Levels Of Rifampin Research Articles

SIMULTANEOUS CONTENT ANALYSIS OF RIFAMPICIN, ISONIAZID, AND PYRAZINAMIDE IN TABLET DOSAGE FORM BY SPECTROPHOTOMETRY ULTRAVIOLET WITH DWM AND RSM

Treatment of active tuberculosis requires the use of combinations of drugs. One of the common combination of drugs to serve as anti-tubercular medication is rifampin, isoniazid and pyrazinamide. However, a research conducted by the Food Drug Administration (FDA) concluded that the combination of anti-tubercular medication may pose some patients to the risk of sub-optimal drug exposure, which may lead to less optimal treatment. This study aimed to determine the drug level of combination of anti-tubercular medication, namely rifampin, isomiazid, and pyrazinamide and to develop a spectrophotometric method using the dual wavelength method (DWM) and ratio substaction method (RSM) in tablet preparations on the market without separation. During the preparation, methanol was used as the solvent, followed by dilution, determination of calibration curve, determination of wavelength (λ), measurement, data analysis and validity test with several parameters ranging from linearity, accuracy, precision, LOD, and LOQ. The research revealed that the drug levels of rifampin, isoniazid, and pyrazinamide from the ultraviolet spectrophotometric method using sequential DWM were 100.3±1.8785; 99.98±2.5943; 100.03±2.076 and the results of the ultraviolet spectrophotometric method using RSM sequentially were 99.73±0.5437; 99.84±1.7598; 99.91±1.4762. Both methods succeeded in determining the drug level of the combination of rifampin, isoniazid, and pyrazinamide in tablet preparations without separation and the results of the validation parameters met the requirements.

RpoB Mutations are Associated with Variable Levels of Rifampin and Rifabutin Resistance in Mycobacterium tuberculosis.

To assess the relationship between the variant rpoB mutations and the degree of rifampin (RIF)/rifabutin (RFB) resistance in Mycobacterium tuberculosis (M. tuberculosis). We analyzed the whole rpoB gene in 177 M. tuberculosis clinical isolates and quantified their minimum inhibitory concentrations (MICs) using microplate-based assays. The results revealed that of the 177 isolates, 116 were resistant to both RIF and RFB. There were 38 mutated patterns within the sequenced whole rpoB gene of the 120 isolates. Statistical analysis indicated that mutations, S450L, H445D, H445Y, and H445R, were associated with RIF and RFB resistance. Of these mutations, S450L, H445D, and H445Y were associated with high-level RIF and RFB MIC. H445R was associated with high-level RIF MIC, but not high-level RFB MIC. D435V and L452P were associated with only RIF, but not RFB resistance. Q432K and Q432L were associated with high-level RFB MIC. Several single mutations without statistical association with rifamycin resistance, such as V170F, occurred exclusively in low-level RIF but high-level RFB resistant isolates. Additionally, although cross-resistance to RIF and RFB is common, 21 RIF-resistant/RFB-susceptible isolates were identified. This study highlighted the complexity of rifamycin resistance. Identification of the rpoB polymorphism will be helpful to diagnose the RIF-resistant tuberculosis that has the potential to benefit from a treatment regimen including RFB.

Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay.

The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h postdose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

Serum Levels of Antituberculosis Drugs and Their Effect on Tuberculosis Treatment Outcome.

Therapeutic drug monitoring in tuberculosis remains controversial. We evaluated the relationship between antituberculosis drug levels in blood and clinical outcome. Serum concentrations of first-line antituberculosis drugs were measured in tuberculosis patients between March 2006 and April 2013. Venous blood was drawn 2 h after drug ingestion and was analyzed using high-performance liquid chromatography-tandem mass spectrometry. We retrospectively reviewed the data and determined the association of serum drug levels with clinical outcome. Among 413 patients, the prevalences of low serum concentrations of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) were 59.9%, 27.8%, 12.8%, and 8.7%, respectively. The low INH group had a greater percentage of patients with a history of tuberculosis treatment (19.2% versus 11.0%; P = 0.026) and was more likely to present with drug-resistant strains (17.6% versus 8.8%; P = 0.049) than the normal INH group; however, low levels of INH, RMP, EMB, and PZA were not related to treatment outcome. Low INH level had a tendency to be associated with 2-month culture positivity, but it was not statistically significant (P = 0.072) in multivariate analysis. Seventeen (4.1%) patients experienced a recurrence. However, the recurrence rate was not statistically different between the low and normal INH groups. Low serum INH may play a role in recurrence and in acquired drug resistance. However, the serum level of INH was not directly related to either treatment response or recurrence rate. The role and usefulness of therapeutic drug monitoring should be evaluated in further prospective studies.

Pharmacokinetics of Rifampin in Peruvian Tuberculosis Patients with and without Comorbid Diabetes or HIV

For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (C(max)) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin C(max) was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different C(max) results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (T(max)) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.

