1. No category

Possible implications of doxycycline-rifampin
interaction for treatment of brucellosis.
J D Colmenero, L C Fernández-Gallardo, J A Agúndez, J Sedeño,
J Benítez and E Valverde
Antimicrob. Agents Chemother. 1994, 38(12):2798. DOI:
10.1128/AAC.38.12.2798.
These include:
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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1994, p. 2798-2802
Vol. 38, No. 12
0066-4804/94/$04.00+0
Copyright X) 1994, American Society for Microbiology
Possible Implications of Doxycycline-Rifampin Interaction
for Treatment of Brucellosis
J. D. COLMENERO,l* L. C. FERNANDEZ-GALLARDO,2 J. A. G. AGUNDEZ,3
J. SEDENO,' J. BENITEZ,3 AND E. VALVERDE2
Unit of Infectious Diseases, Intemal Medicine Department,' and Department of Pharmacy, 2 Mdlaga Regional Hospital,
Mdlaga, and Department of Pharmacology, University of Extremadura, Extremadura,3 Spain
Received 4 January 1994/Returned for modification 1 June 1994/Accepted 29 August 1994
We studied the possible interaction between rifampin and doxycycline in 20 patients with brucellosis treated
patients treated with doxycycline and streptomycin. Furthermore, clearance in patients treated with rifampin
significantly higher than that in patients treated with doxycycline and streptomycin, and consequently, the
elimination half-life and the area under the concentration-time curve were significantly lower. There was no
therapeutic failure or relapse in the group treated with doxycycline and streptomycin, whereas 2 of 10 patients
in the group treated with doxycycline and rifampin had a therapeutic failure or relapse. The plasma
doxycycline levels had an inverse correlation with plasma rifampin levels. In the group treated with rifampin,
those who were rapid acetylators had lower levels of doxycycline. In conclusion, combined treatment with
rifampin reduces the levels of doxycycline in plasma. These data suggest that therapeutic failures or relapses
may result from this interaction.
was
Brucellosis is still
a
serious public health problem in
known, some data suggest that the liver may play an important
part (10). Given that rifampin is metabolized through deacetylation, that those data that do exist suggest that drug levels are
lower in the plasma of patients who are slow acetylators, and
that it has a potent enzymatic inductor effect (4), we designed
the study described here to determine whether combination
therapy with rifampin lowers plasma doxycycline levels and
whether this circumstance is related to the acetylator genotype
of the patient.
many
result
of this infection is low (12), it causes frequent complications,
particularly those affecting the locomotor system, and these
complications sometimes cause serious functional sequelae (3,
15).
The organisms of the genus Brucella are known to have a
high degree of "in vitro" susceptibility to a number of antimicrobial agents (11, 36). However, their location, which is
predominantly intracellular, protects them from the actions of
many antibiotics. This explains to a great extent the tendency
of this organism to cause illness with a long evolution and
frequent relapses (41).
For several decades the treatment of choice for brucellosis
was based on the association of tetracyclines and streptomycin
(13, 29). Several studies carried out in the beginning of the
1980s showed that rifampin had excellent antibrucellar activity.
This fact, together with its good intracellular penetration and
ease of administration, made it a drug of great interest for the
treatment of brucellosis (7, 16, 33).
Studies with animal models and humans showed that rifampin monotherapy for brucellosis resulted in a high number
of therapeutic failures and relapses (20, 28). However, when it
was used in combination with doxycycline there was a clear
synergism and a good therapeutic efficacy (6).
In 1986, the Expert Committee on Brucellosis of the Food
and Agriculture Organization-World Health Organization recommended the combination of doxycycline-rifampin as the
treatment of choice for human brucellosis (24). Later studies
showed that the combination doxycycline-rifampin was less
effective in practice than the classical treatment of tetracycline
and streptomycin (1, 14).
