Serum rifampicin concentration related to dose size and to the incidence of the ‘flu’ syndrome during intermittent rifampicin administration

Dickinson, Jean M.; Mitchison, D.A.; Lee, S. K.; Ong, Y. Y.; O'mahoney, M. G.; Girling, D J; Nnnn, A. J.

doi:10.1093/jac/3.5.445

Cited by 18 publications

(8 citation statements)

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“…The finding that one-sixth of the middle-aged group in the present study experienced SDR during 3HP treatment is unexpected. Although some reports suggest that RPT is the offending drug causing SDR [ 11 , 26 , 27 ], the results of 2 recent studies revealed that the N -acetyl transferase 2 genotype and plasma concentration of INH are associated with the development of SDR [ 14 , 28 ], implying that INH may play a critical role in the pathophysiology of 3HP-related SDR. Although the risk of SDR during 3HP treatment is higher in individuals older than 35 years [ 4 , 11 ], results of the current study demonstrate that SDR risk does not increase further in elderly people.…”

Section: Discussionmentioning

confidence: 99%

Impact of Age on Outcome of Rifapentine-Based Weekly Therapy for Latent Tuberculosis Infection

Huang

Lee

Cheng

et al. 2020

Clinical Infectious Diseases

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Background Weekly rifapentine and isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential. Methods Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (35–65 years), and younger (≤35 years) groups. This study investigated the impact of age on treatment outcome, particularly systemic drug reaction (SDR) and 3HP discontinuation. Results Overall, 134 (23.1%) of 579 participants were elderly. The completion rate was 83.1% in overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) groups, respectively. However, the 3HP discontinuation rate was not significantly different among the three groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced ≥1 adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (p=0.025). This finding was consistently observed in different clinical settings. Hypertensive event accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs. Conclusions With proper medical support and programmatic follow-up, the 3HP completion rate is higher than 70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDR and hypertensive event, respectively.

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Section: Discussionmentioning

confidence: 99%

Impact of Age on Outcome of Rifapentine-Based Weekly Therapy for Latent Tuberculosis Infection

Huang

Lee

Cheng

et al. 2020

Clinical Infectious Diseases

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“…Another potential advantage would have included the ability to give the cumulative weekly dose of rifampin as a single dose without compromising its effect. However, these sorts of high intermittent doses of rifampin are currently not recommended because of the "flu-like" illness encountered in many patients (10,15). This is probably due more to the intermittent nature of the high doses than the just high doses per se (34).…”

Section: Discussionmentioning

confidence: 99%

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin

Gumbo

Louie

Deziel

et al. 2007

Antimicrob Agents Chemother

314

303

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Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampin's half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampin's microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (C max )-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free C max /MIC ratio of >175. The postantibiotic effect duration was >5.2 days and was most closely related to the C max /MIC ratio (r 2 ‫؍‬ 0.96). To explain rifampin's concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free C max /MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.Tuberculosis (TB) is arguably the most important infectious disease to have confronted humankind. Currently, Mycobacterium tuberculosis infects 2 billion of the 6 billion people worldwide (50). The discovery of rifampin 40 years ago (31) was revolutionary in allowing the creation of potent combination drug regimens against this ancient nemesis. Rifampin is the backbone of modern anti-TB chemotherapy by virtue of being active against M. tuberculosis in exponential growth phase as well as possessing activity against nonreplicating persistent bacilli. Major limitations to rifampin use are believed to include its short half-life (t 1/2 ), which allows cycles of M. tuberculosis regrowth and resistance emergence.It has been the belief for almost half a century that if a drug such as rifampin was given once a week in the initial phase of therapy, its short serum t 1/2 of 3 h would allow short periods of microbial killing followed by regrowth between doses (33, 37). The inference is that the length of time that rifampin is above a certain threshold concentration is the most important index associated with M. tuberculosis killing and the prevention of resistance. Thus, one of the strategic goals of the World Health Organization, the pharmaceutical industry, and research scientists has been to develop rifampin congeners with long t 1/2 s, such as rifapentine, which would make intermittent dosing more effective (3,9,24,26).It is widely believed...

