J Antimicrob Chemother 2016; 71: 1759 – 1771

doi:10.1093/jac/dkw024 Advance Access publication 23 March 2016

Rifabutin: where do we stand in 2016?

Yoann Crabol1, Emilie Catherinot2, Nicolas Veziris3,4†, Vincent Jullien5,6† and Olivier Lortholary1,7,8*
1
APHP-Hôpital Necker-Enfants malades, Service de Maladies Infectieuses et Tropicales, Centre d’Infectiologie Necker-Pasteur, Paris,
France; 2Service de Pneumologie, Hôpital Foch, Suresnes, France; 3AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de Bactériologie-Hygiène,
Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Paris, France; 4UPMC, INSERM,
Centre d’Immunologie et des Maladies Infectieuses, E13, Paris, France; 5AP-HP, Hôpital Européen Georges-Pompidou, Pharmacology

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Department, Paris, France; 6Université Paris Descartes, Sorbonne Paris Cité, Inserm U1129, Paris, France; 7Université Paris Descartes,
Sorbonne Paris Cité, Paris, France; 8IHU Imagine, Paris, France

*Corresponding author. Tel: +33-(0)1-42-19-26-63; Fax: +33-(0)1-42-19-26-22; E-mail: olivier.lortholary@aphp.fr

†Both authors contributed equally.

Rifabutin is a spiro-piperidyl-rifamycin structurally closely related to rifampicin that shares many of its properties.
We attempted to address the reasons why this drug, which was recently recognized as a WHO Essential Medicine,
still had a far narrower range of indications than rifampicin, 24 years after its launch. In this comprehensive
review of the classic and more recent rifabutin experimental and clinical studies, the current state of knowledge
about rifabutin is depicted, relying on specific pharmacokinetics, pharmacodynamics, antimicrobial properties,
resistance data and side effects compared with rifampicin. There are consistent in vitro data and clinical studies
showing that rifabutin has at least equivalent activity/efficacy and acceptable tolerance compared with rifam-
picin in TB and non-tuberculous mycobacterial diseases. Clinical studies have emphasized the clinical benefits of
low rifabutin liver induction in patients with AIDS under PIs, in solid organ transplant patients under immunosup-
pressive drugs or in patients presenting intolerable side effects related to rifampicin. The contribution of rifabutin
for rifampicin-resistant, but rifabutin-susceptible, Mycobacterium tuberculosis isolates according to the present
breakpoints has been challenged and is now controversial. Compared with rifampicin, rifabutin’s lower AUC is
balanced by higher intracellular penetration and lower MIC for most pathogens. Clinical studies are lacking in
non-mycobacterial infections.

Introduction Essential Medicine according to the WHO 17th Expert Committee,7

Rifabutin, previously named ansamycin or LM 427, is a spiro-
piperidyl-rifamycin that shares many of the rifamycin family’s
properties, which also encompasses rifampicin and rifapentine.
Rifampicin-based multitherapies are cornerstone treatments of
bacterial infections, including Mycobacterium tuberculosis 1 and
non-tuberculous mycobacteria (NTM),2 staphylococcal chronic
bone infection or prosthetic valve endocarditis and pneumococcal
or staphylococcal meningitis.3 Rifampicin is also a promising drug
for MDR Gram-negative infections.4
Surprisingly, rifabutin indications have been limited so far to
mycobacterial infection treatments. Rifabutin is recommended
for active TB in the case of unacceptable intolerance to rifampicin
or drug – drug interactions,1 historically during the pre-ART
era, at least in some countries, for prevention of disseminated
Mycobacterium avium complex (MAC) in patients with AIDS when
a macrolide cannot be tolerated,2 for severe pulmonary or dissemi-
nated MAC infection and for Mycobacterium kansasii, Mycobacterium
gordonae, Mycobacterium haemophilum, Mycobacterium marinum
and Mycobacterium xenopi infections2 (Table 1).
Since the last extensive rifabutin review article published in
1996,5 and the Cochrane review of clinical trials using rifabutin
in TB in 20076 rifabutin has been recognized in 2009 as an
the drug is no longer protected by patent and its price has been
reduced by 60%. Moreover, a few more articles have been published
that provide more insight into rifabutin use against mycobacteria,
Staphylococcus aureus and MDR Gram-negative bacilli and address
resistance to rifabutin and safety issues.
This article aims to summarize 24 years of rifabutin use since
FDA approval in 1992 and points out the gap to bridge to improve
the use of this old drug in our current clinical practice.
Methods
The search was carried out using MEDLINE from January 1977 to December
2015. English language restriction was applied to the search. We used
the terms ‘rifabutin’ in combination with ‘pharmacokinetic’, ‘pharmaco-
dynamic’, ‘MIC’, ‘mycobacteria’, ‘Staphylococcus’, ‘Gram-negative’, ‘side
effect’, ‘drugs interaction’, ‘solid organ transplant’ and ‘resistance’. Studies
were included if they met the following criteria: (i) contained original data;
(ii) contained data regarding the use of rifabutin; (iii) contained data regard-
ing clinical therapeutic outcomes or adverse effects; and (iv) reported on
randomized controlled trials or case–control studies. Studies were excluded
if they were: (i) unrelated to rifabutin use for antimicrobial purpose; (ii)
related to basic science only; (iii) duplicate reports; and (iv) not written in
English.

