Administration Of Rifampicin Research Articles

Dosing and route of administration of clindamycin given in combination with rifampicin.

The aim of this study was to develop a pharmacokinetic (PK) interaction model of intravenous (i.v.) and oral clindamycin when combined with rifampicin, and to determine whether appropriate clindamycin concentrations could be achieved for different doses and administration routes (oral, intermittent and continuous infusion) of clindamycin. Five hundred and eighteen plasma samples were prospectively obtained from 124 patients treated for bone and joint infections. Population pharmacokinetic analysis was performed using Monolix software. Monte Carlo simulations were run to determine the probability of achieving a minimal clindamycin plasma concentration equal to at least twice the MIC, or an unbound area under the curve/MIC ≥60. A linear one-compartment model with first-order absorption and elimination was developed. Concomitant administration of rifampicin increased clindamycin clearance by an average factor of 3, whereas the impact on clindamycin bioavailability was dose dependent, with decreases from 56 to 11 and 4% for rifampicin doses of 600 mg and 900 mg q12h, respectively. When administered simultaneously with rifampicin, satisfactory clindamycin concentrations could not be obtained when given orally. i.v. administration of a daily 3600 mg dose would be convenient for more than 80% of the patients, but doses of at least 4800 mg/d would be needed for a MIC equal to the 0.25 mg/L European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint for Staphylococcus aureus. Intermittent i.v. administration every 6hours is preferable to q8h regimens for the Cmin/MIC criteria, but still performed poorly compared with continuous infusion. This model satisfyingly described the differential effect of rifampicin on the bioavailability and clearance of clindamycin. As previously described, this combination must not be taken orally. However, administration of clindamycin doses of at least 3600 mg/d by intermittent or, preferably, continuous infusion, can balance the impact of rifampicin.

Study of gene expression of the Toll-like receptor system in the forebrain cortex of rat pups with prenatal alcohol exposure and pharmacologic correction with rifampicin

Ethanol causes changes in the toll-like receptor (TLR) system in the brain promoting activation of neuroinflammatory pathways. Alcohol consumption during pregnancy induces neuroinflammatory processes in the fetus, which can lead to the development of symptoms of fetal alcohol spectrum disorder (FASD). Modeling prenatal alcohol exposure in our experiment resulted in changes in the expression of TLR system genes (Tlr3, Tlr4, Hmgb1, Trif, cytokine genes) in the forebrain cortex of baby rats. The administration of rifampicin (from the first to the seventh day of neonatal development) normalized the altered expression level of the studied genes. This suggests that rifampicin may prevent the development of persistent neuroinflammatory phenomena in the forebrain cortex of baby rats.

The Safety, Acceptability, and Feasibility of Single-Dose Rifampicin as Post-Exposure Chemoprophylaxis for Contacts of Leprosy Patients in Togo: A Mixed-Method Sequential Explanatory Study.

The World Health Organization is encouraging countries to include contact screening and single-dose rifampicin administration as preventive chemotherapy for contacts of leprosy patients in their leprosy control activities. However, no study has been conducted to assess the safety of SDR-PEP and the acceptability and feasibility of this intervention in Togo. To assess the safety of SDR-PEP, we used a cohort design, and for acceptability and feasibility, we used a mixed method, combining a quantitative study to assess the safety of SDR-PEP in a cohort of contacts from recently diagnosed leprosy patients followed by a qualitative study to identify the social, cultural, or institutional factors that would influence the adoption of single-dose rifampicin as post-exposure prophylaxis for contacts of leprosy patients in Togo. For the quantitative study, all identified index patients agreed to the disclosure of their status to their contacts and provided a list of their contacts. All the contacts found agreed to take part in the study, and an appointment was made for screening. However, some contacts were absent on the screening day for no reason. All eligible contacts agreed to take SDR and were followed up after taking the drug. No severe adverse events were reported during the follow-up. For the qualitative study, 72 interviews (66 semi-structured interviews and 6 focus groups) were carried out, and it emerged that, overall, opinions were favorable on the acceptability and feasibility of implementing single-dose rifampicin as post-exposure prophylaxis for contacts of leprosy patients in Togo. However, a number of conditions need to be considered for more effective results.

Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration.

The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC0-8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice.

Optimization of Polylactide-Co-Glycolide-Rifampicin Nanoparticle Synthesis, In Vitro Study of Mucoadhesion and Drug Release.

Despite the large number of works on the synthesis of polylactide-co-glycolide (PLGA) nanoparticles (NP) loaded with antituberculosis drugs, the data on the influence of various factors on the final characteristics of the complexes are quite contradictory. In the present study, a comprehensive analysis of the effect of multiple factors, including the molecular weight of PLGA, on the size and stability of nanoparticles, as well as the loading efficiency and release of the antituberculosis drug rifampicin (RIF), was carried out. Emulsification was carried out using different surfactants (polyvinyl alcohol, Tween 80 and Pluronic F127), different aqueous-to-organic phase ratios, and different solvents (dichloromethane, dimethyl sulfoxide, ethyl acetate). In this research, the PLGA nanoemulsion formation process was accompanied by ultrasonic dispersion, at different frequencies and durations of homogenization. The use of the central composite design method made it possible to select optimal conditions for the preparation of PLGA-RIF NPs (particle size 223 ± 2 nm, loading efficiency 67 ± 1%, nanoparticles yield 47 ± 2%). The release of rifampicin from PLGA NPs was studied for the first time using the flow cell method and vertical diffusion method on Franz cells at different pH levels, simulating the gastrointestinal tract. For the purpose of the possible inhalation administration of rifampicin immobilized in PLGA NPs, their mucoadhesion to mucin was studied, and a high degree of adhesion of polymeric nanoparticles to the mucosa was shown (more than 40% within 4 h). In the example of strain H37Rv in vitro, the sensitivity of Mycobacterium tuberculosis to PLGA-RIF NPs was proven by the complete inhibition of their growth.

Farnesoid X Receptor: Effective alleviation of rifampicin -induced liver injury

Antituberculosis drugs induce pharmacologic cholestatic liver injury with long-term administration. Liver injury resulting from rifampicin is potentially related to the bile acid nuclear receptor FarnesoidXReceptor (FXR). To investigate this, cholestasis was induced in both wild-type (C57BL/6N) mice and FXR knockout (FXR-null) mice through administration of rifampicin (200mg/kg) via gavage for 7 consecutive days. Compared with C57BL/6N mice, FXR-null mice exhibited more severe liver injury after rifampicin administration, characterized by enlarged liver size, elevated transaminases, and increased inflammation. Moreover, under rifampicin treatment, FXR knockout impairs lipid secretion and exacerbates hepatic steatosis. Significantly, the expression of metabolism molecules BSEP increased, while NTCP and CYP7A1 decreased following rifampicin administration in C57BL/6N mice, whereas these changes were absent in FXR knockout mice. Furthermore, rifampicin treatment in both C57BL/6N and FXR-null mice was associated with elevated c-Jun N-terminal kinase phosphorylation (p-JNK) levels, with a more pronounced elevation in FXR-null mice. Our study suggests that rifampicin-induced liver injury, steatosis, and cholestasis are associated with FXR dysfunction and altered bile acid metabolism, and that the JNK signaling pathway is partially implicated in this injury. Based on these results, we propose that FXR might be a novel therapeutic target for addressing drug-induced liver injury.

Sustained Delivery of Rifampicin Nanoformulation Administration Intravitreally Into Rabbit Eyes for Ocular Tuberculosis.