Pharmacokinetics of Antituberculosis Medications Delivered via Percutaneous Gastrojejunostomy Tube

We treated a 23-year-old aboriginal woman with drug-resistant pulmonary tuberculosis (TB). She experienced intolerance to her oral anti-TB medications, had subtherapeutic drug levels, and failed to respond to treatment. She then was effectively treated with percutaneous gastrojejunostomy tube (PGJT) administration of drugs. We present our data on the serum drug levels of rifampin, para-aminosalicylic acid, and levofloxacin after PGJT administration, and compare these values to published levels for oral administration of these drugs. In our patient, serum drug levels peaked and began to decline earlier than in the published data for oral administration of the same drugs.

Use of microsphere technology for targeted delivery of rifampin to Mycobacterium tuberculosis-infected macrophages.

Microsphere technology was used to develop formulations of rifampin for targeted delivery to host macrophages. These formulations were prepared by using biocompatible polymeric excipients of lactide and glycolide copolymers. Release characteristics were examined in vitro and also in two monocytic cell lines, the murine J774 and the human Mono Mac 6 cell lines. Bioassay assessment of cell culture supernatants from monocyte cell lines showed release of bioactive rifampin during a 7-day experimental period. Treatment of Mycobacterium tuberculosis H37Rv-infected monocyte cell lines with rifampin-loaded microspheres resulted in a significant decrease in numbers of CFU at 7 days following initial infection, even though only 8% of the microsphere-loaded rifampin was released. The levels of rifampin released from microsphere formulations within monocytes were more effective at reducing M. tuberculosis intracellular growth than equivalent doses of rifampin given as a free drug. These results demonstrate that rifampin-loaded microspheres can be formulated for effective sustained and targeted delivery to host macrophages.

The Combined Effect of Rifampin and Pyrazinamide within the Human Macrophage

A recent study in the murine model suggested that a combination of rifampin and pyrazinamide used as preventive therapy might shorten the duration of treatment time. Clinical trials using this combination have been initiated, but significant results will not be available for many years. The ex vivo human macrophage model has been instructive in expanding our knowledge of the activity of chemotherapeutic agents against intracellular virulent tubercle bacilli. Prior studies have shown rifampin to have a bactericidal effect in this model while even at clinically unachievable levels, pyrazinamide had only a bacteriostatic impact. This study finds an enhanced bacteriostatic effect when low, nonbactericidal levels of rifampin are combined with clinically achievable levels of pyrazinamide but not with higher bactericidal levels of rifampin. Adding pyrazinamide 2 days after the introduction of rifampin clearly enhanced the combined killing effect. However, reversing the order and adding rifampin 2 days after the introduction of pyrazinamide produced a result weaker than introducing the agents simultaneously. Our findings do not support the use of these agents as a potentially effective preventive therapy combination, but they suggest that the timing of the administration of these chemotherapeutic agents could be an important factor in their effectiveness.

Levels of Rifampin and Ciproftoxacin in Nasal Secretions: Correlation with MIC90 and Eradication of Nasopharyngeal Carriage of Bacteria

To predict the efficacy of antibiotics in eliminating nasopharyngeal carriage of organisms such as Neisseria meningitidis, Haemophilus influenzae, and methicillin-resistant Staphylococcus aureus (MRSA), a novel approach for measuring drug concentrations in nasal secretions was developed. Five healthy individuals received four doses of rifampin and then, at a later date, ciprofloxacin. At 2, 5, and 8 h after the last dose, serum, saliva, and cold-stimulated nasal secretion samples were collected, and drug levels were analyzed by high-performance liquid chromatography. Nasopharyngeal levels of rifampin reached but did not substantially exceed 90% of the minimal inhibitory concentration (MIC90) for H. influenzae, exceeded the MIC90 for N. meningitidis, and were well above that for MRSA. Ciprofloxacin levels in nasal secretions far exceeded the MIC90 for meningococci and Haemophilus organisms but were below that for MRSA. These findings are consistent with the clinical studies showing that rifampin eliminates, in most instances, the nasal carriage of N. meningitidis and to a lesser extent H. influenzae. A single dose of ciprofloxacin has been shown to eradicate meningococci, yet a long course of treatment with this drug is not adequate for MRSA. On the basis of these results, clinical trials with ciprofloxacin to eliminate nasopharyngeal carriage of H. influenzae appear to be warranted.

Pharmacokinetics of antituberculosis drugs in patients.

The pharmacokinetics of rifampin, isoniazid, and ethambutol were determined in 26 ambulatory male patients (aged 49.5 +/- 9.9 yr) with tuberculosis. Rifampin and isoniazid were given individually or together, with or without ethambutol; studies were done after a single dose and after chronic administration. Under the study conditions, with large variability in the extent of disease and physical status and history of alcohol and tobacco abuse and narrow age range, the pharmacokinetics of these three antituberculosis drugs were not modified significantly by patient age. Furthermore, appreciable drug-drug interactions did not occur when the three drugs were administered concurrently. Self-induction of rifampin clearance by chronic dosing with the drug may lead to subtherapeutic levels of rifampin. Administration of isoniazid and ethambutol in two divided doses resulted in peak plasma concentrations below the accepted therapeutic levels of the two drugs. Our findings indicate that at least in the middle-aged patients with tuberculosis, the current single daily dose, multiple-drug regimen is therapeutically sound pharmacokinetically, and clinicians do not have to make adjustments in dosages of these drugs for age and the extent of disease.

