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Why Do We Use 600 mg of Rifampicin in Tuberculosis
Treatment?
Jakko van Ingen,1 Rob E. Aarnoutse,2 Peter R. Donald,3 Andreas H. Diacon,4 Rodney Dawson,5 Georgette Plemper van Balen,1
Stephen H. Gillespie,6 and Martin J. Boeree1
1University Center for Chronic Diseases Dekkerswald and Department of Pulmonary Diseases, 2Department of Clinical Pharmacy, Radboud University Nijmegen Medical
Center, Nijmegen, the Netherlands; 3Departments of Pediatrics and Child Health; 4Internal Medicine, Faculty of Health Sciences, University of Stellenbosch, Cape Town,
5Centre for Tuberculosis Research Innovation, University of Cape Town Lung Institute, Groote Schuur, South Africa; and 6Department of Molecular Medicine, School of
Medicine, University of St Andrews, St Andrews, Scotland, United Kingdom
The 600-mg once daily dose of rifampicin plays a key role in tuberculosis treatment. The evidence underpinning this dose is
scant. A review of the historical literature identified 3 strands of reasoning. The first is the pharmacokinetic argument: The
600-mg dose yields serum drug concentrations well above the minimum inhibitory concentration of rifampicin against
Mycobacterium tuberculosis. The second is the argument that adverse events may be dose related. The third is the economic
argument: Rifampicin was prohibitively expensive at the time of its introduction. Recent in vitro, animal, and early
bactericidal activity studies suggest that the 600-mg once daily dose is at the lower end of the dose-response curve, refuting
the pharmacokinetic argument. The reduced cost and the lack of evidence of toxicity at higher daily doses remove the other
arguments. To optimize tuberculosis treatment, the clinical value of higher doses of rifampicin should be tested in clinical
trials.
In 1957, Sensi and coworkers at Lepetit
Laboratories discovered a new antibiotic
which they named rifamycin. It was
obtained from fermentation cultures of
Amycolatopsis rifamycinica (designated
Streptomyces mediterranei at the time)
and later found to consist of 5 substances, then renamed rifamycin A–E.
Absorption of all of these substances
from the gastrointestinal tract was minimal; hence, they were first developed as
parenteral agents. Rifamycin B proved
most stable, least toxic, and active
Received 18 December 2010; accepted 22 February 2011.
Correspondence: Martin Boeree, MD, PhD, University
Center for Chronic Diseases Dekkerswald, Radboud University Nijmegen Medical Center, PO Box 9101, 6500HB
Nijmegen, the Netherlands ([email protected]).
Clinical Infectious Diseases 2011;52(9):e194–e199
Ó The Author 2011. Published by Oxford University Press on
behalf of the Infectious Diseases Society of America. All
rights reserved. For Permissions, please e-mail: journals.
[email protected].
1058-4838/2011/529-0001$37.00
DOI: 10.1093/cid/cir184
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against a broad spectrum of bacteria,
mainly gram-positive cocci and Mycobacterium tuberculosis [1, 2]. Of note, the
name ‘‘rifamycin’’ refers to the popular
1955 French film noir movie Rififi [2].
Although rifamycin B was sporadically
used clinically in tuberculosis treatment,
the search for an oral equivalent with
good intestinal absorption continued. In
1965, rifampicin, a hydrazone of
a rifamycin B derivate with N-aminoN#-methylpiperazine, proved to be well
absorbed orally and retained its highly
bactericidal action (Figure 1) [1–3]. Rifampicin was approved by the Food and
Drug Administration (FDA) in 1971 [2].
By this time, a range of trials and case
series were finalized or had been published that found efficacy for rifampicincontaining regimens in tuberculosis
treatment [4–12]. Virtually all of these
studies had used a single daily dose of
600 mg of rifampicin [5–11]. Why was
this dose chosen? The reasoning for the
600-mg once daily dosing could not be
extracted from any of the published trials. Given the critical role of rifampicin
in short-course chemotherapy, we performed a review of the literature to try to
understand the reasoning behind the
choice of this dose.
SEARCH STRATEGY AND
SELECTION CRITERIA
We performed a literature search using
PubMed (National Center for Biotechnology Information; http://www.ncbi.nlm.nih.
gov), applying the Medical Subject
Heading (MeSH) terms ‘‘rifampin’’ with
subheading ‘‘history’’ combined with the
MeSH term ‘‘tuberculosis’’; publications
in English, German, French, and Italian
were considered. The review focused on
the first 2 decades after the development
of rifampicin (1957–1977) and those
Figure 1. Chemical structures of rifamycin B and rifampicin.
papers in which rifampicin was explored
as an agent for tuberculosis treatment.