Although the doxycycline elimination process is not totally
parts of the world (43). Although the mortality rate
as a
MATERIALS AND METHODS
Patient population. The present study was carried out with
19 patients with brucellosis in the Unit of Infectious Diseases
of Malaga Regional Hospital. A diagnosis of brucellosis was
made by the isolation of the organism or the presence of
compatible clinical features together with the demonstration of
specific antibodies at significant titers. Significant titers were
considered to be .1/160 for seroagglutination and .1/320 by
the anti-Brucella Coombs test. Blood cultures and serological
tests were done by previously described methods (15).
Once the diagnosis was made, the patients were randomized
into one of two therapeutic groups. Patients in group A were
treated with doxycycline at 100 mg orally every 12 h for 6 weeks
and streptomycin (sulfate) at 1 g intramuscularly daily for the
first 3 weeks. Patients assigned to group B received the same
dose of doxycycline plus rifampin: 600 mg/day orally for those
who weighed between 50 and 60 kg, 900 mg/day for those who
weighed between 61 and 80 kg, and 1,200 mg/day for those who
weighed more than 80 kg. The single doses were given in the
morning for 6 weeks. In patients with spondylitis, both schedules were maintained for 3 months.
Initially, the sample consisted of 19 patients: 9 were in group
A and 10 were in group B. One patient assigned to group B was
later treated with the schedule for patients in group A owing to
a relapse a month after the end of the first treatment. The
study sample was therefore composed of 20 cases, 10 in each
therapeutic group.
Corresponding author. Mailing address: Unit of Infectious DisInternal Medicine Department, Hospital Regional de Malaga,
Camino de Antequera s/n, 29010 Malaga, Spain. Phone: 952390400.
Fax: 952288349.
*
eases,
2798
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randomly with either doxycycline and streptomycin or doxycycline and rifampin. The doxycycline levels in the
plasma of patients in the group treated with rifampin were significantly lower than those in the plasma of
DOXYCYCLINE-RIFAMPIN INTERACTION
VOL. 38, 1994
TABLE 1. Clinical characteristics of patientSa
Characteristic
Group A
Group B
Sex (no. male/no. female)
Age (yr)b
Wt (kg)b
Duration of symptoms (days)b
Blood culture positive (%)
Focal forms (%)
7/3
35.3 ± 18.8
6/4
32.1 ± 12.1
74 ± 11.4
53.7 ± 35.8
70.7 ± 16.7
67.5 ± 73.2
67
40
67
40
a None of the differences between patients in groups A and B was significant.
b Values are means ± standard deviations.
Baseline
3
6
9
12
TABLE 2. Levels of doxycycline in plasma
Mean ± SD doxycycline level (,ug/dl)
Group A
Group B
Significance
2.72 ±
3.97 ±
3.58 ±
2.78 ±
2.12 ±
1.57
1.91
1.47
1.03
0.91
1.05
2.73
2.73
1.35
0.70
±
±
±
±
±
0.67
1.29
1.29
0.43
0.36
P < 0.05
NSa
P < 0.05
P < 0.001
P < 0.0005
a NS, not significant.
the supernatant fraction, 20 [lI was injected directly into the
chromatograph. Each sample was analyzed three times.
Assay performance. The pharmacokinetic parameters elimination half-life (t112g), total body clearance (CL), and area
under the concentration-time curve (AUC) were analyzed by
an open two-compartment model. Since we had access to only
limited information about the absorption phase, in the present
study we used the absorption constant values referred to in the
studies of Saivin and Honin (37) and considered the bioavailability of doxycycline by the oral route to be 90%.
Acetylator genotype evaluation. For evaluation of the acetylator genotype, 20 ml of venous blood anticoagulated with
EDTA was obtained and immediately stored at -80°C until it
was processed.
The acetylator genotype was evaluated by PCR-based allelespecific amplification as described previously (9). Three common mutations at the NAT-2 gene locus were studied, namely,
a C residue at position 481 (481C) to 481T, 590G to 590A, and
857G to 857A. All of these mutations lead to the slow
acetylator phenotype. The subjects homozygous or heterozygous for the wild-type allele were classified as rapid acetylators,
whereas the subjects homozygous for mutant alleles were
classified as slow acetylators.