Diagnosis and treatment of ocular tuberculosis is very challenging. It poses a significant and potential management dilemma after diagnosis as a primary, active, or secondary infection. The higher amounts of orally administered antitubercular drugs are needed to achieve the therapeutic concentration in the eye, which may lead to a higher risk of side effects. However, the intravitreal administration of drugs is not practiced because of the frequent administration of the injections. This study was carried out to develop, optimize, and characterize rifampicin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles to make them sustained release followed by the direct administration of plain rifampicin and rifampicin nano-formulations in the vitreous of rabbit eyes. Both groups were comparatively assessed for the sustained delivery of the two preparations in the vitreous and their systemic toxicity. The characteristics of rifampicin-loaded nanoparticles were 786 nm in size with narrow size distribution along with a zeta potential of -12 mV. The drug encapsulation efficiency and loading capacity were 67.68% w/w and 42.28% w/w, respectively. The four New Zealand white rabbits were divided into two groups and given plain rifampicin (50µl volume) and PLGA nanoformulations of rifampicin (50µl volume) in each eye. In vivo, rifampicin-loaded PLGA nanoparticles produced sustained release of rifampicin for a week, even obtaining the 0.51 µg/ml levels on the seventh day in vitreous against negligible levels after one day for free rifampicin. The Cmax levels for free Rifampicin and Rifampicin nanoparticles were 0.44 µg/ml and 1.86 µg/ml, respectively. In this experimental proof-of-concept study, we have found that rifampicin-loaded PLGA nanoparticles released rifampicin in a sustained manner for up to seven days compared to free drugs only for one day into the vitreous. The intravitreal-administered drug did not reach systemic circulation.

Omeprazole Induces CYP3A4 mRNA Expression but Not CYP3A4 Protein Expression in HepaRG Cells

Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are considered the key to examining the drug-drug interaction (DDI). In this study, using human HepaRG cells as an in vitro model system, we analyzed the potential DDI based on the expression levels of CYP3A4 and CYP1A2. Rifampicin and omeprazole, the potent inducers for CYP3A4 and CYP1A2, respectively, induce expression of the corresponding CYP enzymes at both the mRNA and protein levels. We noticed that, in addition to inducing CYP1A2, omeprazole induced CYP3A4 mRNA expression in HepaRG cells. However, unexpectedly, CYP3A4 protein expression levels were not increased after omeprazole treatment. Concurrent administration of rifampicin and omeprazole showed an inhibitory effect of omeprazole on the CYP3A4 protein expression induced by rifampicin, while its mRNA induction remained intact. Cycloheximide chase assay revealed increased CYP3A4 protein degradation in the cells exposed to omeprazole. The data presented here suggest the potential importance of broadening the current DDI examination beyond conventional transcriptional induction and enzyme-activity inhibition tests to include post-translational regulation analysis of CYP enzyme expression.

Embelin mitigates hepatotoxicity induced by isoniazid and rifampicin in rats

Isoniazid and rifampicin are reliable drugs against tuberculosis, but while effective, their use is associated with the risk of drug-induced liver damage. Embelin, a natural parabenzoquinone derived from the Embelia ribes plant, has gained attention for its potential therapeutic properties, antioxidant and organ-protective effects. The study aimed to assess the hepatoprotective properties of embelin against liver dama­ge induced by isoniazid and rifampicin in rats. Wistar rats were used, and liver damage was induced by administration of isoniazid (100 mg/kg) and rifampicin (100 mg/kg). Embelin was given at doses of 50, 75, and 100 mg/kg for 21 days. All the drugs were given orally. Serum levels of the oxidative stress markers, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) activity measured by enzymatic assay kits (Elabscience, China), and the levels of tumour necrosis factor-α (TNF-α), interleukins IL-1β and IL-6 measured by ELISA kits (Randox, UK) were estimated. Embelin administration at varying doses effectively restored AST, ALT, ALP, SOD and catalase activity and notably decreased MDA and nitric oxide concentration as well as expression of inflammatory cytokines TNF-α, IL-1β and IL-6 in the serum of animals with drug-induced liver damage. These findings underscore embelin’s hepatoprotective effects, likely attributed to its radical scavenging properties and ability to suppress cytokine production. Keywords: antioxidant effect, cytokine suppression, embelin, hepatoprotection, isoniazid, rifampicin

