Evaluation of current dosing guidance for oral rifampicin treatment in adult patients with osteoarticular infections.
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ABSTRACT:
SUBMITTER: Marsot A
PROVIDER: S-EPMC7576626 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTreatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations.MethodsProspective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites.ResultsAzithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC.ConclusionPK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations.Clinical trial registrationClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.
| S-EPMC8543792 | biostudies-literature
Project description:BackgroundOsteoarticular infections (OAIs) are commonly treated with prolonged intravenous (IV) antimicrobials. The Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial demonstrated that oral (PO) antibiotics are noninferior to IV antibiotics in the treatment of OAIs. We surveyed infectious disease (ID) physicians about their use of PO antibiotics in the treatment of OAIs.MethodsAn Emerging Infection Network survey with 9 questions regarding antibiotic prescribing for the treatment of OAIs was sent to 1475 North American ID physicians. The questions were mostly multiple choice and focused on the use of definitive oral antibiotic therapy (defined as oral switch within 2 weeks of starting antibiotics) and chronic suppressive antibiotic therapy (SAT).ResultsOf the 413 physicians who reported treating OAIs, 91% used oral antibiotics at least sometimes and 31% used them as definitive therapy, most often for diabetic foot osteomyelitis and native joint septic arthritis. The oral antibiotics most frequently used for OAIs included trimethoprim-sulfamethoxazole, doxycycline/minocycline, and linezolid for Staphylococcus aureus, amoxicillin/cefadroxil/cephalexin for streptococci, and fluoroquinolones for gram-negative organisms. The most common rationales for not transitioning to oral antibiotics included nonsusceptible pathogens, comorbidities preventing therapeutic drug levels, and concerns about adherence. SAT use was variable but employed by a majority in most cases of periprosthetic joint infection managed with debridement and implant retention.ConclusionsNorth American ID physicians utilize oral antibiotics and SAT for the management of OAIs, although significant practice variation exists. Respondents voiced a need for updated guidelines.
| S-EPMC11167670 | biostudies-literature
Project description:AimsTo propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto-induction, saturable pharmacokinetics and high interoccasion variability.MethodsRifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24 hours and area under the plasma concentration-time curve up to 24 hours (AUC0-24h ). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC.ResultsThe suggested exposure target for Bayesian dose optimisation was a steady state AUC0-24h of 181-214 h × mg/L. The observed MICs ranged from 0.016-0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000 mg (20-50 mg/kg) with a mode of 1800 mg (30 mg/kg, n = 24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h -only target.ConclusionsA new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.
| S-EPMC6783589 | biostudies-literature
Project description:BackgroundThe weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.MethodsRifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median area under the curve (AUC0-24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.ResultsThe difference of median AUC0-24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.ConclusionsWeight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.
| S-EPMC7819529 | biostudies-literature
Project description:Incubation for 14 days is recommended for the culture of microorganisms from osteoarticular infections (OAI), but there are no recommendations for postoperative antibiotic stewardship concerning empirical antimicrobial therapy (EAT), while prolonging broad-spectrum EAT results in adverse effects. The aim of this study was to describe the local OAI epidemiology with consideration of bacterial growth times to determine which antibiotic stewardship intervention should be implemented in cases of negative culture after 2 days of incubation. We performed a 1-year, single-center, noninterventional cohort study at the Pitié-Salpêtrière hospital OAI reference center. Samples were taken as part of the local standard of care protocol for adult patients who underwent surgery for OAI (native or device related) and received EAT (i.e., piperacillin-tazobactam plus daptomycin [PTD]) following surgery. The time to culture positivity was monitored daily. Overall, 147 patients were recruited, accounting for 151 episodes of OAI, including 112 device-related infections. Microbiological cultures were positive in 144 cases, including 42% polymicrobial infections. Overall, a definitive microbiological result was obtained within 48 h in 118 cases (78%) and within 5 days in 130 cases (86%). After 5 days, only Gram-positive bacteria were recovered, especially Cutibacterium acnes, Staphylococcus spp., and Streptococcus spp. Overall, 90% of culture-positive OAI were correctly treated with the locally established EAT. EAT guidance for OAI was in agreement with our local epidemiology. Our results supported antibiotic stewardship intervention consisting of stopping piperacillin-tazobactam treatment at day 5 in cases of negative culture. IMPORTANCE Osteoarticular infections (OAI) remain challenging to diagnose and to treat. One of the issues concerns postoperative empirical antimicrobial therapy (EAT), which is usually a combination of broad-spectrum antibiotics. This EAT is maintained up to 2 weeks, until the availability of the microbiological results (identification and drug susceptibility testing of the microorganisms responsible for the OAI). Our results provide new data that will help to improve OAI management, especially EAT. Indeed, we have shown that antibiotic stewardship intervention consisting of stopping the antibiotic targeting Gram-negative bacteria included in the EAT could be implemented in cases where culture is negative after 5 days of incubation. The benefits of such an antibiotic stewardship plan include improved patient outcomes, reduced adverse events (including Clostridioides difficile infection), improvement in rates of susceptibilities to targeted antibiotics, and optimization of resource utilization across the continuum of care.
