Intravenous Rifampicin Research Articles

Hyper‐IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters

<scp>Hyper‐IgE</scp> syndrome presenting with early life craniosynostosis in monozygotic twin sisters

Antibiotic management of native mitral valve infectious endocarditis in patient with unaffected prosthetic aortic valve: A case report

Infectious endocarditis is a rare but feared condition, most frequently caused by Staphylococcus aureus. We describe the case of an 81-year-old male patient presenting with intermittent fever and dyspnea. Cardiac evaluation with transthoracic echocardiogram showed the presence of heart failure with suspicion of endocarditis. Consequently, a transesophageal echocardiogram demonstrated vegetation on the native mitral valve with an unaffected prosthetic aortic valve. Blood cultures were positive for S. aureus. Literature concerning endocarditis originating from a native valve in patients with a prosthetic valve is limited. We applied a new treatment scheme consisting of intravenous floxapen 12 g/24 h in a continuous infusion combined with intravenous rifampicin 2×300 mg daily for a duration of 6 weeks resulting in complete regression of the vegetation. In addition, we were successful in preventing disease propagation to the prosthetic valve. There is a need for more adequate research to prove the prophylactic benefit of this treatment.

Brucellar epididymo-orchitis: Symptoms, diagnosis, treatment and follow-up of 50 patients in Iran

Epididymo-orchitis (EO) is a disease of both the epididymis and ipsilateral testis. Brucellar epididymo-orchitis (BEO) is an uncommon localized infection of the testis and epididymis which occurs in about 2-14% of all patients with brucellosis as a result of urine Brucella removal or due to blood-borne septic metastasis. Between January 2018 and June 2021, 50 patients with fever, chills, swelling, and pain of the testicle (testicles) were referred to our center. Two approaches were used for the treatment of brucellarepididymo-orchitis among these individuals. Intravenous Gentamicin and Doxycycline were used in seven cases, while Rifampicin was added to this combination for the remaining 43 patients. Intravenous Gentamicin was administered for 7 days and the other drugs were used for 45 days. All patients were followed up for six months by monitoring the symptoms and signs of the disease. None of the patients had been diagnosed with brucellosis before referral to our clinic. 43 patients were successfully treated by. Intravenous Gentamicin, Doxycycline and Rifampicin, whereas seven patients were fully treated using. Intravenous Gentamicin and Doxycycline. The two therapeutic groups were hospitalized for 7.56±3.45 (3-23) and 10.14±1.77 (8-13) days, respectively. Treatment failure, drug side effects, and disease complications were not observed in any of the cases over a 6-month follow-up period. Physicians should be alert regarding Brucellarepididymo-orchitis (BEO) within the differential diagnosis of nonspecific epididymo-orchitis, especially in regions where the disease is endemic. Delay in diagnosis or inappropriate management of BEO may result in complications.

Hemophagocytic Lymphohistiocytosis and Severe Hypoxemia in a Preterm Infant.

Hemophagocytic Lymphohistiocytosis and Severe Hypoxemia in a Preterm Infant.

Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial.

BackgroundHigher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but is impractical in high burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral 35 mg/kg and intravenous 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis.Materials and methodsWe performed a randomized parallel group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (intravenous 20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using non-compartmental analysis and exposures compared by geometric mean ratio (GMR).ResultsForty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high dose oral, n= 15; intravenous, n = 14). Median CD4 count was 130 cells/mm3 (IQR 66 - 253). Rifampicin geometric mean AUC0-24 was 42.9 μg.h/mL (95% CI, 24.5 – 75.0) for standard dose; 295.2 μg.h/mL (95% CI, 189.9 – 458.8) for high dose oral; and 206.5 μg-h/mL (95% CI, 154.6 – 275.8) for intravenous administration. Rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 - 2.21) and Cmax GMR was 0.89 (90% CI, 0.63 – 1.23) for high dose oral with respect to intravenous dosing.ConclusionsPlasma rifampicin AUC0-24 was higher after an oral 35 mg/kg dose compared with intravenous administration at 20 mg/kg dose over the first few days of TB treatment. Findings support oral rifampicin dosing in future tuberculous meningitis trials.