EFFECTIVENESS AND SAFETY OF CARBOPLATIN-CONTAINING ANTITUMOR THERAPY REGIMENS IN A MODEL OF COEXISTANCE OF LUNG CARCINOMA AND TUBERCULOSIS

Introduction. Treatment of the coexistent pathology of lung cancer and tuberculosis remains the prerogative of experimental research, since the optimal treatment strategy for the coexistence of these two diseases has not yet been developed. The purpose was to study the effectiveness and safety of carboplatin-containing antitumor therapy regimens in combination with anti-tuberculosis chemotherapy. Material and methods. The study was conducted on 64 C57BL/6 mice aged two months with a previously modeled coexistant pathology of lung carcinoma and tuberculosis. Depending on the therapy, 4 groups were formed: 1 – control without treatment (n=16), 2 – antitumor (carboplatin + paclitaxel) + antituberculosis therapy (n=16), 3 – antitumor (carboplatin + pemetrexed) + antituberculosis therapy (n=16), 4 – antitumor (carboplatin + gemcitabine) + anti-tuberculosis therapy (n=16). The anti-tuberculosis therapy regimen included the administration of isoniazid, rifampicin, pyrazinamide and ethambutol. The antitumor effect (tumor growth index, tumor growth inhibition), antituberculosis effect (CFU per lung weight), toxicity (clinical blood test parameters, biometric indicators of internal organs), and survival were assessed. Statistical processing was carried out using non-parmetric statistics methods. Results. The lowest average body weight was recorded in group 4 from 7 to 21 days. The greatest differences between groups in the volume of the tumor node were observed from 12 to 16 days of the experiment under the influence of antitumor drugs. At the same time, the greatest inhibition of tumor growth was observed in group 4. On day 9 in group 2 there were signs of the myelo-immunosuppressive effect of antitumor therapy in the form of a decrease in the concentration of leukocytes, lymphocytes and monocytes. In the study groups, there were no statistically significant differences in the survival rate of the experimental and control groups. In all experimental groups, significantly lower spleen MC values were recorded, and in group 4, significantly lower liver MC values were also recorded. The highest level of mycobacterial load was recorded in the control group. The lowest CFU per lung weight was found in the carboplatin and gemcitabine treatment group. Conclusion. Carboplatin-containing chemotherapy regimens for lung carcinoma in tuberculosis-infected mice have both antitumor and antituberculosis effects. The most pronounced antimycobacterial activity was recorded when using a combination of antituberculosis therapy with carboplatin and gemcitabine.

Could subcutaneous rifampicin administration be an effective approach for reducing episiotomy infections?

The aim of this prospective cross-sectional study was to investigate whether cleaning the episiotomy line with rifampicin solution before suturing will reduce infection and wound dehiscence in women who had vaginal delivery with episiotomy. A prospective cross-sectional study was conducted with a total of 400 primigravida patients. In the study group, irrigation with rifampicin of the subcutaneous tissue of the episiotomy incision was applied, and in the control group, there was no irrigation. Patients were evaluated for infection at the 1st, 3rd week, and 1-month controls. The groups were compared according to episiotomy infection and wound dehiscence rates. The episiotomy infection rate of the whole group was 8.5%, the wound dehiscence rate was 3.75%, and the average time of occurrence of the infection was 5.35±2.21 days. The most common infection findings were local pain and purulent discharge at 4.75%. In the control group, where the infection occurred earlier, the infection and wound dehiscence rates were significantly higher [11.5% vs. 5.5%; 6.0% vs. 1.5% (p<0.05)]. Purulent discharge was the most common finding in the control group, and local pain in the study group, but no significant difference was found between the two groups in terms of findings (p<0.05). When only the patients who developed episiotomy infection were evaluated among themselves, the only significant difference was found in wound dehiscence, which was higher in the control group (p<0.05). Considering the high rates of episiotomy in our country, subcutaneous irrigation with rifampicin is a good option that can be kept in the foreground due to its low cost and ease of application.

