceptibility testing, the patients were well
fed and well rested, and their other medical
conditions were managed properly. It there-
fore was not clear why these patients were
not responding to therapy. The only aspect of
their care that was not directly controlled was
the delivery of drugs into their systemic cir-
culation.
The only assays available at the time were
bioassays that required the discontinuation of
all other antibiotic agents for at least 24 hours
to measure the drug of interest. This made it
very difficult to collect blood samples for
assay. The Infectious Diseases Pharmacoki-
83
netics Laboratory therefore was established
to provide TDM and pharmacologic research
services to our patients with mycobacterial
infections. Over time, these services have
been made available to clinicians across the
United States and, on occasion, to clinicians
around the world.
We know that the standard doses of INH,
rifampin, and pyrazinamide work well for
most patients with drug-susceptible tubercu-
losis. Such patients generally absorb the
drugs normally, producing good C,,, :MIC
ratios and prolonged time > MIC, particu-
larly for INH and rifampin. Most such pa-
tients therefore will not require TDM as long
as they respond to therapy in the predicted
manner. Should they remain acid-fast bacilli-
smear positive after 1-2 months of DOT, TDM
should be considered to rule out malabsorp-
tion of the tuberculosis drugs.
Under the best of circumstances, patients
with MDR-TB and MAC receive drugs with
poor C,,, : MIC ratios and time > MIC, even
with complete absorption. We simply do not
have adequately potent drugs to predictably
cure these infections. If these patients fail to
absorb the doses normally, the C, : MIC ra-
tios will be less than 1, which, in vitro, would
be subinhibitory. Because patients with gas-
trointestinal diseases or AIDS have difficulty
absorbing antimycobacterial agents, they are
good candidates for TDM.’9-21Alternatively,
patients with renal or hepatic disease may
have difficulty eliminating antimycobacterial
drugs from the body.ls Standard doses may
produce toxicity in such patients, a problem
that can be avoided by using TDM.
PUBLISHED EXPERIENCE
MONITORING THE
TUBERCULOSIS DRUGS
Recent reports suggest that the achieve-
ment of the proposed target serum concentra-
tion is important for clinical efficacy.’,6,9,13, *w3
In 1992, we reported a case of a patient with
AIDS and tuberculosis who apparently had
adequately responded to antituberculosis
therapy.’ During the course of his treatment,
however, and despite documented compli-
ance with the regimen, the patient experi-
enced a clinical and bacteriologic relapse. The
susceptibility pattern of his tuberculosis iso-
late had not changed. He was subsequently
shown to have antituberculosis drug serum
concentrations well below the proposed effec-
84 PELOQUIN
tive ranges. Adjustment of the doses resulted
in serum concentrations within proposed ef-
fective ranges and a lasting improvement in
his condition (the patient survived into mid-
1995). We subsequently described 31 patients
with AIDS and tuberculosis who failed to
achieve effective serum concentrations of an-
tituberculosis In many cases, their
physicians had ordered serum concentrations
because the patients had failed to respond
to what usually should have been adequate,
observed dosages. Effective serum concentra- jects. Group I subjects were healthy volunteers;
tions of antituberculosis drugs therefore ap-
pear to be required for clinical efficacy.
Although these data showed that below
normal serum concentrations occurred with
some frequency in patients with AIDS, it was
not possible to calculate the incidence with
which that occurred. Our experience in AIDS
patients with disseminated MAC infection
showed that all 27 patients had serum con-
centrations of rifampin, ethambutol, clofazi-
mine, or ciprofloxacin well below the pro-
posed effective ranges6 All of these patients
had CD4 counts of fewer than 50 cells/mm3,
18 of the 27 had low concentrations for all
four drugs, and many of them had serum
concentrations close to zero for several of the
drugs. Unless these drugs exert a local effect
against MAC along the gut lumen, it is un-
likely that such low concentrations are con-
tributing to the care of these patients. Al-
though "good" drug concentrations in the
tissues are advocated when treating MAC,
the drugs cannot get to the tissues unless
they get into the blood stream first. In AIDS
patients with disseminated MAC, drug mal-
absorption appeared to be common, and may
compromise therapy.
We subsequently conducted a prospective,
pilot investigation into the incidence of low
antituberculosis drug serum concentrations in
patients with advanced AIDS and tuberculosis.
This study included 26 AIDS patients with
CD4 counts of fewer than 200 c e l l ~ / m m23~ . ~ that
Lower-than-normal 2-hour serum ("peak")
concentrations were common for the antitu-
berculosis drugs in this patient sample.23Se-
rum concentration results were compared
with the low end of our published normal
ranges.1517 Twenty-one of 26 patients (81%) culosis chemotherapy showed that patients
had 2-hour concentrations between 60% and
90% of predicted minimum for at least one
drug (median, 1.5 drugs per patient).= Seven-
teen of these patients (65% of the total) had
moderately low 2-hour concentrations (be-
tween 30% and 60% of predicted minimum),
and 14 patients (54% of the total) had very
low 2-hour concentrations (<30% of pre-
dicted minimum for at least 1 Low
or very low rifampin and ethambutol 2-hour
serum concentrations occurred in most pa-
tients receiving those drugsz3In contrast, the
absorption of INH and pyrazinamide ap-
proached normal in many of the subjects.