Tuberculosis in the intensive care unit: alternative treatment regimens and association with mortality.

Adequate anti-tuberculosis (TB) treatment is an important factor that can affect the patient's outcome. Higher mortality is found in patients who do not receive optimal treatment that includes isoniazid and rifampicin. The objective of this study is to evaluate the association of use of alternative TB treatment regimens (without rifampicin and isoniazid) and mortality among patients requiring intensive care. Retrospective cohort study, from January 2010 to December 2018. Patients aged >18years with a TB diagnosis, admitted to the ICU of a general, tertiary care, university-affiliated hospital (Hospital de Clínicas de Porto Alegre - HCPA) were included. Data on TB treatment used and outcomes of treatment were collected. 462 patients met the inclusion criteria and were included in the analysis; 284 used the usual treatment regimen (rifampicin, isoniazid, pyrazinamide and ethambutol - all orally), and 178 used alternative treatment regimens (IV levofloxacin plus oral ethambutol plus IM streptomycin or IV amikacin, without rifampicin and isoniazid). The mortality was higher among users of alternative treatment regimens (63.5%) than among usual treatment regimen users (51.4%) (P=0.011). In a multivariate analysis, age, albumin and death were independently associated with alternative treatment regimens use. TB programmes in which IV rifampicin is not widely available should consider including it, especially for critically ill TB patients, for whom there may be improved survival.

Efficacy of infusion chemotherapy in patients with pulmonary tuberculosis with treatment failure and malabsorption syndrome

Objective. To investigate the effectiveness of infusion chemotherapy in patients with pulmonary tuberculosis (TB) with treatment failure and malabsorption syndrome.&#x0D; Materials and methods. We observed 52 patients with newly diagnosed pulmonary TB with treatment failure, who were diagnosed with malabsorption syndrome. Patients were divided into two groups: 1st group (main) included 24 patients who received rifampicin and ethambutol intravenously, pyrazinamide and isoniazid orally; 2nd group (control) – 28 patients who received standard therapy orally. The severity of malabsorption syndrome was determined by a violation of intestinal penetration. Intestinal penetration was determined by the concentration of lactulose and mannitol (lactulose-mannitol test) in urine. The concentration of rifampicin, isoniazid, ethambutol in the serum was determined by liquid chromatography on a chromatograph Perkin Elmer (USA).&#x0D; Results and discussion. The examination revealed a violation of the rate of intestinal penetration in all studied patients, compared with healthy donors. The concentration of anti-TB drugs in the serum was significantly lower than the therapeutic average in group 2 compared with group 1 (p&lt;0,05). In patients of group 1 after the intensive phase of treatment, the disappearance of clinical symptoms of the disease was observed in 22 (91.3±5.8 %) and 17 (60.7±6.3 %) patients (p&lt;0.05), cessation of mycobacterial excretion – in 20 (83.3±4.3 %) and 14 (50.4±4.6 %) (p&lt;0.05), resorption of infiltrative changes and healing of destruction cavities in the lungs – in 12 (50.2±5.3 %) and 10 (35.7±4.7 %) (p&lt;0.05) compared with group 2.&#x0D; Conclusions. In patients with malabsorption syndrome with ineffective treatment and low intestinal penetration, which leads to reduced serum concentrations of anti-TB drugs in the intensive phase of treatment, it is advisable to increase the effectiveness of intravenous rifampicin and ethambutol.