Successful Outpatient Treatment of Severe Diabetic-Foot Myositis and Osteomyelitis Caused by Extensively Drug-Resistant Enterococcus faecalis with Teicoplanin plus Rifampicin: A Case Report.

BACKGROUND Foot ulcers are high-morbidity and debilitating complications of diabetes mellitus, and carry significantly increased rates of associated major amputations. They contribute to significantly worse quality of life. Osteomyelitis is a frequent complication of diabetic foot ulcers, since bacteria can contiguously spread from soft tissues to the bone, involving the cortex first and then the bone marrow. Unfortunately, clinically unsuspected osteomyelitis is frequent in persisting diabetic foot ulcers. It is associated with limb amputations and increased mortality. CASE REPORT We describe a 76-year-old man with long-standing insulin-treated type 2 diabetes, who experienced extensively drug-resistant Enterococcus faecalis diabetic foot myositis and osteomyelitis associated with sepsis. He was successfully treated with surgical debridement combined with the administration of teicoplanin plus rifampicin in the outpatient setting, completing, in total, a twelve-week course of antibiotic therapy. CONCLUSIONS Clinically unsuspected osteomyelitis in patients with persisting diabetic foot ulcers has been associated with infections from highly resistant bacteria. Early and accurate diagnosis of diabetic foot osteomyelitis, as well as proper therapeutic approach (antimicrobial and surgical), is of great importance to reduce the risk of minor and major amputations, septic shock leading to multiple organ failure, and overall mortality.

Rifampicin efficacy against doxorubicin-induced cardiotoxicity in mice

BackgroundThe toxic effect of doxorubicin on the heart limits its clinical usage in cancer therapy. This work intended to investigate, for the first time, the efficacy of rifampicin administration against doxorubicin-induction of cardiotoxicity in mice. Forty adult male albino mice were distributed into four sets: Control, Doxorubicin, Doxorubicin + Rifampicin 0.107, and Doxorubicin + Rifampicin 0.214, with n = 10 for each. Heart histopathology and biochemical assays for heart function tests [creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), cardiac troponin I (cTnI), atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF)], oxidative stress [malondialdehyde (MDA) and superoxide dismutase (SOD)], and minerals [phosphorus, sodium, potassium, and calcium] were done.ResultsDoxorubicin-induced cardiotoxicity using a total dose of 15 mg/kg was confirmed histologically. Cardiomyocytes showed congestion, necrosis, edema, and inflammatory cell infiltration. Biochemically, elevations in LDH, CK, and AST activities, p < 0.001, as well as increases in cTnI and ANP levels, p < 0.001, increased oxidative stress (MDA, p < 0.001), high minerals (Na, K, p < 0.001, P, p < 0.01, and Ca, p < 0.05), with reduced VEGF concentration, p < 0.001, and low antioxidant (SOD, p < 0.001) were observed in the Doxorubicin group compared to control. Co-treatment with rifampicin significantly (p < 0.001) reduced the increased oxidative stress, high Na and K, increased LDH, CK, AST, cTnI, and ANP, and elevated the low SOD toward the normal ranges. Our histological data supported our biochemical data; rifampicin dose 0.214 mg/kg showed better improvements than dose 0107.ConclusionsOur results demonstrated that rifampicin could help protect the body against doxorubicin-induced cardiotoxicity through its antioxidative effect.