Once the treatment was concluded the patients were followed clinically and bacteriologically monthly for at least 6
months. Therapeutic failure was considered to be the persistence of symptoms after the third week of treatment, and
relapse was considered to be the reappearance of symptoms
once the treatment had finished.
Statistical analysis. Statistical analysis of the results was
performed by using the Statistical Package for Social Sciences.
To assess the difference between mean values the Student t test
and the Wilcoxon test were used. The Pearson correlation
coefficient was used to study the relation between variables. A
P value of less than 0.05 was considered significant.
RESULTS
Of the total number of patients included in the study, 13
(65%) were men and 7 (35%) were women. The mean age was
33.3 ± 15.6 years (r = 17 to 69).
The duration of the symptoms was 60.2 ± 55.7 days. Three
or more blood samples from 18 patients were cultured, with a
positive result for 12 (66.6%) patients. The isolated organism
was Brucella melitensis biovar 1 for all 12 patients.
TABLE 3. Pharmacokinetic parameters for doxycyclinea
CL (liters/h)
AUC (,ug h/ml)
Group
t1/21 (h)
72.6 ± 35.3
1.55 ± 0.73
A
10.59 ± 4.71
30.4 ± 12.3
B
4.32 ± 2.26
3.59 ± 1.79
a p was < 0.005 for all comparisons. Values are means ± standard deviations.
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All of the patients included in the study had normal hepatic
and renal functions, and none of them received any drugs or
took any alcohol during the treatment period.
From days 7 to 10 after the start of treatment, once the
equilibrium phase of doxycycline had been reached, the patients were admitted to the hospital 12 h prior to the commencement of the study and remained in the hospital until the
conclusion of the pharmacological part of the study.
Doxycycline and rifampin levels were measured in plasma
obtained from whole-blood samples withdrawn just before
(point 0) and 3, 6, 9, and 12 h after the administration of
doxycycline and rifampin or doxycycline and streptomycin.
They were analyzed by high-pressure liquid chromatography
with Perkin-Elmer equipment consisting of a binary pump
(LC-250), a manual sample injector with bypass and bucle
volume of 20 ,ul, a diode array detector (LC-235, operated at
0.005 AV and a wavelength of 340 nm), an analytic column
(Lichrospher 100RP-18; 5 ,um, 125 by 4 mm [inner diameter]).
A solution of 0.1 M citric acid-acetonitrile (20:80; vol/vol) at a
flow rate of 1 ml/min was used as a mobile phase for doxycycline, and for rifampin a solution of acetonitrile-acetate buffer
(0.1 M sodium acetate with 1% triethanolamine adjusted to
pH 4 with acetic acid [55:45; vol/vol]) was used at a flow rate of
1 ml/min.
The doxycycline and rifampin standards were kindly provided by Pfizer Corporation (Brussels, Belgium) and Marion
Merrell Dow (Madrid, Spain). As an internal standard, papaverine chloride was used. The other solvents and reactive agents
used were of analytical grade.
The stock standard solutions were prepared by dissolving
doxycycline HCl (1 mg/ml) and rifampin (2 mg/ml) in methanol. Papaverine chloride was dissolved in acetonitrile-water
(90:10; vol/vol) at a concentration of 2 mg/ml. These solutions
were stable for a period of at least 30 days at -20°C. By using
the stock solutions and through dissolution in icteric human
plasma, the working standards of doxycycline and rifampin
were prepared at concentrations of 2.5 and 10 ,ug/ml, respectively. The internal standard of papaverine was prepared by
dissolving the stock solution in acetonitrile at a concentration
of 20 p,g/ml.
Both methods were found to be precise. The calibration
graphs for rifampin and doxycycline were linear over concentration ranges of between 0.5 and 25 ,ug/ml and 0.2 and 5
,ug/ml, respectively.
The intra- and interassay coefficients of variation for doxycycline concentrations of 0.2 and 5 ,ug/ml were 4.1 and 2.1%
and 6.2 and 3.5%, respectively. For rifampin the intra- and
interassay coefficients of variation for concentrations of 0.5 and
25 ,ug/ml were 4.2 and 1.4% and 5.0 and 1.8%, respectively.
