Possible implications of doxycycline-rifampin interaction for treatment of brucellosis

Abstract

We studied the possible interaction between rifampin and doxycycline in 20 patients with brucellosis treated 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 patients treated with doxycycline and streptomycin. Furthermore, clearance in patients treated with rifampin was 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.Brucellosis is still a serious public health problem in many parts of the world (43). Although the mortality rate as a 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).

Doxycycline-rifampin versus doxycycline-streptomycin in treatment of human brucellosis due to Brucella melitensis. The GECMEI Group. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas

“…on May 12, 2018 by guest http://aac.asm.org/ between the two therapeutic regimens (12). It should be emphasized, however, that this trial did not address the mechanism of therapeutic efficacy directly and that our suggestions regarding the mechanism are only speculative.…”

“…Administration of DR treatment for shorter periods has been associated with a relapse rate of 30 to 40% in other studies (4,50). Interaction of rifampin with doxycycline has been reported in recent studies (8,12,23). Rifampin is one of the most potent inducing agents for hepatic mycrosomal enzymes and leads to decreased levels of doxycycline in serum, in the same patients, when administered in combination (23).…”

Efficacy of Three-Week Oxytetracycline or Rifampin Monotherapy Compared with a Combination Regimen against the Filarial Nematode Onchocerca ochengi

“…The reasons for this failure were not determined, but in duotherapy for brucellosis, pharmacokinetic interference between DOX and RIF has been reported. Hence, plasma levels of DOX were reduced by 50% in brucellosis patients exhibiting metabolic induction of hepatic microsomal enzymes (45), while in a larger study, a statistically significant inverse correlation between DOX and RIF plasma concentrations was apparent, which resulted in two cases of therapeutic failure or relapse (46). Moreover, there was a trend for DOX levels to be lower in brucellosis patients also receiving RIF who had a "rapid acetylator" N-acetyltransferase-2 genotype (46).…”

“…Hence, plasma levels of DOX were reduced by 50% in brucellosis patients exhibiting metabolic induction of hepatic microsomal enzymes (45), while in a larger study, a statistically significant inverse correlation between DOX and RIF plasma concentrations was apparent, which resulted in two cases of therapeutic failure or relapse (46). Moreover, there was a trend for DOX levels to be lower in brucellosis patients also receiving RIF who had a "rapid acetylator" N-acetyltransferase-2 genotype (46). Although, to the best of our knowledge, no studies on liver function following RIF therapy have been performed on ruminants, a detrimental effect on OXY pharmacokinetics caused by metabolic induction is a plausible explanation for the poor efficacy of duotherapy in our study.…”

Unraveling Ambiguous NAT2 Genotyping Data

“…About 50% of white individuals are classified as slow acetylators, and these individuals show impaired metabolism of many therapeutically useful arylamine and hydrazine drugs (1 ). In patients with tuberculosis who receive isoniazid, determination of the N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2) genotype or phenotype has been proposed as a method for predicting adverse reactions as well as before the concomitant administration of drug combinations such as procainamide-phenytoin or doxycycline-rifampin (1)(2)(3). In addition, the NAT2 polymorphism modulates the risk for the development of bladder (4,5 ) and liver cancer (6 ).…”