RESULTS
We found a total of 3137 publications;
1003 were from the period 1957–1977.
Relevant papers were selected on the
basis of the title and abstract, where
available. From our review of the literature, we extracted 3 main arguments
that ultimately led to the 600-mg daily
dose of rifampicin, although this is, inevitably, a post hoc analysis: (1) the
pharmacokinetic argument; (2) the toxicity argument; and (3) the cost argument.
Pharmacokinetics
Early pharmacokinetic studies established that a single daily dose of 600 mg
of rifampicin yielded serum concentrations of 7.0 lg/mL 90 min after ingestion, or 8.80–12.0 lg/mL after
2 hours—that is, well above .2 lg/mL,
the mean minimum inhibitory concentration (MIC) of M. tuberculosis [13–15].
Higher doses yielded significantly higher
serum concentrations and half-life [14–
17]; one study in France applied 900 mg
of rifampicin once daily and found mean
serum concentrations of 16.2 lg/mL 3 h
after intake [18]. Since peak serum
concentrations (Cmax) are reached 2 h
after intake [15, 16], the value of Cmax
was likely to be higher. One year later,
Furesz and coworkers measured peak
serum concentrations (after 2 h) of 20.87
6 3.25 lg/mL after a single 750-mg dose
and 27.70 6 4.16 lg/mL after administration of 900 mg of rifampicin in healthy
volunteers [14]. Still, they stressed that
the 600-mg doses already ensured therapeutic (ie, equal to or above the MIC)
blood levels for 24 h after administration
[14].
Toxicity
A second argument underlying the 600mg dose is based on a fear of hazardous
adverse effects of higher doses. In the
literature, there is little evidence that
higher daily doses lead to increased
toxicity. Very few studies used higher
daily doses, and the few that have been
performed report little or no safety and
toxicity data [12, 16–19]. Thus, we are
presented with a few anecdotal notes.
Looking back at their use of 900 mg of
rifampicin, Constans and coworkers said
that this was ‘‘liable to induce slight
disorders’’ but did not provide additional data [9]; Favez and coworkers
drew similar conclusions [12]. In the
United States Public Health Service
(USPHS) study 19, drug-induced hepatitis frequency did not differ between
patients who were given 450, 600, or 750
mg of rifampicin [20]. In contrast, intermittent therapy with high doses of
rifampicin (once or twice weekly) has
been associated with increased toxicity,
but its nature is quite distinct from the
hepatotoxicity that is most common in
daily dosed rifampicin therapy [20, 21].
Intermittent high doses of rifampicin
(1200 mg twice weekly with 900 mg of
isoniazid) led to rifampicin sensitization
and antibody formation; in one study,
11 (22%) of the 49 patients discontinued
treatment after developing mostly fever,
thrombocytopenia, or renal failure,
which is designated as the ‘‘flu-like
syndrome’’ [21]. This experience with
high-dose intermittent rifampicin resulted in an end to clinical trials with
high-dose rifampicin.
Cost
The third argument is economical in
nature. All early publications on the use
of rifampicin warned about its cost. At
the time, rifampicin was expensive to
produce and it was thought that, because
of its semisynthetic nature, it would remain so [1, 8, 22, 23]. This cost pressure
affected the pace of implementation of
the drug we now know to be central to
short-course chemotherapy. In the late
1960s and early 1970s, rifampicin was
considered a second-line drug, at first to
add to previously unsuccessful regimens
[5] and later to be part of retreatment
regimens [24]. Rifampicin long held its
position as a second-line drug, since
first-line triple therapy (streptomycin,
isoniazid, and para-aminosalicylic acid)
was already highly effective and
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rifampicin was considered too expensive
for extensive use [24, 25]; hospital prices
were 2.5 p for 10 g of para-aminosalicylic
acid, 22 p for 1 g of ethambutol, and 68 p
for 600 mg of rifampicin (the latter
comparable to £3.79 or $6.05 today; calculated at http://www.nationalarchives.gov.uk/currency/) [25]. For this same reason,
the British Medical Research Council
(BMRC)
preferred
isoniazid-pyrazinamide regimens over equally active
isoniazid-rifampicin regimens as rifampicin cost more than £110 for 6 months,
which was .4 times the cost of pyrazinamide. The benefit of their study
was formulated giving ‘‘good prospects
of developing practical short-course
regimens which do not contain rifampicin’’ [8]. This view was contested by
others based on the principle that
shortening tuberculosis treatment would
justify (and, in part, make up for) the
expense [22]. In the second half of the
1970s, rifampicin became a first-line
drug, at least for countries that could
afford its extensive use [26, 27]. The
evidence to support its use and introduce successful treatment with 6month short-course regimens overruled
the associated cost [20, 26, 27]. Still, use
of this costly drug was at times met with
vehement criticism [28].