# The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Table 1. WHO, ATS, IDSA and CDC recommendations for rifabutin in M. tuberculosis (2003) and MAC (2007) infectionsa
M. tuberculosis 1
Prophylactic no recommendation
Curative no antiretrovirals: 300 mg daily or 2– 3 times weekly
antiretrovirals: 150 mg daily with PIs; 150 mg 2– 3×/w
with ritonavir; 600 mg daily with efavirenz
AMK, amikacin; AZM, azithromycin; CLR, clarithromycin; E, ethambutol; RIF, rifampicin; RFB, rifabutin; S, streptomycin; /w, per week.
a
There are no recommendations available for the use of rifabutin in non-mycobacterial infections.
Among 608 results, 170 articles were selected after reading the
Materials and methods section by Y. C. The search was supplemented by
consultation of the bibliographies of the articles retrieved. The American
Thoracic Society, IDSA and WHO recommendations for the treatment of
TB and NTM were also consulted.
Pharmacokinetics
Stable at pH 2 – 8, rifabutin is not destroyed by stomach acid or
antacids and can be taken with or without food. Rifabutin has a
low bioavailability of 20%, but a large volume of distribution of
9.3 L/kg at steady state. The maximum plasma concentration of
rifabutin in patients is 0.52+0.29 mg/L after a standard 300 mg
dose (Table S1, available as Supplementary data at JAC Online).
Rifabutin has a higher intracellular penetration and tissue distribu-
tion than rifampicin. The higher lipophilicity of rifabutin, which has
a 100-fold higher oil/water partition coefficient than rifampicin,
could account for this difference.5 In vitro, rifabutin intracellular/
plasma concentration ratios in neutrophils and monocytes are
9 and 15, respectively.8,9 Radioactivity studies in rats showed up
to a 14-fold higher tissue distribution after administration of
rifabutin than rifampicin.10 In a human study, concentrations
of rifabutin and rifampicin in CSF averaged 50% and 10% – 20%
of those in serum, respectively.11 Compared with rifampicin,
rifabutin has a narrower induction spectrum and 30% – 60%
weaker CYP3A4 induction properties.12 – 15 However, unlike rifam-
picin, rifabutin is hydrolysed by the CYP3A4 enzyme, which is
responsible for rifabutin under- and over-dosage with CYP3A4
inducers and inhibitors. Since rifabutin active metabolites are sig-
nificantly eliminated by the kidney, a 50% dose reduction is
recommended if creatinine clearance is ,50 mL/min.16 In
patients with underlying liver disease, both drugs should be
used with at least monthly liver function test monitoring. Dose
reduction is necessary in patients with severe liver dysfunction
(Child –Pugh score .10).5,17
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MAC2
adults with AIDS with CD4 count ≤50 cells/mm3: AZM 1200 mg/week or CLR
1000 mg/day; RFB 300 mg/day is also effective, but less well tolerated
non-severe nodular/bronchiectatic pulmonary disease: 3 times weekly regimen
of CLR (1000 mg) or AZM (500 mg), RIF (600 mg) and E (25 mg/kg)
severe nodular/bronchiectatic or fibrocavitary lung disease: daily regimen of
CLR (500–1000 mg) or AZM (250 mg), RIF (600 mg) or RFB (150 –300 mg)
and E (15 mg/kg); a reduction to RFB 150 mg/day, particularly in older
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patients with nodular/bronchiectatic disease, may be necessary when RFB is
combined with clarithromycin; consideration of 3×/w AMK or S early in
therapy; patients should be treated until culture negative on therapy for
1 year
disseminated disease: CLR (1000 mg/day) or AZM (250 mg/day) and E (15 mg/
kg/day) +RFB (150 –450 mg/day); RFB 150 mg if PIs and CLR or AZM; RFB
300 mg with CLR; RFB 300–450 mg with AZM; therapy can be discontinued
with resolution of symptoms and reconstitution of cell-mediated immune
function
Pharmacodynamics
Rifamycins inhibit transcription and protein synthesis by binding to
the b subunit of the prokaryotic DNA-dependent RNA polymerase,
encoded by the rpoB gene.18 This mechanism of inhibition occurs
even during brief periods of microbial metabolism, which could
explain the unique activity of the rifamycins for latent infections.19
The difference in susceptibility to rifamycins does not reside in
their molecular affinity for the RNA polymerase itself, but rather
has to do with efflux pump mechanisms. Indeed, the drug con-
centration resulting in 50% inhibition of transcription, of WT and
mutants of M. tuberculosis are very similar between rifamycins.20
The pharmacokinetic/pharmacodynamic measure that is the
most predictive of efficacy of rifabutin is the AUC/MIC ratio.21
Though pharmacokinetic/pharmacodynamic targets have yet to
be described for rifabutin, AUC0 – 24 ,4.5 mg.h/L is associated
with failure or relapse of TB and with acquired rifamycin-resistant
mycobacteria in patients with AIDS.21
Rifabutin MICs
Mycobacteria
Rifabutin has considerably lower MIC values than rifampicin for
MAC (MIC ratio 5 – 10), M. tuberculosis (MIC ratio 2 – 4) and
Mycobacterium leprae (MIC ratio 10)22 (Table S2). Rifabutin is
also active against most NTM though rifabutin has higher MIC
values against rapidly growing mycobacteria.24,25
Synergistic effects against MAC have been noted consistently
with combinations of rifabutin and ethambutol such that the per-
meability of the outer cell envelope of MAC may be increased.26
Previous M. tuberculosis breakpoints for rifabutin [0.5 and
1 mg/L for agar dilution (7H10 agar) and broth dilution (BACTEC)
methods, respectively27] have been recently re-evaluated in rela-
tion to its MIC WT distribution and the presence of mutations in
rpoB. The authors’ conclusion was that strains with a rifabutin
Review
MIC value of 0.064 – 0.5 mg/L and a resistance mutation in rpoB
should not be classified as susceptible, but intermediate, to
avoid giving MDR patients an ineffective treatment regimen.28,29
For NTM species, rifabutin laboratory cut-offs (2 mg/L for agar
dilution method) have not been confirmed to be clinically mean-
ingful. However, a rifabutin MIC of ≤0.125 mg/L is correlated with
blood culture conversion among patients with AIDS with MAC
bacteraemia.30 Of note, these breakpoints for M. tuberculosis or
NTM species were set on limited clinical outcome data and were
only available from the CLSI and not from the WHO.
S. aureus
JAC
used in combination with polymyxins, compared with polymyxins
alone, has been shown to improve the likelihood of microbiological
cure of the life-threatening infection due to carbapenem-resistant
Acinetobacter baumannii. 4 A potential mechanism of this synergy
could involve disruption of the bacterial outer membrane by
colistin, facilitating penetration of rifampicin. 35 However, the
30 day mortality rate was the same in the two arms. Whether
rifampicin may have altered drug clearance and consequently
therapeutic treatment outcome of colistin used in this study
remains unknown.
For now, activity of rifabutin against Gram-negative bacteria