Rifampin blood and tissue levels in patients undergoing cardiac valve surgery.

Single 600-mg capsules of rifampin were given orally to 26 patients as prophylaxis during cardiac valve replacement. Antibiotic concentrations were measured in blood (serum or plasma) and tissue (excised cardiac valve). The serum or plasma levels of rifampin in 18 patients who ingested this drug 2 h before they received preoperative opiates and anticholinergics intramuscularly were not significantly different from the levels in four normal volunteers who received the drug. These levels were 15.9 +/- 6.5 micrograms/ml (mean +/- standard deviation) 2 h after drug administration, 7.1 +/- 4.3 micrograms/ml 8 h after drug administration and 2 h after a mean of 1.4 h on cardiopulmonary bypass, and 1.6 +/- 1.6 micrograms/ml 24 h after drug ingestion. The valve tissue level was 3.8 +/- 2.7 micrograms/g (mean +/- standard deviation; n = 10). This value was 65% of the simultaneous serum and plasma levels and 31% of the peak serum and plasma levels. Eight patients who were given rifampin at the same time that they received other preoperative medications had significantly lower blood levels than the 18 patients who received rifampin 2 h earlier (P less than 0.001). No rifampin was detected in valves from seven of these patients. Decreased rifampin absorption due to simultaneous administration with opiates and anticholinergics was the probable reason for the low plasma and serum levels observed. These data suggest that, if properly dosed, rifampin administered orally gives high blood and valve tissue levels, which are affected minimally by cardiopulmonary bypass in patients undergoing cardiac valve surgery.

Susceptibility of Haemophilus influenzae Type b to Rifampin and Sulfisoxazole

A total of 100 and 97% of Haemophilus influenzae type b strains from major infections were susceptible, respectively, to levels of rifampin and sulfisoxazole attainable in saliva. It is theoretically feasible to eliminate Haemophilus influenzae from the nasopharynx with these drugs.

Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin, and cephalothin.

Levels of rifampin, gentamicin, sisomicin, and cephalothin in normal and osteomyelitic rabbit bones were measured, and the efficacy of these drugs in the treatment of osteomyelitis was evaluated. Single drug regimens, including rifampin for 14 days and gentamicin, sisomicin, and cephalothin each for 28 days, were relatively ineffective (5%-33% sterile bone cultures). Rifampin, administered for 28 days, sterilized the bones of 55% of treated animals. The combination of gentamicin and rifampin, given for either 14 or 28 days, sterilized the bones of 67% of treated animals. The combinations of rifampin plus sisomicin and of rifampin plus cephalothin, given for 28 days, were significantly more effective than these agents alone, sterilizing 90%-95% of bones. The combination of rifampin, sisomicin, and cephalothin, given for only 14 days, sterilized the bones of all treated rabbits. Staphylococci isolated from the bones of therapeutic failures that had received rifampin alone or in combination with other antibiotics were highly resistant to rifampin (minimal inhibitory concentration, greater than 250 mug/ml), whereas the organisms recovered from animals not receiving rifampin remained sensitive. Results of in vitro studies of synergy and/or bactericidal activity of antibiotic combinations correlated with in vivo results in some, but not all, instances.

Serum concentration of rifampin after oral administration

The serum levels of rifampin after single 450 mg doses were much the same when taken as 3 gelatin capsules and 1 sugar‐coated tablet. The concentrations of rifampin in the serum of pulmonary tuberculosis patients on prolonged rifampin‐containing regimens were lower than the levels in control sub;ects and patients on a drug regimen Without rifampin. The difference is significant after 4 hours. The increased elimination of the drug should be taken into account in planning long‐term therapy with rifampin.

Rifampin

In a double blind study in naval recruits, rifampin reduced the percentage of meningococcal carriers by 80%, compared with controls. It was well tolerated in four daily 600-mg doses. Levels of rifampin in serum samples exceeded the minimal inhibitory concentration (MIC) of rifampin required to inhibit meningococci vitro. Rifampin levels in saliva exceeded the MIC for all meningococcal reference strains tested in vitro at 3.5 hours after a third 600-mg daily dose. At 6.5 hours after a fourth 600-mg dose, the range of rifampin levels in saliva samples extended above and below the range of MIC of rifampin for the reference strains. The efficacy of rifampin in the eradication of the meningococcal carrier state has been established. It should prove safe and effective in carriers of sulfadiazine-resistant meningococci under limited conditions.