DISCUSSION
This review of the literature reveals that
pharmacokinetic, toxicity, and cost arguments ultimately led to the 600-mg
daily dose of rifampicin that eventually
made its way into tuberculosis treatment
guidelines [26, 29, 30]. A more explicit
comment came from Richard O’Brien
and Andrew Vernon who, in their 1998
editorial [31], stated that determination
of the optimal dose of rifampicin ‘‘was
done by the USPHS Tuberculosis Study
19 which established 600 mg as the optimal dose for most adults.’’ That randomized trial evaluated daily dosages of
450 mg (7.5 mg/kg), 600 mg (10 mg/kg),
and 750 mg (12.5 mg/kg) of rifampicin
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with a fixed dose of isoniazid and observed no significant difference in the
rate of sputum conversion or the rate of
relapse between those who received 600
mg and those who received 750 mg of
rifampicin, with a lower rate of sputum
conversion and a higher rate of treatment failure among those who received
450 mg of rifampicin [20]. Interestingly,
the 600-mg dose had become standard
practice even before FDA approval of
rifampicin for tuberculosis treatment
occurred in 1971 [4–12] and it is still
recommended as the maximum daily
dose for daily and intermittent treatment [30]. Deviations from the 600-mg
dose in trials were either small (6150
mg in the USPHS study [20]) or part of
regimens that diverged so far from
common practice that it was difficult to
single out the effect of rifampicin. An
important example is the study by Kreis
and coworkers, published in 1976, which
tested two 3-month regimens of highdose rifampicin (1,200 mg daily or every
other day) combined with high daily
doses of isoniazid and streptomycin
[19]. These regimens yielded almost
100% sputum culture conversion, but
16% of patients relapsed after 12–24
months [19]. From today’s perspective,
the most likely contributor to the high
initial cure rate achieved is the high dose
of rifampicin; addition of pyrazinamide
to this regimen would likely have further
increased its efficacy. This alone makes
the entrenched maximum daily dose of
600 mg of rifampicin worth revisiting.
More importantly, what renders
a dose optimal from today’s point of
view? According to current standards,
the optimal dose of rifampicin would be
derived from relationships between
dosing, drug exposure achieved, and
desirable and undesirable responses in
phase 1 and 2 studies with clearly differing doses of rifampicin, followed by
pivotal phase 3 studies of regimens. We
found no evidence of such a sequence of
studies. The historical pharmacokinetic,
toxicity, and cost arguments have largely
been refuted by more recent scientific
progress.
Pharmacokinetics
Although the pharmacokinetic argument
is compelling, it was based on the assumption that rifampicin is active when
serum concentrations exceed the MIC
throughout the dosing interval, which
means that the ratio of the trough concentration (Cmin) to the MIC is the
relevant pharmacodynamic index (timedependent inhibition) [1, 13, 14, 32].
Similar reasoning is illustrated by the
statement by Constans that the 900-mg
dose applied in a pilot of their trial was
‘‘unnecessarily high’’ [9].
In the following decades, in contrast,
it was assumed that the efficacy of rifampicin is concentration-dependent,
correlating with peak plasma concentration (Cmax) divided by the MIC [33].
This view was based on the intracellular
target of rifampicin: other drugs with
intracellular targets (eg, aminoglycosides
and fluoroquinolones) were shown to
have concentration-dependent activity,
albeit against extracellular, fast-growing
bacteria. Concentration-dependent activity and the associated postantibiotic
effect also better explained the efficacy of
intermittently administered rifampicin
[33]. Recent studies have challenged this
assumption and established that the activity of rifampicin is exposure-dependent;
the area under the concentration-time
curve (AUC) divided by the MIC correlates better with killing than the value of
Cmax /MIC [34, 35]. Of note, the choice of
medium (eg, solid or liquid medium) influences MIC measurements [32].