| S-EPMC9812015 | biostudies-literature
Project description:Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography–tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections.
| S-EPMC9501058 | biostudies-literature
Project description:Background: Acute hematogenous osteomyelitis (OM) and septic arthritis require immediate diagnosis and treatment by an interdisciplinary team of pediatric infectious disease specialists and pediatric orthopedic surgeons. Adverse outcomes such as growth disturbance, bone deformity, and chronic infections have been described in older studies. However, there is only little known about long-term follow-up of patients of the last two decades. Therefore, we aimed to evaluate subjective and objective long-term outcomes of these children with osteoarticular infections treated in the millennial years. Methods: Cross-sectional study performed in two pediatric centers including patients admitted for OM and/or SA between 2005 and 2014 and follow-up consultations in 2019. Patients with symptoms of ≤2 weeks duration at initial presentation were contacted. Subjective outcomes were assessed by standardized interview, objective outcomes by clinical examination. Medical charts were used to extract data from the initial presentations. Statistical analysis was performed by non-parametric tests and Fisher's exact test. Results: Of 147 eligible patients 77 (52%) agreed to participate, of which 68 (88%) had an interview and physical examination and 9 (12%) an interview only. Thirty-three (39%) had OM, 26 (34%) SA, and 21 (27%) combined OM/SA. Median (IQR) age at follow-up was 13.3 (10.5-18.0) years with a median (IQR) follow-up of 7.1 (6.1-8.6) years. Persistent complaints including pain, functional differences and scar paresthesia, reported by 21 (28%) patients, were generally mild and only 3 (5%) required ongoing medical care. Objective sequelae including pain, limited range of motion, unilateral axis deformity or asymmetric gait were found in 8 (12%) participants. Older age, female sex, joint involvement, surgical intervention, persistent fever, and C-reactive protein elevation were associated with adverse clinical outcome. Conclusions: Adverse outcomes were observed in a considerable number of patients, most of which were minor, and only few required ongoing medical care. Long-term follow up is advisable for patients with risk factors identified during the initial presentation. This study was registered on ClinicalTrials.gov (NCT03827980).
| S-EPMC7737431 | biostudies-literature
Project description:IntroductionDrug concentrations in tuberculosis patients on standard regimens vary widely with clinically important consequences. Areas covered: We review the available literature identifying factors correlated with pharmacokinetic variability of antituberculosis drugs. Based on population pharmacokinetic models and the weight, height, and sex distributions in a large data base of African tuberculosis patients, we propose simplified weight-based doses of the available fixed dose combination(FDC) for adults with drug susceptible tuberculosis. Emerging studies will support optimized weight-based dosing for children. Other sources of important pharmacokinetic variability include genetic variants, drug-drug interactions, formulation quality, and methods of preparation and administration. Expert commentary: Optimized weight band-based dosing will result in more equitable distribution of drug exposures by weight. The use of high doses of isoniazid in patients with drug-resistant tuberculosis would be safer and more effective if a feasible test was developed to allow stratified dosing according to acetylator type. There is an urgent need for more suitable formulations of many second-line drugs for children. The adoption of new technologies and efficient FDC design may allow further advances for patients and treatment programs. Lastly, current efforts to ensure adequate quality of antituberculosis drug products are not preventing the use of substandard products to treat patients with tuberculosis.
| S-EPMC6364307 | biostudies-literature
Project description:BackgroundWe evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin.MethodsInfants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported.ResultsTwenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively.ConclusionsDolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.
| S-EPMC10954323 | biostudies-literature
Project description:We retrospectively evaluated antimicrobial therapy in 145 randomly selected patients with osteoarticular infections across 8 hospitals. One hundred nine (75%) were eligible for oral antimicrobial therapy, but only 18 received it: 5 of 39 (13%) in 2018 versus 13 of 70 (19%) in 2019-2020 (P = .44). Oral antimicrobials may be underutilized for osteoarticular infections in routine practice.
| S-EPMC9472666 | biostudies-literature