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“…Second, rifampin showed no effect on chemotaxis induced by activated serum (C5a) or on C5a-induced shape changes, both of which require PML viability. Finally, the effects of rifampin reported here were observed at concentrations readily attained in serum during rifampin therapy (7,8,11,16,23).…”

Section: Discussionmentioning

confidence: 62%

Rifampin affects polymorphonuclear leukocyte interactions with bacterial and synthetic chemotaxins but not interactions with serum-derived chemotaxins

Gray¹,

Smith²,

Hollers³

et al. 1983

Antimicrob Agents Chemother

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Three independent experimental approaches support the hypothesis that rifampin competes for receptors on polymorphonuclear leukocytes (PMLs) with small peptide chemoattractants, e.g., N-formylmethionylleucylphenylalanine (FMLP), but not with serum-derived chemoattractants (CSa) Chemotaxis of phagocytes toward infectious agents constitutes one important element in successful host defense against infectious disease. Since antibiotics are the agents used most often during therapy of infectious diseases, investigations of the possible influence of antibiotics on chemotaxis are warranted.In preliminary studies, examination of a panel of antibiotics for their effects on chemotaxis of polymorphonuclear leukocytes (PMLs) confirmed that rifampin was a potent inhibitor of chemotaxis toward Escherichia coli culture filtrates (13,14). However, the unusual shape of dose-response inhibition curves and other data led to the hypothesis that rifampin competes for receptors on PMLs with bacterial and synthetic peptide chemotaxins but not with serum-derived chemotaxins. (G. D. Gray, K. A. Knight, and C. A. Talley, Fed. Proc. 39:878,1980) The current study was performed to further evaluate this hypothesis. Three independent experimental approaches were used to study rifampin. We tested its effects on chemotaxis, on the binding of radiolabeled chemotactic ligands to PMLs, and on chemotaxin-induced shape changes in PMLs. Rifampin effects were investigated with two types of chemoattractants that bind to different sites on PMLs: small peptide chemoattractants such as N-formylmethionylleucylphenylalanine (FMLP) and serum-derived (C5a) chemoattractants (2,3,5,6,21,31). MATERIALS AND METHODSMaterials. The following reagents were purchased from Vega Biochemicals, Tucson, Ariz.: FMLP, methionylleucylphenylalanine, and carbobenzoxyphenylalanylmethionine (CBZPM); from Sigma Chemical Co., St. Louis, Mo.: N-formylmethionylphenylalanine, puromycin, tetracycline, cycloheximide, erythromycin, and pepstatin; from Calbiochem, La Jolla, Calif.: rifampin (rifampicin) and rifamycin SV; from Worthington Biochemicals, Freehold, N.J.: human serum albumin; from MCI Biomedical, Rockland, Mass.: SeaKem agarose; from Aldrich Chemical Co., Milwaukee, Wis.: N-methylpiperazine; and from New England Nuclear Corp., Boston, Mass.: N-formylmethionylleucyl[3H]phenylalanine (3H-FMLP) (specific activity, 56.9 Ci/mmol). Clindamycin and lincomycin were obtained from the Upjohn Co., Kalama-zoo, Mich. Sterile filtrates were prepared from cultures of Propionibacteria granulosum (UC-6565) and E. coli (UC-51).Isolation of human PMLs. Two different PML isolation procedures were used. PMLs used in the chemotaxis and radiolabeled-ligand studies were isolated as described previously (5, 21). The PMLs used in the shape change studies were isolated by a slightly different method (9, 30). In both cases, polymorphonuclear neutrophils were present in concentrations of .95%.

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Serum rifampicin concentration related to dose size and to the incidence of the ‘flu’ syndrome during intermittent rifampicin administration

Cited by 18 publications

References 0 publications

Impact of Age on Outcome of Rifapentine-Based Weekly Therapy for Latent Tuberculosis Infection

Impact of Age on Outcome of Rifapentine-Based Weekly Therapy for Latent Tuberculosis Infection

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin

Rifampin affects polymorphonuclear leukocyte interactions with bacterial and synthetic chemotaxins but not interactions with serum-derived chemotaxins

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