Treatment with High Dose Rifampicin in Tuberculous Meningitis: A Case Report

&lt;p class="m-1735312214968439241gmail-paragraph"&gt;&lt;strong&gt;Introduction&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;&lt;strong&gt;:&lt;/strong&gt; Tuberculous meningitis continues to be associated with considerable mortality and morbidity.A randomized comparison of higher-dose intravenous rifampicin (approximately 13 mg/kg per day) versus a standard oral dose in adults with tuberculous meningitis showed that mortality among patients who received higher intravenous dose was 50% lower than those who received the standard dose.&lt;sup&gt;1 &lt;/sup&gt;While there are other contradictory results regarding the use of high-dose rifampicin in patients with tuberculous meningitis.&lt;/p&gt;&lt;p class="m-1735312214968439241gmail-paragraph"&gt;&lt;strong&gt;Method&lt;/strong&gt;&lt;strong&gt; :&lt;/strong&gt; We hereby report a case of a 20-year-old female patient presented with a history of fever, palpable neck lymph nodes and headache since 1 month before admission. Neurological examination revealed nuchal rigidity without other neurological deficits. Head MRI with contrast showed meningitis with tuberculoma in the right parietal lobe +/- 0.4 cm and neck ultrasonography showed multiple lymphadenopathy with 1 cm in diameter. Cerebrospinal fluid examination revealed tuberculous meningitis. The patient had been treated with rifampicin 450 mg, other tuberculosis regiments, levofloxacin, and dexamethasone. After one week of treatment, the patient developed generalized seizure and deterioration of consciousness. Imaging re-evaluation showed multiple acute infarction in the cortical and subcortical left frontal lobe, bilateral insula, bilateral temporal lobe, right parietal lobe to the corpus callosum, more prominent leptomeningeal contrast, and communicating hydrocephalus. Ventriculoperitoneal shunt was done. The patient was then treated with a higher dose of Rifampicin (15 mg/kg ~ 900 mg) and showed improvement after 2 weeks of treatment without any abnormal laboratory findings.&lt;/p&gt;&lt;p class="Body"&gt;&lt;strong&gt;Conclusion : &lt;/strong&gt;The usage of high dose rifampicin is still controversial. From this case we can conclude that by giving high dose rifampicin, the patient has a better outcome without any significant side effects. Thus, we support the hypothesis of using high-dose rifampicin in patients with tuberculous meningitis that does not respond to the standard treatment.&lt;/p&gt;

"Frightening" Resistant Clostridial Myonecrosis: A Case Report

Clostridial myonecrosis is a diffuse necrotizing infection of deep soft tissues. It is known for its acute, rapid progression, poor prognosis, and high mortality. We report a case of traumatic clostridial myonecrosis, a 17-year-old, previously healthy female reported to our department with the complaint of pain in her left arm a week after she suffered a fall from her chair on to her left arm. Due to the injury sustained in the incident, under suspicion of a forearm fracture, a cast was applied to her left arm at a local polyclinic. However, after a few days, she reported unbearable pain, which led to the removal of the cast, and that is when diffuse crepitations due to gaseous accumulation were noted in her entire left upper limb. A week later, X-ray studies failed to reveal any fracture or abnormality. The patient was started on broadspectrum antibiotic coverage with intravenous (IV) benzylpenicillin, rifampicin, and clindamycin for a considerable period of time, but there was no improvement in her condition and the infection continued to spread into adjacent soft tissues, requiring intervention with hyperbaric oxygen therapy.

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study)

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018)

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study).

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin onsurvival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018).

Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients

High-dose intravenous (i.v.) rifampicin improved the outcome of tuberculous meningitis (TBM) in a previous study. Unfortunately, i.v. rifampicin is not available in many high-endemic settings. This study examined exposures to and safety of higher oral rifampicin doses compared with i.v. rifampicin. Thirty adult Indonesian TBM patients were randomised to rifampicin 750 mg (ca. 17 mg/kg) orally, 900 mg (ca. 20 mg/kg) orally or 600 mg (ca. 13 mg/kg, as used previously) i.v. over 1.5 h for 14 days, combined with other TB drugs. The pharmacokinetics of rifampicin was assessed in the critical phase of TBM treatment (≤3 days after treatment initiation) and at ≥9 days. In the first days of treatment, the geometric mean (range) plasma AUC0–24 values following rifampicin 750 mg orally, 900 mg orally and 600 mg i.v. were 131.4 (38.1–275.1), 164.8 (66.9–291.2) and 145.7 (77.7–430.2) mg⋅h/L, respectively; Cmax values were 14.3 (6.1–22.2), 16.2 (5.7–28.3) and 24.7 (13.9–37.8) mg/L. CSF concentrations correlated with plasma exposures. After ≥9 days, AUC0–24 values had decreased to 100.1, 101.2 and 94.9 mg⋅h/L. Transient grade 3 ALT increases (8/30 patients) and one grade 4 ALT increase occurred, not related to rifampicin exposure. Higher oral rifampicin doses resulted in approximately similar plasma AUC0–24 but lower plasma Cmax values compared with 600 mg i.v. over 1.5 h. Exposures to rifampicin varied substantially and decreased due to autoinduction. Liver function disturbances occurred in this severely ill population. Future studies should examine even higher rifampicin doses in TBM treatment.

Carbapenem-resistant Acinetobacter baumannii septicemia and meningitis in a neonate treated with colistin and netilmycin

A term, male infant with a large frontoethmoidal encephalomeningocele underwent a cranial defect repair with excision of nasoencephalocele after the mass had ruptured. Two days after operation, the wound became infected and the infant developed sepsis and meningitis due to carbapenem-resistant Acinetobacter baumannii. Ultrasonographic study of the brain revealed severe obstructive hydrocephalus and evidence of ventriculitis. He was treated with intravenous netilmycin, ampicillin/sulbactam and oral rifampicin. Four days later, the blood and cerebrospinal fluid cultures grew no organism but the infant still had persistent thrombocytopenia with evidence of disseminated intravascular coagulation, so colistin 5 mg/kg/day given intravenously every 8 hr was added. His condition gradually improved. He was treated with intravenous amphotericin B concomitantly due to nosocomial fungal infection. Colistin was given for 6 weeks; netilmycin, ampicillin/sulbactam and rifampicin were given for 4 weeks. There was no rising of serum creatinine even though he also received other nephrotoxic agents. Intravenous colistin in combination with netilmycin and rifampicin may be a potentially effective and safe therapy for meningitis caused by carbapenem-resistant A. baumannii in infant.

Pan-regional (cervico-thoraco-lumbo-sacral) spinal epidural abscess with multi-level discitis, vertebral body osteomyelitis and facet joint septic arthritis: complete resolution with non-operative management

Abstract Background and importance Pan-regional (i.e. cervico-thoraco-lumbo-sacral [CTLS]) spinal epidural abscess (SEA) is rare: only 7 cases have been reported to date. Clinical presentation A 68 year old male, without immunosuppression, presented with severe thoracic back pain and fulminant septicaemia. CT and MRI revealed a Pan-regional CTLS SEA associated with multi-level discitis, vertebral body osteomyelitis and facet joint septic arthritis. Blood cultures grew Staphylococcus aureus sensitive to flucloxacillin and rifampicin. Given the extent of suppuration, the lack of a clinical spinal ‘level’, as well as haemodynamic instability, neurosurgical management was conservative: with intravenous flucloxacillin and rifampicin. Over several weeks, his condition slowly improved: but at no point was any spinal ‘level’ apparent neurologically. He eventually made a complete clinical and radiological recovery without any operation which was maintained at one year review. Conclusion Even pan-regional CTLS SEA with multi-level discitis, vertebral body osteomyelitis and facet joint septic arthritis can be managed non-operatively. A complete clinical and radiological resolution can be achieved with antibiotics alone.

Unilateral visual loss secondary to cat scratch disease in a healthy young man

Cat scratch disease is a benign clinical syndrome manifested as lymphadenopathy, fever and sometimes with atypical symptom of blurring of vision. It occurs following cat's bites or scratches. This case report presented a healthy young man presented with left eye blurring of vision for 1 month duration preceeded by history of recurrent low grade fever with previous history of being scratched by cat. Examination revealed optic disc edema with macula star. Thorough investigations were done and shown positive titre towards Bartonella henselae. He responded well with intravenous ceftazidime, oral doxycycline and rifampicin. His vision improved to 6/9 and 6/6 with pinhole after 3 months.