For a bacterium that resides in macrophages, especially in early phases of
infection, rifampicin concentrations in
alveolar macrophages and epithelial lining fluid (ELF) may be more relevant
than those in plasma. Rifampicin concentrations in ELF and bronchial biopsy
specimens are slightly below those in
serum, whereas those in alveolar macrophages are .10 times higher [36, 37].
Consequently, AUC/MIC or Cmax/MIC
ratios compatible with bacterial killing
were generally achievable in serum and
alveolar macrophages, but not in ELF
[37]. The use of a 1,200-mg rifampicin
dose significantly improved attainment
of AUC/MIC or Cmax/MIC ratios compatible with bacterial killing [37]. If the
600-mg dose was applied, rifampicin
concentrations attained at the site of infection were too low [36, 37]. Recently,
Gumbo and coworkers demonstrated
that exposure to higher concentrations of
rifampicin led to a nonlinear increase in
rifampicin concentrations inside the
bacteria, a phenomenon possibly related
to saturation of bacterial efflux pumps
[35]. Whether raising these concentrations in the bacterium and at the site
of infection by application of higher rifampicin doses actually improves killing
of the bacteria and, ultimately, treatment
outcome remains to be investigated.
Thus, the current dose of rifampicin
used in internationally recommended
regimens has not been based on careful
evaluation of relationships between dosing, drug exposure achieved at the site of
infection, and desirable and undesirable
(surrogate parameter) responses. The
wide acceptance and perceived success of
the currently available regimens may have
led to the relative paucity of studies
evaluating the pharmacodynamics of rifampicin. Admittedly, the pharmacodynamics related to the slow-growing,
intracellular M. tuberculosis bacteria and
their capacity for dormancy may be too
complex to be explained by simple pharmacodynamic parameters [33]. Nevertheless, recent pharmacodynamic studies
suggest that the current dose of rifampicin
is at the lower end of the dose-response
curve [34, 38–40], as already suggested by
the above-mentioned study by Kreis et al
[19, 39]. In this respect, it should be
mentioned that both early and recent
pharmacokinetic studies have revealed
a nonlinear increase of rifampicin concentrations upon increase of the rifampicin dose [13–17, 41]—that is, a relatively
small increase in dose is associated with
a more than proportional increase in rifampicin AUC. Clearly, this characteristic
should be further assessed in future
studies that explore the utility of higher
doses of rifampicin.
rifampicin to be used safely. Although
there are significant safety concerns
about the use of high intermittent doses
of rifampicin, an extrapolation to daily
dosage is not warranted without clinical
trial evidence.
Toxicity
Cost
The nonlinear pharmacokinetics of rifampicin would be expected to go along
with a greater than proportional decrease in tolerability if higher doses are
applied. Yet, this has not been observed
in studies that did apply higher doses
[14–17]; recent studies of higher rifampicin doses (13 mg/kg [41] and 20 mg/
kg [40]), although hampered by small
patient numbers and short-term use,
also did not record increased hepatotoxicity or other adverse events. The
toxicity reported for intermittent highdose rifampicin treatment [21] has been
retrospectively ascribed to the intermittency of dosing rather than the
magnitude of the dose [39]; nonetheless,
it may have prevented the research
community from identifying the correct
dosage regimen for rifampicin.
Higher doses of rifampicin (900–1,200
mg) have been used in other disease,
including brucellosis, legionnaires disease, and leishmaniasis, without significant tolerability problems. In these
contexts, rifampicin is coadministered
with less toxic drugs such as erythromycin, doxycycline, or co-trimoxazole
and is used for weeks rather than
months [42–44].
Rifampicin may not be the most toxic
drug in the multidrug regimen currently
used for tuberculosis. In studies of 4month rifampicin monotherapy for
latent tuberculosis, hepatotoxicity was
rare compared with its frequency in rifampicin-pyrazinamide treatment. This
may be due to the pyrazinamide or to
drug interactions rather than to rifampicin itself [45]. The arrival of novel
antituberculosis drugs and novel combinations may shed more light on
this issue and allow higher doses of
In their review of 40 years of BMRC
studies on tuberculosis treatment, Fox,
Ellard, and Mitchison repeatedly remind
us that the first short-course therapy
trials were designed ‘‘to use the minimum amount of expensive rifampicin’’
(in East Africa) or did not include rifampicin because of the high cost (Hong
Kong and Singapore) [29]; rifampicin
made up 90% of the cost of drugs in
rifampicin-based short-course regimens
[23]. These financial restrictions are no
longer warranted; the price of a complete
treatment regimen for a single patient,
based on the 2HRZE4HR regimen, is
now $38.15, through the Stop TB Partnerships’ Global Drug Facility (http://
www.stoptb.org/gdf/). This price equals
the price of 1 week of rifampicin monotherapy in 1973.