The processing of the samples involved several steps. The
combination of 0.5 ml of problem serum with 0.5 ml of the
papaverine solution was mechanically agitated for 7 min and
was centrifuged at 9,500 rpm for 10 min. After separation of
Time (h)
2799
2800
COLMENERO ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 4. Relation between levels of rifampin and doxycycline
Time (h)
Correlation coefficient (r)
Baseline
3
6
9
12
TABLE 6. Levels of doxycycline in patients treated with rifampin
Significance
-0.143
-0.319
-0.851
-0.719
-0.513
NSa
NS
P < 0.005
P < 0.05
NS
a NS, not significant.
Doxycycline level
Time (h)
Rapid acetylators
Baseline
3
6
9
12
0.95 ±
2.35 ±
1.42 ±
1.24 ±
0.65 ±
(p.g/mI) ina:
Significance
Slow acetylators
0.43
0.52
0.32
0.19
0.35
1.03 ±
3.06 ±
2.72 ±
1.42 ±
0.74 ±
NSb
0.75
1.55
1.20
0.35
0.41
NS
P = 0.07
NS
NS
a Values are means ± standard deviations.
b NS, not significant.
cline plus rifampin (Table 3).
The levels of rifampin in the plasma of group B patients
were 0.68 ± 0.41, 14.8 ± 6.00, 8.3 ± 2.9, 4.8 ± 2.2, and 2.2 ±
1.5 mg/liter at 0, 3, 6, 9 and 12 h, respectively, after ingestion
of the drug.
We detected an inverse relation between the levels of
doxycycline and rifampin which was statistically significant at 6
and 9 h (r = -0.851 and -0.719; P = 0.005 and P = 0.02,
respectively) (Table 4).
Of the 19 patients studied, 6 (31.5%) were rapid acetylators:
2 (20%) were in group A (1 was homozygous and 1 was
heterozygous) and 4 (40%) were in group B (2 were homozygous and 2 were heterozygous).
The levels of rifampin in plasma were greater in the rapid
acetylators. These differences were statistically significant at 3
and 6 h (Table 5). Inversely, the levels of doxycycline were
lower in the rapid acetylators treated with rifampin, although
these differences had no statistical significance (Table 6).
Although only two patients in the group treated with the
doxycycline-streptomycin schedule were rapid acetylators, our
results appear to indicate that in this group there were no
differences in doxycycline levels by acetylator genotype (data
not shown).
Eighteen patients, 90% of the total, were cured with just one
course of therapy. The other two patients, both in group B,
presented with a relapse and a therapeutic failure, respectively.
The first patient relapsed 1 month after the end of the
treatment, with fever and low back pain caused by spondylitis
which was cured after a new course of doxycycline plus
rifampin for 3 months. The second patient had right orchiepididymitis that failed to respond to therapy. He was therefore
Time (h)
Baseline
3
6
9
12
0.58
20.6
10.9
6.65
3.03
For more than 40 years tetracyclines have been the basis of
treatment for brucellosis (32, 35). Furthermore, the use of
tetracyclines in monotherapeutic schedules is known to be less
effective than the use of tetracyclines in association with a
second antibrucellar drug (17). Once it was established that the
combination of tetracycline and streptomycin presented in
vitro synergistic antibrucellar activity and that it was highly
effective, this schedule became the treatment of choice for
brucellosis (23). However, the vestibular toxicity of streptomyPlasma concentration (,ug/ml)
4
3
2
Significance
Slow acetylators
± 010
± 2.37
± 1.88
± 2.62
± 2.43
a Values are means ± standard deviations.
NS, not significant.
b
DISCUSSION
I
TABLE 5. Plasma rifampin levels
Plasma rifampin level (,ug/ml) ina:
Rapid acetylators
changed to the therapeutic schedule for group A patients, and
the symptomatology disappeared after 15 days, with a definitive cure. The levels of doxycycline in the plasma of this patient
while receiving both therapeutic schedules are shown in Fig. 1.
