Authors: Mariana Albano, Melissa J Karau, Kerryl E Greenwood-Quaintance...

After staphylococci, streptococci and enterococci are the most frequent causes of periprosthetic joint infection (PJI). MICs and minimum biofilm bactericidal concentrations of rifampin, rifabutin, and rifapentine were determined for 67 enterococcal and 59 streptococcal PJI isolates. Eighty-eight isolates had rifampin MICs of ≤1 μg/ml, among which rifabutin and rifapentine MICs were ≤ 8 and ≤4 μg/ml, respectively. There was low rifamycin antibiofilm activity except for a subset of Streptococcus mitis group isolates. Rifampin is an antibiotic with antistaphylococcal biofilm activity used in the management of staphylococcal periprosthetic joint infection with irrigation and debridement with component retention; some patients are unable to receive rifampin due to drug interactions or intolerance. We recently showed rifabutin and rifapentine to have activity against planktonic and biofilm states of rifampin-susceptible periprosthetic joint infection-associated staphylococci. After staphylococci, streptococci and enterococci combined are the most common causes of periprosthetic joint infection. Here, we investigated the antibiofilm activity of rifampin, rifabutin, and rifapentine against 126 Streptococcus and periprosthetic joint infection isolates. In contrast to our prior findings with staphylococcal biofilms, there was low antibiofilm activity of rifampin, rifabutin, and rifapentine against PJI-associated streptococci and enterococci, apart from some Streptococcus mitis group isolates.

Topics: Anti-Bacterial Agents; Bacterial Infections; Biofilms; Enterococcus; Humans; Microbial Sensitivity Tests; Prosthesis-Related Infections; Rifabutin; Rifampin; Staphylococcal Infections; Staphylococcus

PubMed: 34259553
DOI: 10.1128/Spectrum.00071-21

Authors: Katharina Kusejko, Álvaro Auñón, Bernhard Jost...

BACKGROUND

Cutibacterium species are common pathogens in periprosthetic joint infections (PJI). These infections are often treated with β-lactams or clindamycin as monotherapy, or in combination with rifampin. Clinical evidence supporting the value of adding rifampin for treatment of Cutibacterium PJI is lacking.

METHODS

In this multicenter retrospective study, we evaluated patients with Cutibacterium PJI and a minimal follow-up of 12 months. The primary endpoint was clinical success, defined by the absence of infection relapse or new infection. We used Fisher's exact tests and Cox proportional hazards models to analyze the effect of rifampin and other factors on clinical success after PJI.

RESULTS

We included 187 patients (72.2% male, median age 67 years) with a median follow-up of 36 months. The surgical intervention was a 2-stage exchange in 95 (50.8%), 1-stage exchange in 51 (27.3%), debridement and implant retention (DAIR) in 34 (18.2%), and explantation without reimplantation in 7 (3.7%) patients. Rifampin was included in the antibiotic regimen in 81 (43.3%) cases. Infection relapse occurred in 28 (15.0%), and new infection in 13 (7.0%) cases. In the time-to-event analysis, DAIR (adjusted hazard ratio [HR] = 2.15, P = .03) and antibiotic treatment over 6 weeks (adjusted HR = 0.29, P = .0002) significantly influenced treatment failure. We observed a tentative evidence for a beneficial effect of adding rifampin to the antibiotic treatment-though not statistically significant for treatment failure (adjusted HR = 0.5, P = .07) and not for relapses (adjusted HR = 0.5, P = .10).

CONCLUSIONS

We conclude that a rifampin combination is not markedly superior in Cutibacterium PJI, but a dedicated prospective multicenter study is needed.

Topics: Aged; Anti-Bacterial Agents; Debridement; Female; Humans; Male; Prospective Studies; Prosthesis-Related Infections; Retrospective Studies; Rifampin; Treatment Outcome

PubMed: 33300545
DOI: 10.1093/cid/ciaa1839

Authors: Camilo A Ruiz-Bedoya, Filipa Mota, Elizabeth W Tucker...

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

Topics: Animals; Antitubercular Agents; Humans; Inflammation; Mice; Models, Animal; Rabbits; Rifampin; Tuberculosis, Meningeal

PubMed: 35085105
DOI: 10.1172/JCI155851

Authors: Jeonghyun Chang, Heungsup Sung, Kyung-Wook Jo...