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Rifabutin MIC50s (0.0625 – 2 mg/L) for S. aureus are 1 – 128-fold
lower than rifampicin (1 – 16 mg/L) in biofilm,31 which has to be
tempered by a 10 times lower rifabutin free Cmax (Table 2).
Rifabutin and teicoplanin are synergistic against S. aureus in
vitro. 32 In vivo activity of rifabutin has been tested against the S.
aureus Smith strain in an acute lethal mouse model of septicae-
mia. The 50% effective dose (ED50) of rifampicin was 6- and 4-fold
lower than the ED50 of rifabutin for MSSA (0.1 and 0.6 mg/kg) and
MRSA (0.3 and 1.2 mg/kg), respectively.33,34
Rifabutin efficacy has recently been assessed in an in vivo biofilm
model of a clinical isolate of S. aureus. Log reductions of viable bac-
teria in biofilm at 24 h were in the same range compared with
rifampicin (5 – 8 and 5 – 10 for rifampicin and rifabutin, respect-
ively).31 There is, in general, limited data on the effect of rifabutin
on S. aureus in vitro and a total lack of clinical studies.
Gram-negative bacteria
Rifamycins have poor activity against Enterobacteriaceae and
Pseudomonas species. In randomized controlled studies, rifampicin
has only been studied in vitro and there was a significant increase
in its activity when Escherichia coli and Pseudomonas aeruginosa
were exposed to permeability-increasing peptides derived from
polymyxin B.36 Rifabutin-based combination therapy may be
valuable and deserves further attention for MDR Gram-negative
infections.
Mechanisms of resistance
Mutations within an 81 bp fragment of the rpoB gene, found
between rpoB codons 507 and 533, are responsible for .95%
of rifampicin-resistant isolates of M. tuberculosis. 37 Mutations
in this domain at codons 531, 526 and 513 are generally asso-
ciated with high-level rifampicin and rifabutin resistance.38,39
In up to 25% of cases,40 – 42 some rifampicin-resistant isolates
with mutations at codon 516 remain phenotypically susceptible
to rifabutin based on a critical concentration of 0.5 mg/mL.43
However, these M. tuberculosis strains have a rifabutin MIC
significantly higher than strains without any detectable muta-
tions in rpoB (shift from 0.03 – 0.06 to 0.125 – 0.25 mg/L). So
far, there are no clinical, pharmacological or microbiological

Table 2. Percentage of mycobacterial strains susceptible in vitro to rifabutin in the test panel, per species

Strains susceptible to rifabutin (%)a Methodology Origin of isolatereference

TB complex
M. tuberculosis susceptible to rifampicin n¼22 100 7H10 agar Sweden28
M. tuberculosis resistant to rifampicin n¼41 –73 15– 26 7H10 agar Sweden28
7H10 agar Turkey39