Overall, all 10 group A patients were cured, whereas there
were two failures among group B patients. There were no
differences in the AUCs for the two therapeutic failure and
relapse patients and the remainder of the group treated with
rifampin.
0.74
11.9
7.04
3.85
1.77
±
±
±
±
±
0.51
4.99
2.55
1.50
0.73
NSb
P < 0.05
P = 0.05
P = 0.07
NS
0
0
3
6
9
12
Time after intake of doxycycline (h)
FIG. 1. Doxycycline levels in the plasma of patient 12 during the
doxycycline-rifampin schedule (-) and after a change to doxycyclinestreptomycin (A).
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Eight patients (40%) presented with a focal form of disease.
Four cases of epididymitis, two cases of spondylitis, one case of
sacroiliitis, and one breast abscess were detected.
Both groups of patients were homogeneous for the more
relevant clinical parameters (Table 1).
The levels of doxycycline at the baseline (time zero) and 6,
9, and 12 h after ingestion of the drug were significantly lower
in group B patients (Table 2). Furthermore, both tl2,3 and
AUC were significantly lower in group B patients. Conversely,
CL was increased significantly in patients treated with doxycy-
VOL. 38, 1994
14, 39, 40).
Rifampin exerts its enzymatic inductor effect by causing a
marked proliferation of the smooth endoplasmic reticulum and
increasing the hepatic content of cytochrome P-450 (22). Some
studies have suggested that this inductor effect is related to
both the dose of the drug and the duration of treatment (31).
Our results seem to support this hypothesis, since the levels of
doxycycline in plasma had an inverse relationship to those of
rifampin.
Although the elimination process is only partially known, a
considerable proportion of doxycycline may be metabolized in
the liver, since it does not accumulate in patients with renal
failure (21).
In a previous study patients treated with equal doses of
rifampin and doxycycline showed different doxycycline levels,
which could apparently indicate interindividual differences in
the sensitivity to the enzymatic inductor effect of rifampin (18).
2801
These differences can also be related to the existence of slow
metabolizors in the study population (30).
The decrease in the levels of doxycycline in the plasma of
patients who are rapid acetylators appears to be related to the
higher levels of rifampin in this group. Currently, there are no
data to explain the apparent relation between the rapid
acetylator genotype and the increased levels of rifampin in
plasma. This relation could be explained in part by an acetylation-deacetylation imbalance of this drug. This disequilibrium has been described in the metabolism of numerous
chemical compounds, such as acrylamides (26, 27), 4-aminobiphenyl (25), and sulfadimethoxine (38).
In conclusion, the results of our study indicate that rifampin
lowers the levels of doxycycline in the plasma in of patients
receiving the combined treatment, and this is likely to result in
lower therapeutic efficacy in patients with brucellosis. Finally,
we suspect that the discrepancies in the therapeutic efficacies
of the combination doxycycline-rifampin compared with that of
the doxycycline-streptomycin schedule found in previous clinical trials could be explained by the different prevalences of
patients with slow metabolizors and acetylator genotypes in the
study populations.
ACKNOWLEDGMENTS
We thank Luis Lozano for technical assistance.
The study was supported in part by grants CYTIT-SAF92-0333,
FISS 89/0305, and FISS 93/0632. This work has been carried out within
the European Collaborative Group of the Center for Cooperation in
the Field of Scientific and Technical Research of the European
Communities, project Bl-phase II.
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of those who received streptomycin. Likewise, t1l2, and AUC
were also reduced significantly, whereas the doxycycline CL
was increased significantly.
Although the number of patients included in the study was
small and it was not our intention to demonstrate differences in
the therapeutic efficacies of the two schedules, we nevertheless
once again observed that the number of therapeutic failures or
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This finding supports those of previous clinical trials, which
showed a lower degree of efficacy of the doxycycline-rifampin
schedule compared with that of the classical treatment (1, 2,
DOXYCYCLINE-RIFAMPIN INTERACTION
2802
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