Alterations in histomorphology, biochemical parameters and gross morphometry in liver of albino rats following administration of rifampicin and isoniazid

Background: Rifampicin (RIF) and Isoniazid (INH) are two main medicinal drugs used as first line regimen in the treatment of Tuberculosis. These drugs have shown to induce hepatotoxicity and alteration of liver parenchyma upon their administration. The aim of this study was to investigate the gross morphometric, histomorphological and biochemical effect of INH and RIF on the liver architecture. Methods: Adult albino rats with an average weight of between 150g to 250g were used in the study. A total of 12 rats were randomly assigned into 2 groups each group containing 6 rats. Group one was the control group (no intervention). Group two was the experimental group, given INH (50mg/kgbwt) and RIF (50mg/kgbwt). At the end of the experiment, after 21 days, the albino rats were sacrificed humanely, liver harvested, weighed and the gross parameters measured using a ruler and caliper. Blood samples were taken for liver serum biomarkers analysis. Thereafter, the livers were processed and stained with Haematoxylin and Eosin for histological examination. Results: There was a significant (p value &lt; 0.0001) decrease in gross morphometric measurements of the weight, length, width, thickness in experimental group. The three selected liver biochemical parameters (ALT, AST and ALP) were observed to be high above their normal ranges. The liver sections in positive control group showed deranged histomorphological features. Conclusion: co-administration of Rifampicin and Isoniazid can have effect on gross morphometric, histomorphology and liver biochemical parameters of the liver therefore, their administration should be done in caution.

Impact of Obesity on the Drug-Drug Interaction Between Dolutegravir and Rifampicin or Any Other Strong Inducers.

Obesity is increasingly prevalent among people with HIV. Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions (DDIs) and, thus, the related recommendations for dose adjustment. Virtual clinical DDI studies were conducted using physiologically based pharmacokinetic (PBPK) modeling to compare the magnitude of the DDI between dolutegravir and rifampicin in nonobese, obese, and morbidly obese individuals. Each DDI scenario included a cohort of virtual individuals (50% female) between 20 and 50 years of age. Drug models for dolutegravir and rifampicin were verified against clinical observed data. The verified models were used to simulate the concurrent administration of rifampicin (600 mg) at steady state with dolutegravir (50 mg) administered twice daily in normal-weight (BMI 18.5-30 kg/m2), obese (BMI 30-40 kg/m2), and morbidly obese (BMI 40-50 kg/m2) individuals. Rifampicin was predicted to decrease dolutegravir area under the curve (AUC) by 72% in obese and 77% in morbidly obese vs 68% in nonobese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. The combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m2.

Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections

Oral combination of clindamycin and rifampicin is relevant for the treatment of staphylococcal osteoarticular infection (SOAIs). However, rifampicin induces CYP3A4, suggesting a pharmacokinetic interaction with clindamycin with unknown pharmacokinetic/pharmacodynamic (PK/PD) consequences. This study aimed to quantify clindamycin PK/PD markers before and during rifampicin co-administration in SOAI. Patients with SOAI were included. After initial intravenous antistaphylococcal treatment, oral therapy was started with clindamycin (600 or 750 mg t.i.d.), followed by addition of rifampicin 36 h later. Population PK analysis was performed using the SAEM algorithm. PK/PD markers were compared with and without rifampicin co-administration, each patient being his own control. In 19 patients, clindamycin median (range) trough concentrations were 2.7 (0.3-8.9) mg/L and <0.05 (<0.05-0.3) mg/L before and during rifampicin administration, respectively. Rifampicin co-administration increased clindamycin clearance by a factor 16 and reduced the AUC0-8h/MIC by a factor 15 (P < 0.005). Clindamycin plasma concentrations were simulated for 1000 individuals, without and with rifampicin. Against a susceptible Staphylococcus aureus strain (clindamycin MIC 0.0625 mg/L), >80% of individuals would reach all proposed PK/PD targets without co-administration of rifampicin, even with low clindamycin dose. For the same strain, when rifampicin was co-administered, the probability to reach clindamycin PK/PD targets dropped to 1% for %fT>MIC=100% and to 6% for AUC0-24h/MIC > 60, even with high clindamycin dose. Rifampicin co-administration with clindamycin has a high impact on clindamycin exposure and PK/PD targets in SOAI, which could result in clinical failure even for fully susceptible strains.