In this study, we aimed to assess the performance of the Xpert MTB/RIF assay for the detection of pulmonary tuberculosis compared to the acid-fast bacilli (AFB) smear and culture analysis, and the incidence of rifampin resistance using the drug susceptibility test. The specimens referred for AFB smear and culture analysis and Xpert MTB/RIF assay from April 2015 to March 2018 were retrospectively reviewed. The sensitivity, specificity, and mean cycle threshold (Ct) values obtained in Xpert MTB/RIF assay and for rifampin resistance were analyzed. The results of Xpert MTB/RIF assay for pulmonary tuberculosis were evaluated based on the AFB smear grade. Among 3,840 specimens, 491 were positive in Xpert MTB/RIF assay and 626 in culture analysis. The sensitivity and specificity of Xpert MTB/RIF assay were 75.6% and 99.4%, respectively. The sensitivity of Xpert MTB/RIF assay for smear-positive/culture-positive specimens was 98.6% and that of smear-negative and -trace/culture-positive specimens was 63.1%. The positivity of Xpert MTB/RIF assay for culture-positive specimens was 89.9%, 98.6%, 95.7%, 100.0%, and 100.0% for the smear grades trace, 1+, 2+, 3+, 4+, respectively. The Ct values of 491 specimens significantly decreased as the AFB smear grade increased (P < 0.0001). The Ct values of smear-positive, -trace, and -negative specimens were 21.7 ± 4.2, 26.5 ± 3.9, and 27.4 ± 3.6, respectively. Rifampin resistance evaluated using Xpert MTB/RIF assay and culture analysis exhibited a correlation of 98.3%. The region covered by probe E was the most frequently mutated region (50.0%). Xpert MTB/RIF assay demonstrated reliable performance in detecting pulmonary tuberculosis from smear-positive and culture-positive specimens; however, further improvements are still required to detect smear-negative and culture-positive specimens.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Incidence; Mycobacterium tuberculosis; Polymerase Chain Reaction; Republic of Korea; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tertiary Care Centers; Tuberculosis, Pulmonary

PubMed: 33790071
DOI: 10.7883/yoken.JJID.2020.978

Randomized Controlled Trial

Authors: Terhi J Lohela, Satu Poikola, Mikko Neuvonen...

BACKGROUND

Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin.

METHODS

In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes.

RESULTS

Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters.

CONCLUSIONS

Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Topics: Administration, Intravenous; Administration, Oral; Adult; Analgesics, Opioid; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Double-Blind Method; Drug Interactions; Female; Finland; Glucuronates; Healthy Volunteers; Humans; Hydromorphone; Inactivation, Metabolic; Male; Rifampin; Young Adult

PubMed: 33177323
DOI: 10.1213/ANE.0000000000005229

Comparative Study

Authors: Kentaro Iwata, Naomi Morishita, Masami Nishiwaki...

Objective Treating latent tuberculosis infection (LTBI) is essential for eliminating the serious endemicity of tuberculosis. A shorter regimen is preferred to longer regimens because the former has better adherence with a better safety profile. However, lengthy treatment with isoniazid is still recommended in Japan. Based on the latest evidence, we switched from a conventional nine-month isoniazid regimen to a shorter four-month rifampin regimen for the treatment of LTBI. Methods To evaluate the safety and efficacy of the shorter regimen, we conducted Bayesian analyses using a stochastic mathematical model to calculate the posterior probabilities of several parameters. Patients Clinical data of 13 patients in the isoniazid group and 5 in the rifampin group were used for the Bayesian analyses. The outcomes measured were completion of the treatment, adverse effects, number of clinic visits, and medical costs. Results The medial posterior probability of the isoniazid group completing the treatment was 66% [95% credible interval (CrI) 43-89%], whereas that of the rifampin group was 86% (95% CrI 60-100%). The probability that the completion rate in the rifampin group was better than that in the isoniazid group was as high as 88% (95% CrI 0-100%). Other parameters, such as the number of clinical visits and duration of treatment, were better with rifampin therapy than with isoniazid therapy, with comparable medical costs. Conclusion Four months of rifampin therapy might be preferred to isoniazid for treating LTBI in Japan.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Bayes Theorem; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoniazid; Japan; Latent Tuberculosis; Male; Markov Chains; Middle Aged; Monte Carlo Method; Rifampin

PubMed: 32669488
DOI: 10.2169/internalmedicine.3477-19

Authors: Shashikant Srivastava, Gunavanthi D Boorgula, Jann-Yuan Wang...