NTM
M. avium n ¼688 86– 98 7H10 agar Netherlands25
MGIT 960 Switzerland101
M. intracellulare n¼201 94– 100 7H10 agar Netherlands25
MGIT 960 Switzerland101
M. marinum n ¼61 97 7H10 agar Netherlands25
M. kansasii n¼262 100 7H10 agar Netherlands25
M. xenopi n ¼50 100 7H10 agar Netherlands25
M. gordonae n¼278 100 7H10 agar Netherlands25
M. abscessus n¼82 7 7H10 agar Netherlands25
M. chelonae n¼54 6 7H10 agar Netherlands25
M. fortuitum n¼46 17 7H10 agar Netherlands25
M. mucogenicum n ¼15 67 7H10 agar Netherlands25
M. alvei n ¼5 60 7H10 agar Netherlands25

a
According to CLSI breakpoint concentration.
TB complex: CLSI recommends 0.5 mg/L as a critical concentration for rifabutin in Middlebrook 7H10 medium.
NTM: CLSI recommends 2 mg/L as a critical concentration for rifabutin in Middlebrook 7H10 medium.

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data to confirm that such isolates can be treated with
rifabutin.28
Clinical studies of efficacy of rifabutin against
M. tuberculosis
Latent TB
In a randomized controlled open-label study involving 44 HIV-
positive patients infected with latent M. tuberculosis, a twice-weekly
course of rifabutin at 300 mg combined with an isoniazid regimen
for 3 months had a non-significant lower rate of treatment default
Pulmonary TB in HIV-positive or -negative patients
Data from three randomized clinical trials among 868 patients (50
patients with HIV) suggest that rifabutin- and rifampicin-based
regimens are equally effective in pulmonary TB, with 24 weeks
culture conversion ranging from 91% in patients with AIDS45 to
94% in HIV-negative patients (Table 3). The overall rate of relapse
was similar in both regimens, and ranged from 0.6% to 1.2% in
the rifampicin group and from 3.8% to 5.1% in the rifabutin
group. However, a systematic Cochrane review in 2013 pointed
out inadequate methodology in those studies and the need for
further trials in HIV-positive patients.6

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and adverse effects than the daily standard isoniazid 6 month re- In a large randomized controlled study (520 HIV-negative
gimen (rates of treatment default were 18.7% and 28.5%, patients) the 150 mg/day rifabutin group compared with
respectively).44 the 300 mg/day group had the highest proportion of patients

Table 3. Rifabutin efficacy against TB in clinical trials

Time of culture conversion Control

Reference/year Design Treatment evaluation, weeksa RFB group group

HIV-negative patients
Gonzalez-Montaner RCT; n¼520 (RFB versus RIF)+INH+E+Z 24 94%a 96%
et al.46/1994 RFB 150– 300 mg/day (random)
McGregor et al.61/1996 RCT; n¼298 (RFB versus RIF)+INH+E+Z 24 93.8% 93.5%
RFB 300 mg/day

HIV-positive patients
Schwander et al.45/1995 RCT; n¼50 (RFB versus RIF)+INH+E+Z 24 22/24 (91%) 22/25 (88%)
(none received ART) RFB 150– 300 mg/day (weight) 8 18/24 (81%)b 11/25 (48%)
Burman et al.102/2006 OS; n¼126 RFB+INH+E+Z 24 relapse 97.6% —
(81% of patients RFB 2×/w 4.8% —
received ART)
Rawson et al.103/2015 case–control study; (RFB versus RIF)+INH+E+Z 24 months relapse 2/41 (5%) 5/130 (4%)
n¼171 (100% RFB 150×3/week–450 mg/day
received ART) (according to ART)

MDR TB
anonymous47/1992 CT; n ¼22 (RFB versus RIF)+X1 .6 7/11 (61%) 7/11 (61%)
RFB 450– 600 mg/day (weight)
Pretet et al.48/1992 OS; n¼39 RFB+FQ+X2 48 14/23 (61%) —
RFB 450– 600 mg/day (weight)
Lee et al.104/1996 OS; n¼36 RFB+X3 48 17/36 (47%) —
RFB 150– 450 mg/day (weight)
Parola et al.71/1999 OS; n¼25 RFB+INH+E+X4 NA 24/25 (96%) —
RFB 150– 300 mg/day
Jo et al.49/2013 nested case– (RFB versus 0)+X5 72 10/14 (71%)b 19/42 (45%)
control; n ¼56 RFB 300 mg/day
14 patients RFB-susceptible
MDR TB versus 42 patients
RFB-susceptible MDR TB

CT, controlled trial; E, ethambutol; FQ, fluoroquinolone; INH, isoniazid; MDR, resistant to rifampicin and isoniazid; n, number of patients; NA, not available;
OS, open study; PAS, 4-amino salicylic acid; RCT, randomized controlled trial; RFB, rifabutin; RIF, rifampicin; X, companion drugs (X1, group of one to three
drugs including PAS, capreomycin, kanamycin, pyrazinamide, ethambutol and ethionamide; X2, group of one to five drugs including streptomycin,
ethambuthol, pyrazinamide, kanamycin, thioamide, quinolone, cycloserine, PAS, capreomycin and clofazimine; X3 and X4, unknown companion
drugs; and X5, individualized regimens on the basis of their direct susceptibility testing results including pyrazinamide, ethambuthol, streptomycin,
kanamycin, capreomycin, moxifloxacin, cycloserine, PAS, prothianamide and linezolid); Z, pyrazinamide.
a
Smear conversion was defined by culture or sputum smear conversion from positive to negative.
b
Significant difference.