Sahai and colleagues24reported the results
of a bioavailability study of INH, rifampin,
and pyrazinamide in four groups of 12 sub-
groups 11,111, and IV were human immunode-
ficiency virus-positive (HIV+) subjects with-
out tuberculosis. Group I1 had CD4 counts
greater than 300/mm3, group I11 had CD4
counts fewer than 200/mm3, and group IV
had CD4 counts fewer than 200/mm3 plus
three or more loose stools per day.22Serum
concentrations were compared with published
normal ranges. Group I subjects displayed the
predicted serum concentrations (no malab-
sorption), whereas groups I1 through IV dis-
played declining serum concentrations that
paralleled their deteriorating clinical condi-
tions.= Thirty-three percent of group I1 sub-
jects had low serum concentrations for at least
one drug; 50% in group 111 and 67% in group
IV had low concentrations for at least one
drug.22Twenty-five percent of group 111 sub-
jects and 33% of group IV subjects had low
serum concentrations for at least two drugs.**
Combining all HIV+ groups and comparing
them with healthy volunteers showed a rela-
tive rifampin C,,, of 59% or less and a rela-
tive pyrazinamide C,,, of 76% or lessz2Com-
paring group IV patients with group I11
patients showed that diarrhea reduced the
INH C,, an additional 39y0.~'This well-con-
trolled study therefore confirms and expands
our results, clearly showing that HIV+ pa-
tients do not absorb tuberculosis drugs nor-
mally.
The troubling aspect of these findings is
~ ~ patients may absorb only portions of
their drug regimen, in effect putting them on
fewer tuberculosis drugs or even monother-
apy. The latter condition may lead to the
selection of drug resistance, as described sub-
sequently. Furthermore, early trials in tuber-
can respond temporarily to monotherapy. An
early response to tuberculosis drug therapy
therefore should be expected, even in the
presence of drug malabsorption. By the time
the patient shows clinical signs of trouble, it
may be too late to prevent drug resistance.
 USING THERAPEUTIC DRUG MONITORING TO DOSE THE ANTIMYCOBACTERIAL DRUGS
Clinicians therefore must have a high index
of suspicion for drug absorption problems in
this population. The specific host response to
AIDS responsible for the low drug concentra-
tions is not known. A separate issue we do
not detail here is the problem of drug interac-
tions. Increased use of the protease inhibitors
seriously complicates the treatment of tuber-
culosis in patients with AIDS. Most of the
tuberculosis drugs are cleared hepatically, ri-
fampin is a well-known hepatic enzyme in-
ducer, and protease inhibitors appear to be
potent hepatic enzyme inhibitors. These find-
ings highlight the need to define drug behav-
ior on a case-by-case basis in AIDS patients
so that proper doses can be given.
Other investigators have used our assay
services to investigate tuberculosis drug be-
havior in their patients with tuberculosis.
Turner and colleagues23 reported several
cases of non-AIDS patients infected with tu-
berculosis who failed to respond to therapy.
These patients were subsequently shown to
have low serum concentrations of antituber-
culosis drugs. Patel and coworkers13reported
two HIV-infected patients who received DOT
who relapsed with drug-resistant isolates.
When their serum concentrations were deter-
mined, they were found to be quite low. The
authors13 concluded that drug malabsorption
contributed to the development of drug resis-
tance. The experiences of Turner and Patel are
consistent with the unpublished experience
of clinicians at several tuberculosis treatment
centers across the United States for whom we
have provided clinical assay services. It is
also consistent with our experience at NJC.
Selected patients, particularly those with con-
current illnesses, appear to malabsorb their
tuberculosis drugs. These patients may be at
risk of further drug resistance if they absorb
only part of their tuberculosis drug regimen.
When patients fail to respond to DOT, it is
reasonable to verify drug absorption.
Because patients with MDR-TB often fail to
respond to seemingly appropriate treatment,
we routinely adjust drug doses to achieve the
proposed effective serum concentration^.'^, l6
Tuberculosis studies conducted by the Public
Health Service (PHS) during the 1960s and
1970s showed that lower doses of INH, rifam-
pin, and ethambutol were clearly less effec-
tive than the subsequently defined usually
effective doses.*,3, 9, l2 Unfortunately, these
studies did not include serum concentration
monitoring. The available data, however, sug-
gest that INH, rifampin, and ethambutol
85
show linear pharmacokinetics over the doses
used in the PHS studies.l8 It therefore is rea-
sonable to conclude that the lower doses of
those drugs 'resulted in lower serum concen-
trations, and that the lower serum concentra-
tions produced less desirable clinical and bac-
teriologic outcomes. Given these results with
INH, rifampin, and ethambutol, the most po-
tent oral agents for tuberculosis, it is very
likely that adequate serum concentrations are
even more important for the much weaker
"second-line'' agents used to treat MDR-TB.