PERBANDINGAN BIAYA PEMERIKSAAN LABORATORIUM PADA PASIEN TUBERKULOSIS MULTIDRUG RESISTANCE (TB-MDR) DENGAN TUBERKULOSIS EXTENSIVE DRUG RESISTANCE (TB-XDR): STUDI PADA RUMAH SAKIT TERSIER DI BANDUNG

Introduction. Tuberculosis (TB) is one of the oldest diseases known to attack humans, caused by the bacterium Mycobacterium tuberculosis. Multi-drug-resistant TB (MDR-TB) is a stage or condition in which Mycobacterium tuberculosis becomes minimally resistant to rifampicin administration and also insonicotinylhydrazine (INH). Extensive-drug-resistant TB (XDR-TB) is an MDR-TB with Mycobacterium tuberculosis immune characteristics against one of the fluoroquinolone class drugs and one of the second-line injection OAT (capreomycin, kanamycin, and amikacin). The aim of this study was to find out the description of variation in laboratory costs of MDR-TB/XDR patients on one treatment cycle.&#x0D; Method. The inclusion criteria were patients who had been diagnosed with MDR-TB/XDR and performed laboratory tests. The design of this study was a cross-sectional retrospective analytics using medical records of MDR-TB/XDR patients in MDR division.&#x0D; Results. There were 30 MDR-TB research subjects and 2 XDR-TB research subjects examined for laboratory examination. Comparison of laboratory mean of MDR-TB/XDR (p = 0,018).&#x0D; Discussion. There was a significant difference in the total cost of MDR-TB/XDR laboratory examinations in one treatment cycle.&#x0D; Conclusion. Laboratory examination of MDR-TB/XDR patients requires considerable cost, this is due to the side effects of OAT that require patient clinical monitoring.&#x0D; &#x0D;

Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii

Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection. The objective is to predict drug disposition in biological tissues. Treatment efficacy is extrapolated by assessing respective pharmacodynamic (PD) indices, as well as parameters associated with the emergence of resistance. Physiologically-based pharmacokinetic models of rifampicin and colistin were utilized to predict tissue exposures. Dosing regimens and administration routes for combination therapy were evaluated in terms of in vitro antimicrobial susceptibility of A. baumannii associated with targeted PD indices and resistance parameters. Simulated exposures in blood, heart, lung, skin and brain were consistent with reported penetration rates. The results demonstrated that a combination of colistin and rifampicin using conventional intravenous (i.v.) doses could achieve effective exposures in the blood and skin. However, for lung infections, colistin by inhalation would be required due to low lung penetration from intravenous route. Inhaled colistin alone provided good PD coverage but this practice could encourage the emergence of additional resistance which may be overcome by a combination regimen that includes inhaled rifampicin. This in silico extrapolation provides valuable information on dosing regimens and routes of administration against CRAB infections in specific tissues. The PBPK modeling approach could be a non-invasive way to inform therapeutic benefits of combination antimicrobial therapy.

The effect of rifampicin on expression of the toll-like receptor system genes in the forebrain cortex of rats prenatally exposed to alcohol.

Ethanol causes long-term changes in the toll-like receptor (TLR) system, promoting activation of neuroinflammation pathways. Alcohol use during pregnancy causes neuroinflammatory processes in the fetus; this can lead to the development of symptoms of fetal alcohol spectrum disorder (FASD). Our study has shown that prenatal alcohol exposure (PAE) induced long-term changes in the TLR system genes (Tlr3, Tlr4, Ticam, Hmgb1, cytokine genes) in the forebrain cortex of rat pups. Administration of rifampicin (Rif), which can reduce the level of pro-inflammatory mediators in various pathological conditions of the nervous system, normalized the altered expression level of the studied TLR system genes. This suggests that Rif can prevent the development of persistent neuroinflammatory events in the forebrain cortex of rat pups caused by dysregulation in the TLR system.

Effect of Rifampicin on the Pharmacokinetics of Evogliptin in Healthy Volunteers.

Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics. An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference. Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration. Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.