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completing treatment, highest bacteriological conversion rates
and lowest incidence of adverse events (AEs).46
MDR TB
In the only controlled study that compared rifabutin with rifampi-
cin as part of a variable multidrug regimen in 22 patients with
chronic MDR pulmonary TB, the rate of sputum smear conversion
was 61% in both groups after 6 weeks.47 So far, other studies
supporting the use of rifabutin in MDR TB are retrospective, with
non-similar treatment groups, have limited sample size and do
not take into account rpoB mutation status.6,48,49
Clinical studies of rifabutin against MAC and
other NTM
Prophylactic treatment of disseminated MAC disease
Rifabutin-based daily prophylactic regimen in patients with AIDS
has been shown to improve survival in a meta-analysis of two ran-
domized double-blind multicentre trials since 1993, in 1146
patients, all performed during the pre-HAART era.50
Since then, two subsequent trials proved superiority of the
prophylactic macrolides regimen over the rifabutin regimen
among 1871 patients with AIDS with ,100 CD4 cells/mm3.51,52
Indeed, the risk of MAC disease was reduced by 44% –50% with
macrolides versus rifabutin. During the HAART era, primary
prophylaxis of disseminated MAC disease has become a contro-
versial issue.
Curative treatment of disseminated disease due to MAC
In randomized controlled trials, rifabutin in combination with a
macrolide and ethambutol did not improve microbiological out-
come, but was associated with a significant decrease in relapse
compared with placebo53 and with a relative risk of death of
0.46 (Table 4). In addition, rifabutin may protect against develop-
ment of clarithromycin resistance. Among responders, only 2%
receiving rifabutin developed clarithromycin resistance versus
14% in the placebo group.53,54 None of the trials so far directly
compared rifabutin and rifampicin.
Treatment of MAC lung disease in HIV-negative patients
Daily or intermittent regimens with macrolides associated with
ethambutol and rifamycins to avoid emergence of resistance
to macrolides are recommended.55 Overall, 24 – 48 week smear
conversion ranges from 61% to 86%. In a subanalysis of studies
where rifabutin or rifampicin were used, there were no significant
differences in outcome between these rifamycins.30,56,57 Despite
a lower tolerance of rifabutin among the elderly, switching from
rifampicin to rifabutin 150 – 300 mg/day is proposed in the most
severe cases (severe cavitary disease, treatment failure or true
disease relapse) because of less severe alterations in clarithro-
mycin metabolism than rifampicin.58
Clinical studies of activity of rifabutin in other infections than
mycobacterial and Helicobacter pylori infections are lacking
so far.
JAC
AEs
Major side effects
Haematological
Rifabutin-related neutropenia depends on dose,59 but also HIV sta-
tus, PI or macrolide co-administration and age.60 At 300 mg/day,
the discontinuation rate for severe neutropenia is not different
from control arms and ranges from 0% to 2%.51,61,62 Up to 12%
of HIV-negative patients with MAC lung disease require dose
adjustment.63
In large clinical trials, 0.5% –0.7% to 4.6% of patients experi-
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ence severe grade III thrombocytopenia at 300 mg/day and
450 mg/day, respectively.46,61 However, at 300 mg/day a higher
rate (up to 19%) has been reported among solid organ transplant
recipients with TB, suggesting underlying drug–drug interaction.64
Gastrointestinal symptoms
Gastrointestinal symptoms associated with rifabutin seem to be
related to age, rifabutin dose and macrolide co-administration.
Dosage adjustment or discontinuation of rifabutin for gastro-
intestinal symptoms is required in 2% – 5% of HIV-negative
patients treated for TB,46,48,61 in 3%– 15% of patients with AIDS
treated with rifabutin monotherapy for the prevention of MAC dis-
ease,51,52,62 reaches 27% when rifabutin is combined with cla-
rithromycin for disseminated MAC disease among patients with
AIDS53 and peaks at 30% – 50% in elderly patients treated with
rifabutin for MAC lung disease as part of a macrolide/azalide
regimen.56,57,59
Eyes
Uveitis is a rare (,0.01%) complication when the drug is given
alone at a standard (300 mg daily) dose,65 but can reach up to
8% – 38% when rifabutin is administered at higher doses or in
combination with clarithromycin, PIs or antifungal azoles.51,59,65
Treatment with topical steroids and cycloplegics usually leads to
rapid resolution of the uveitis without rifabutin discontinuation
except in refractory or recurrent cases of uveitis. Cystoid macular
oedema,66 retinal vasculopathy67 and corneal endothelial depos-
its68 – 70 have also been reported, in HIV-positive or -negative
patients.
Minor side effects
Orange discoloration of body fluids
Orange discoloration of body fluids is a universal effect of the
rifamycins.
Elevated AST
Elevated AST occurs in 10% of patients with TB treated with rifam-
picin or rifabutin,61 but ,1% of patients have symptomatic hepa-
titis. The safety of rifabutin treatment for TB in the case of chronic
liver disease has been reported in a case series with 25 patients.71
Rheumatological
Polyarthralgia occurs in 1% – 2% of persons receiving a
standard 300 mg dose of rifabutin,59 but is frequent at doses
.1000 mg/day.11 Lupus syndrome secondary to rifabutin has
also been occasionally reported.72
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Table 4. Rifabutin efficacy against MAC disease