The clinical results already presented docu-
ment poor clinical and bacteriologic re-
sponses in patients who have antituberculosis
drug serum concentrations below the pro-
posed effective ranges. The available data
support the hypothesis that successful tuber-
culosis therapy depends upon the achieve-
ment of effective serum concentrations of an-
tituberculosis drugs.
PRACTICAL ISSUES AND
ASSAY TECHNOLOGY
Serum concentrations are usually obtained
using plain red-top vacuum tubes and direct
venipuncture. Indwelling intravenous devices
may be used to obtain samples, provided the
same device was not used to administer the
drug. Otherwise, residual drug in the port
may falsely elevate the reported serum con-
centration. Certain catheters have multiple
ports (Hickman, Groshong, etc.), and one port
can be designated for obtaining blood sam-
ples once the catheter has been thoroughly
flushed with a drug-free solution. Regardless
of how the samples are collected, the actual
time of dose administration and the actual
times of the blood collection (not the sched-
uled times) must be recorded.'O For intrave-
nous infusions, the actual start and finish
times should be recorded. Otherwise, the
assay results will not be interpretable. Blood
samples should be centrifuged promptly, the
serum transferred into labeled polypropylene
tubes and frozen promptly in the coldest
available freezer, preferably - 70°C.
The assays need to be specific for the drug
of interest. In particular, they must separate
the drug of interest from other drugs present
in the patients' blood, and they must separate
the parent compound from any metabolites.
This is true regardless of whether or not the
metabolites are microbiologically active. In
this regard, bioassays, which are quite useful
86 PELOQUIN
for a variety of testing purposes, are inferior
to specific methods, such as radioimmunoas-
says, fluorescence polarization immunoassays
(TDx, Abbott), high-performance liquid chro-
matography, gas chromatography, or capil-
lary electrophoresis. The latter techniques are
currently used at NJC for measuring the se-
rum concentrations of the antimycobacterial
drugs.
Two-hour post-dose concentrations are
used for the normal ranges with oral tubercu-
losis drugs, because nearly all such doses
should have been absorbed by that time.15,
16, Of course, there are always exceptions,
and a few patients appear to have delayed
absorption. Second blood collections 6 hours
after the dose can confirm that occurrence.
Predose "troughs" are generally useless for
the tuberculosis drugs because most are not
measurable in the blood 24 hours after a dose.
When it is important to determine the elimi-
nation half-life of the drug, such as in patients
with decreased renal function, at least two
post-dose samples are needed. The samples
should be drawn at intervals greater than the
typical half-life of the drugs. Rifampin, for
example, has a 2 to 3 hour half-life in most
patients, so samples should be drawn 4 hours
apart (2 and 6 hours post dose).
For drugs given intravenously, two post-
dose concentrations can be used to back-cal-
culate the C,,, at the end of an infusion, or
to calculate forward to the next scheduled
dose (Cmin). When determining the volume of
distribution, a third sample can be obtained
immediately before the timed dose. The base-
line before the first dose of a drug is zero,
and can be used as a free third sample. First-
dose serum concentrations approach those
obtained at steady-state for drugs initiated
with a loading dose and for drugs with short
(1-4 hour) serum half-lives that are dosed
once daily.
SUMMARY
The available data suggest that selected pa-
tients with tuberculosis and MAC fail to re-
spond to therapy because they malabsorb
their medications. In particular, patients with
AIDS and known gastrointestinal diseases
have problems absorbing these drugs. In ad-
dition, because MDR-TB and MAC are so dif-
ficult to treat, TDM with the antimycobacte-
rial drugs offers the clinician a chance to
ensure that the patient achieves serum con-
centrations above the MIC of the pathogen.
TDM has become the standard of practice at
the National Jewish Center for Immunology
and Respiratory Medicine. By combining spe-
cific' and sensitive assays, carefully collected
samples, and clinical expertise, we are able to
control and optimize antimycobacterial drug
therapy. We continue to refine our approach
with ongoing pharmacokinetic and pharma-
codynamic research, including the develop-
ment of population pharmacokinetic models.
We hope that these efforts will provide in-
sight into the nature of current therapeutic
problems. We also hope they will help us
improve the clinical outcomes of our patients.
References
1. Berning SE, Huitt GA, Iseman MD, et al: Malabsorp-
tion of antituberculosis medications by a patient with
AIDS. N Engl J Med 3271817-1818, 1992
2. Comstock GW, Hammes LM, Pi0 A: Isoniazid pro-
phylaxis in Alaskan boarding schools: A comparison
of two doses. Am Rev Respir Dis 100:773-779, 1969
3. Doster B, Murray FJ, Newman R, et al: Ethambutol
in the initial treatment of pulmonary tuberculosis.
Am Rev Respir Dis 107177-190, 1973
4. Evans WE: General principles of applied pharmaco-
kinetics. In: Evans WE, Schentag JJ, Jusko WJ (eds):
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Address reprint requests to
Charles A. Peloquin, PharmD
Director, IDPL
National Jewish Center for Immunology
and Respiratory Medicine
1400 Jackson Street
Denver, CO 80206