Rifampicin as Adjunct to Colistin Therapy in the Treatment of Multidrug-Resistant Acinetobacter baumannii

To evaluate the available evidence regarding the efficacy and safety of rifampicin, as adjunct to colistin, in the treatment of multidrug resistant Acinetobacter baumannii (MDR-AB). We searched MEDLINE (1966 to January 2014) using the following search terms: A baumannii, drug resistance, treatment, colistin, and rifampicin and combinations. In addition, the bibliographies of relevant articles were searched for additional citations. The search was limited to English-language references and adults. Studies in which colistin was not administered intravenously were excluded. In addition, we excluded meeting abstracts and single case reports. The search strategy identified 5 observational studies and 2 randomized controlled trials that evaluated the combination of intravenous colistin and rifampicin for the treatment of MDR-AB. All observational studies included a small sample size, and the microbiological clearance associated with the combination therapy ranged from 60% to 100%. The randomized controlled trials reported reduced time to microbiological clearance and higher microbiological eradication rate in the colistin/rifampicin group compared with colistin alone. However, there was no difference between both groups in the overall mortality, infection-related mortality, and the length of stay. Furthermore, rifampicin was associated with a higher incidence of hepatotoxicity. Studies evaluating the combination of rifampicin and colistin in the treatment of MDR-AB are limited. The currently available evidence does not support the addition of rifampicin to colistin because of the lack of improved clinical outcomes with the combination therapy and the risk of rifampicin-induced hepatotoxicity.

Tuberculous Meningitis: Diagnostic and Radiological Features, Pathogenesis and Biomarkers

Central nervous system tuberculosis is the most severe form of extrapulmonary tuberculosis disease. We aim to review the diagnostic and radiological features, pathogenesis, and biomarkers of tuberculous meningitis. We also aim to look at the latest development of research of the disease. The diagnosis of tuberculous (TB) meningitis is difficult because the disease presents with unspecific clinical features. However, the disease has excellent clinical response to antituberculous therapy. Good prognosis depends on prompt diagnosis with treatment and radiological findings are very important. There is an increase in the levels of serum and cerebrospinal fluid (CSF) TNF-in TB meningitis patients. IL-6 level is also increased in patients with tuberculoma and exudates. There is an increase in the levels of serum and CSF TNF-α and IFN-γ in TB meningitis patients. There is also a rise in the levels of IL-8, IFN-alpha, IFN-gamma, IL-10, CSF matrix metalloproteinases, CSF tissue inhibitors of matrix Metalloproteinases, VEGF level, caspase-1 and IL-1β. Signal-regulatory protein alpha is overexpressed at mRNA level. High dose intravenous rifampicin (800 mg daily) is associated with reduced mortality in patients with advanced disease.

Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial

Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Intensified intravenous rifampicin in tuberculous meningitis

Intensified intravenous rifampicin in tuberculous meningitis

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

Identifying kinetic determinants of hepatic elimination of drugs would be crucial for better understanding its pharmacokinetics and predicting drug interactions. Present study investigated the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel in rats.The non-renal clearance (CLNR; hepatic elimination) of docetaxel were significantly reduced by co-administration of intravenous rifampicin, a potent inhibitor of organic anion transporting peptides (OATPs; Oatps), at a dose of 20 mg/kg. Docetaxel uptake into isolated rat hepatocytes was found to be temperature/concentration/energy-dependent, saturable, and reduced by Oatps inhibitors (rifampicin and bromosulfophthalein). Moreover, docetaxel uptake into perfused rat liver was significantly reduced in the presence of 10-µM rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 µM.Based on the comparison of intrinsic clearances related to hepatic clearance, it can be suggested that sinusoidal uptake could be the rate-determining process in the overall hepatic elimination of docetaxel in rats.