Reference/year Design Treatment Outcome measure RFB arm Control

Bacteraemia in AIDS patients

Dautzenberg et al.105/1996 RCT-DB-P; n¼23 RFB versus P 14 days smear conversion 7/10 (70%)a 1/13 (10%)
RFB 600 mg/day
Dautzenberg et al.106/1991 OS; n¼50a RFB+E+CFZ+INH 12 weeks smear conversion 16/23 (69%) —
RFB 300– 600 mg/day (weight)
Sullam et al.107/1994 RCT-DB-P; n¼24 (RFB versus P)+E+CFZ 12 weeks smear conversion 6/9 (67%) 1/7 (14%)
RFB 600 mg/day

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Dautzenberg et al.74/1996 RCT-DB-P; n¼200 (RFB versus P)+E+CFZ+INH 12 weeks smear conversion 25/55 (45%) 18/47 (38%)
RFB 450–600 mg/day
median time to smear 43 days 69 days
conversion
Shafran et al.108/1996 RCT; n¼229 (RFB+CLR) 16 weeks smear conversion 69%a 29%
versus (RIF+CFZ+CIP)
+E
RFB 600 mg/day median survival 8.6 months 5.2 months
May et al.53/1997 RCT; n¼144 RFB+E+CLR 24 weeks smear conversion 14/67 (21%) 9/67 (13%)
versus CLR+CFZ relapse 6/28a 22/28
RFB 450 mg/day CLR resistance 2/67 21/67
Gordin et al.54/1999 CT-P; n¼ 198 (RFB versus P)+E+CLR 16 weeks smear conversion 61% 63%
RFB 300 mg/day
CLR resistance 1/44 (2%) 6/42 (14%)
Benson et al.109/2003 RCT; n¼160 (RFB versus 0)+E+CLR 12 weeks smear conversion 51% 40%
relapse 6%a 24%
risk of death RR¼0.46 —
Cohn et al.110/1999 RCT; n¼85 (RFB versus CFZ)+E+CLR 10.4 months survival 51% 48%
8 weeks smear conversion 21/27 (78%) 21/27 (78%)
Lung disease in HIV-negative patients
O’Brien et al.111/1990 OS; n¼406 RFB+X ? higher RFB dose —
RFB 150, 300 or 450 mg/day associated with
(random) sputum conversion
and survival
Wallace et al.112/1994 OS; n¼30 RFB+E+CLR+S 24 weeks smear conversion 14/19 (74%) —
Wallace et al.113/1996 OS; n¼50 RFB/RIF+E+CLR+S 48 weeks smear conversion 32/36 (82%) —
24 weeks smear conversion 24/29 (83%)
Griffith et al.56/2000 OS; n¼59 RFB+E+CLR 24 weeks smear conversion 32/41 (78%) —
3×/week:
RFB 300–600 mg (weight)
Griffith et al.114/1996 OS; n¼29 RFB+E+AZM +S 24 weeks smear conversion 14/21 (67%) —
RFB 300–600 mg/day
Griffith et al.57/2001 OS; n¼103 RFB/RIF+E+AZM+S 48 weeks smear conversion 56/103 (61%) —
daily versus 3×/w regimen
RFB 150–300 mg daily
RFB 300–600 mg 3×/w
Wallace et al.115/2014 OS; n¼180 RFB/RIF+E+AZM/CLR daily 48 weeks smear conversion 154/180 (86%) —
versus 3×/w regimen
RFB 150 mg daily
RFB 150–300 mg/week

CT, controlled trial; AZM, azithromycin; CLR, clarithromycin; CFZ, clofazimine; CIP, ciprofloxacin; DB, double blind; E, ethambutol; I, isoniazid; n, number of
patients; OS, open study; P, placebo; RCT, randomized controlled trial; RR, relative risk; S, streptomycin; RFB, rifabutin; RIF, rifampicin; /w, per week;
X, choice of companion drugs was left to the physicians.
a
Significant difference.