LOOKING FORWARD
It is important to re-engage with the
question of the optimal dose of rifampicin. Most importantly, the tuberculosis pandemic is still uncontrolled; there
is a pressing need to improve the treatment of tuberculosis so that patients test
negative on smear and culture as quickly
as possible. In small-scale studies, high
doses (20 mg/kg) of rifampicin have already been shown to have bactericidal
activity up to twice that of the 600-mg
dose (10 mg/kg) [40, 46]. Moreover, rifampicin has a sterilizing effect—the
capacity to kill the remaining mycobacteria that undergo sporadic metabolism
and that remain after the initial phase of
treatment [47]. The sterilizing effect of
rifampicin provides the most exciting
reason to address this issue: if higher
doses of rifampicin are safe and well
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tolerated and kill tubercle bacilli more
rapidly, then we may be able to shorten
tuberculosis treatment further. This will
have an immediate effect on completion
and cure rates. The original 600-mg dose
has helped to reduce treatment duration
of the multidrug regimen to 6 months
but failed to reduce the duration of
treatment to 4 months, as 5%–15% of
the patients experienced bacteriological
relapses in the BMRC Study 4 trials [29,
48]; a further reduction should still be
our goal. In addition, faster smear and
culture conversion decreases the size of
the infectious pool of patients in the
community and can reduce further
transmission of tuberculosis. Second,
higher doses of rifampicin may expose
the bacteria to AUC/MIC values that
prevent the emergence of resistance or,
according to the concept of mutant
prevention concentration [49], increase
concentrations to a level that prevents
the emergence of rifampicin-resistant
mutants, thus decreasing the risk of the
emergence of multidrug-resistant tuberculosis. Currently, 3.6% of all individuals with incident tuberculosis
worldwide have multidrug-resistant tuberculosis, although this percentage is
likely underestimated because access to
drug susceptibility testing is limited in
many high-incidence areas [50]. Optimizing first-line regimens is an important strategy to limit the emergence of
multidrug-resistant tuberculosis. Third,
there has been a recent study that higher-dose rifampicin may play a role in
infections caused by low-level resistant
strains (ie, MICs of 1–2 mg/L, just above
the 1-mg/L break-point concentration).
Such resistance may be overcome by
applying higher doses of rifampicin (J.
van Ingen, in press). Fourth, the drug is
available and affordable, and there is
widespread experience with its clinical
use. If higher doses prove to be more
efficacious and tolerable, a new regimen
could be implemented quickly.
From the above points, it is clear that
dose-ranging, tolerability, and extended
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bactericidal activity studies of high doses
of rifampicin are warranted; the time is
now. Fortunately, this field is currently
in motion. Dose-ranging and tolerability
studies are in the planning phase, and
phase 2 studies of high-dose rifampicin
are now being performed in Tanzania
and planned in Peru and Brazil.
In summary, we present evidence that
the current 600-mg once daily dose of
rifampicin in tuberculosis treatment
may not be optimal. The reason behind
this dose is obscure, but arguments are
largely pharmacokinetic and economical
in nature, with a concern about toxicity
on the basis of intermittent high-dose
rifampicin. The 600-mg dose is at the
lower end of the dose-response curve,
and the nonlinear pharmacokinetics and
dose-dependent activity of rifampicin
mean that studies of higher dosages
within the multidrug antituberculosis
treatment regimens are urgently required. More active regimens including
higher doses of rifampicin may help to
reduce the duration of tuberculosis
treatment with immediate benefits on
treatment completion rates and the
emergence of multi-drug-resistance.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Acknowledgments
We are collaborators within the European and
Developing Countries Clinical Trials Partnership-(EDCTP-) funded Pan African Consortium
for the Evaluation of Antituberculosis Antibiotics
(PanACEA) Consortium; this consortium executes trials of novel tuberculosis treatment regimens, including application of higher doses of
rifampicin.
Potential conflicts of interest. All authors:
no conflicts.
14.
15.
16.
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