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Review
Flu-like syndrome and immunological reactions
Flu-like syndrome and immunological reactions are scarcer in
patients taking rifabutin than rifampicin (,0.1% versus 0.4% –
0.7%73) and are more likely to occur with intermittent administra-
tion or after a prolonged interruption of rifamycin therapy.
JAC
Skin
Rash is rarely (,0.1%) associated with rifabutin.74 Unusual
pigmentation in patients with AIDS,75 pseudojaundice that
resolves with the discontinuation of the drug76 and acute general-
ized exanthematous pustulosis77 have been reported.

Table 5. Main drug –drug interactions of rifabutin adapted from Baciewicz et al.116 – 118

Companion drugs’ RFB’s pharmacokinetic

Companion drug/pharmacokinetic pharmacokinetic change with

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target change with RFB companion drugsa Clinical outcome Reference(s)

Antifungal drugs
VCZ/trough 1 –5 mg/L trough trough RFB favourable outcome with low-dose RFB 119,120
(150 mg once daily) and high-dose
VCZ (300 mg three times a day)
PCZ/trough .0.7 mg/L Cmax 43%; AUC 49% Cmax 31%; AUC 72% 4/12 RFB-related side effects with 300 mg 121,122
RFB once daily+200 mg PCZ once
daily—avoid
ITZ/trough 1 mg/L trough 94% trough 153% therapeutic ITZ plasma level if increase ITZ 123– 125
to 900 mg once daily, but RFB-related
uveitis; serum ITZ concentrations did not
reach the therapeutic range of 1 mg/L in
80% (8/10) of patients treated with
200 mg ITZ twice daily and 300 mg
RFB once daily
FCZ no data AUC 76% 300 mg RFB once daily+200 mg FCZ 126,127
once daily
Antimycobacterial drugs
azithromycin/Cmax .0.3 mg/L no significant change no significant change no significant bilateral pharmacokinetic 128
interaction
clarithromycin/Cmax .2.5 mg/L trough 63% AUC 76% 127,129,130
Antistaphylococcal drugs
TMP/SMX SMX hydroxylamine no significant change could be involved in the TMP/SMX side 131,132
AUC 55% effect in HIV-infected patients
Antimalarial drugs
atovaquone proguanil AUC 34% no significant change 133
dapsone AUC; clearance 67% no significant change no change in dapsone hydroxylamine 132,134
formation, toxic dapsone derivative
Antiretroviral agents 116
see Table 6
Immunosuppressive drugs
see Table S3
Others
atenolol no significant change no significant change
theophylline no significant change no significant change 135
contraceptive AUC 35% ethinyl no significant change use alternative form(s) of birth control 136
oestradiol; AUC 13%
norethindrone
methadone no significant change no significant change 137,138
buprenorphine AUC 35% no significant change no opiate withdrawal symptoms 139

RFB, rifabutin; , increase; , decrease; %, exposure relative to the value without RFB; FCZ, fluconazole; ITZ, itraconazole; PCZ, posaconazole; SMX,
sulfamethoxazole; TMP, trimethoprim; VCZ, voriconazole.
a
Expected RFB trough ,50 mg/L.

1765
Review

Pregnancy gastrointestinal intolerance). Females and those with hepatitis C

There are insufficient data to recommend the use of rifabutin in
pregnant women and the drug should be used with caution in
pregnancy.78
Studies evaluating switching from rifampicin to rifabutin
Safety of rifabutin after rifampicin-related AEs has been reported in
small case series.79 – 81 A larger retrospective study confirmed the
safety of rifabutin replacing rifampicin among 221 HIV-negative
adults having rifampicin-related AEs. Of these patients, 21% and
7% experienced mild and severe rifabutin-related AEs respectively
or B virus co-infection were more prone to rifabutin-related severe
AEs and required more cautious monitoring.82
Drug– drug interactions
Advantages over rifampicin
Rifabutin has a weak liver induction of CYP enzyme and is an
interesting alternative to rifampicin in the setting of patients trea-
ted with drugs metabolized through CYP (Table 5) such as patients
with HIV under PIs or NNRTIs (Table 6), transplant patients under

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(neutropenia, severe hepatitis and uveitis). Arthralgia, dermato- calcineurin inhibitors (Table S3), but also drug addicts under
logical events and cholestasis had a higher recurrence rate (60%, methadone or buprenorphine or patients with heart disease
23% and 9%, respectively) than other AEs (5% for hepatitis and under atenolol.83

Table 6. Main drug –drug interactions of rifabutin with antiretroviral agents, adapted from CDC150 including update on darunavir, nelfinavir, tipranavir
and dolutegravir interactions

Antiretroviral pharmacokinetic RFB pharmacokinetic change with antiretroviral

change with RFB and the recommended dose adjustment (mg) in adults Reference

NRTIs
abacavir no no
didanosine
emtricitabine
lamivudine
stavudine
tenofovir
zidovudine
PIs
atazanavir/ritonavir no; AUC 15% yes; RFB 150/day
darunavir/ritonavir no; AUC 57% yes; RFB 150/day; RFB AUC 60% 151
fosamprenavir/ritonavir no; AUC 15% yes; RFB 150/day
indinavir/ritonavir no; AUC 32% yes; RFB 150/day
lopinavir/ritonavir no; AUC 0% yes; RFB 150/day
nelfinavir no; AUC 0% –32% yes; RFB 150/day; RFB AUC 22% (if RFB 300 2×/w) 152
ritonavir no; AUC 0% yes; RFB 150 2– 3×/w
saquinavir/ritonavir no; AUC 40% yes; RFB 150/day
tipranavir/ritonavir no; AUC 0% yes; RFB 150/day; RFB AUC 190% 153
NNRTIs
delavirdine NR; AUC 80% NR
efavirenz (if efavirenz is used, the rifamycin no; AUC 0% yes; RFB 600/day; RFB AUC 20%
of choice is rifampicin)
etravirine no; AUC 37% no; RFB AUC 17% 154
nevirapine no; AUC 16% no; RFB AUC ns
rilpivirine NR NR; RFB AUC 46%
CCR-5 receptor antagonists
maraviroc no no
Integrase inhibitors
dolutegravir no; AUC 5% ND 155
raltegravir no; AUC 16% no
elvitegravir co-formulated with cobicistat, NR; Cmin 64% NR; RFB AUC 500% 156
tenofovir and emtricitabine (StribildTM )

ND, no data; NR, not recommended; ns, non-significant; RFB, rifabutin; , increase; , decrease; %, exposure relative to the value without RFB; /w,
per week.
http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs.

1766
Review
Disadvantages over rifampicin
If the co-administered drug is a CYP3A inhibitor (or inducer), a sig-
nificant risk of rifabutin high concentrations (or underexposure,
failure and resistance) and related side effects might exist and
rifabutin dose adaptation is mandatory. This is the case with
most inhibitor drugs such as PIs, macrolides (except azithromy-
cin), azole drugs and diltiazem or verapamil or CYP3A inducers,
such as NNRTIs or phenytoin. Higher rates of gastrointestinal
and haematological side effects have been reported with the
co-prescription of rifabutin and macrolides, which may not only
be related to pharmacokinetic interactions.63
Risk of resistance emergence
Mycobacteria
In vitro, rifabutin shows promising results in limited mutant pre-
vention concentration data in M. tuberculosis strains.84,85
Since the first case report in 1995,86,87 M. tuberculosis resist-
ance to rifampicin after rifabutin prophylaxis for MAC in patients
with AIDS has been demonstrated in a case – control study.88
Similarly, rifampicin-resistant M. tuberculosis TB relapses following
rifabutin-based intermittent curative TB treatment in patients
with HIV under PIs have been reported87 and later related to
lower rifabutin plasma concentrations21 and the intermittent rifa-
mycin dosing schedule in the intensive phase of treatment. 89
Rifampicin-resistant M. kansasii infection in a patient with AIDS
receiving rifabutin prophylaxis has also been reported.90
Other bacteria
In in vitro studies, the frequency of occurrence of spontaneous
mutants of S. aureus strains is similar with rifampicin and rifabutin
(3.2×1026 and 1.2×1026, respectively).34
In 1994, two cases of catheter-related bacteraemia due to
rifampicin-resistant S. aureus and Staphylococcus epidermidis
in a patient with AIDS receiving rifabutin monotherapy were
reported.91
Discussion
The largest potential added value of rifabutin compared with
rifampicin could apply to TB/HIV co-infected patients under PIs.
However, the benefits of rifabutin may be lower than expected
in resource-limited countries where therapeutic drug monitoring
and drug susceptibility for rifabutin are limited and where the
absence of a rifabutin-based fixed-dose combination for TB
might be a constraint to ensure good adherence to TB treatment.
Despite advances in the field, there is an urgent need to bridge the
knowledge gap of this WHO Essential Medicine. Pharmacokinetic/
pharmacodynamic targets for rifabutin remain to be defined.
Clinical trials to investigate the role of rifabutin in the case of
MDR TB, but rifabutin-susceptible, isolates are lacking. Rifabutin
deserves further investigation into biofilm-associated S. aureus
infection or those infections caused by multiply resistant
Gram-negative bacilli.
Conclusions
Compared with rifampicin, rifabutin’s lower AUC is balanced
by higher intracellular penetration and lower MIC for most patho-
gens. Therefore, AUC/MIC parameters of the two drugs are quite
JAC
similar, but rifabutin has a much lower CYP3A induction property.
There are consistent in vitro and clinical data showing that rifabu-
tin has equivalent efficacy and tolerance compared with rifampi-
cin in TB and NTM diseases, though the level of evidence is lower in
HIV-infected patients.
The last few years of research in the field of TB treatment/
resistance have challenged current recommendations. MIC WT
distribution studies in relation to mutation in the rpoB gene do
not support the old breakpoint for M. tuberculosis or the use of rifa-
butin in the case of rifampicin resistance.
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Acknowledgements
We thank Nour Shamas, PharmD, BCPS for critical reading and editing of
the manuscript prior to submission.
Transparency declarations
None to declare.
Supplementary data
Tables S1 – S3 are available as Supplementary data at JAC Online (http://
jac.oxfordjournals.org/).
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