There is limited high-quality evidence to guide the optimal treatment of Mycobacterium kansasii pulmonary disease. We retrospectively collected clinical data from 33 patients with M. kansasii pulmonary disease to determine the time-to-sputum culture conversion (SCC) upon treatment with a standard combination regimen consist of isoniazid-rifampin-ethambutol. Next, MIC experiments with 20 clinical isolates were performed, followed by a dose-response study with the standard laboratory strain using the hollow-fiber system model of M. kansasii infection (HFS-). The inhibitory sigmoid maximum effect () model was used to describe the relationship between the bacterial burden and rifampin concentrations. Finally, clinical trial simulations were performed to determine the clinical dose to achieve the optimal rifampin exposure in patients. The SCC rate in patients treated with combination regimen containing rifampin at 10 mg/kg of body weight/day was 73%, the mean time to SSC was 108 days, and the mean duration of therapy was 382 days. The MIC of the M. kansasii laboratory strain was 0.125 mg/L, whereas the MICs of the clinical isolates ranged between 0.5 and 4 mg/L. In the HFS- model, a maximum kill () of 7.82 log CFU/mL was recorded on study day 21. The effective concentration mediating 80% of the (EC) was calculated as the ratio of the maximum concentration of drug in serum for the free, unbound fraction () to MIC of 34.22. The target attainment probability of the standard 10-mg/kg/day dose fell below 90% even at the MIC of 0.0625 mg/L. Despite the initial kill, there was M. kansasii regrowth with the standard rifampin dose in the HFS- model. Doses higher than 10 mg/kg/day, in combination with other drugs, need to be evaluated for better treatment outcome.

Topics: Antitubercular Agents; Humans; Lung Diseases; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Retrospective Studies; Rifampin

PubMed: 35315686
DOI: 10.1128/aac.02320-21

Randomized Controlled Trial

Authors: Øystein Espeland Karlsen, Pål Borgen, Bjørn Bragnes...

BACKGROUND

The evidence supporting rifampin combination therapy in prosthetic joint infections (PJI) is limited due to the lack of controlled studies. The aim of this study is to evaluate the effect of adding rifampin to conventional antimicrobial therapy in early staphylococcal PJIs treated with debridement and retention of the implant (DAIR).

METHODS

In this multicenter randomized controlled trial, 99 patients with PJI after hip and knee arthroplasties were enrolled. They were randomly assigned to receive rifampin or not in addition to standard antimicrobial treatment with cloxacillin or vancomycin in case of methicillin resistance. The primary endpoint was no signs of infection after 2 years of follow-up.

RESULTS

Forty-eight patients were included in the final analyses. There were no differences in patient characteristics or comorbidities between the two groups. There was no significant difference in remission rate between the rifampin combination group (17 of 23 (74%)) and the monotherapy group (18 of 25 (72%), relative risk 1.03, 95% confidence interval 0.73 to 1.45, p = 0.88).

CONCLUSION

This trial has not proven a statistically significant advantage by adding rifampin to standard antibiotic treatment in acute staphylococcal PJIs.

TRIAL REGISTRATION

The Regional Ethics Committee and the Norwegian Medicines Agency approved the study (EudraCT 2005-005494-29), and the study was registered at ClinicalTrials.gov at Jan 18, 2007 ( NCT00423982 ).

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cloxacillin; Debridement; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prosthesis-Related Infections; Rifampin; Staphylococcal Infections; Time Factors; Treatment Outcome; Vancomycin

PubMed: 32859235
DOI: 10.1186/s13018-020-01877-2

Probing the Molecular Mechanism of Rifampin Resistance Caused by the Point Mutations S456L and D441V on Mycobacterium tuberculosis RNA Polymerase through Gaussian Accelerated Molecular Dynamics Simulation.

Authors: Qianqian Zhang, Shuoyan Tan, Tong Xiao...

Rifampin is the first-line antituberculosis drug, with RNA polymerase as the molecular target. Unfortunately, strains that are resistant to rifampin have been identified in clinical settings, which limits its therapeutic effects. In clinical isolates, S531L and D516V (in ) are two common mutated codons in the gene , corresponding to S456L and D441V in However, the resistance mechanism at the molecular level is still elusive. In this work, Gaussian accelerated molecular dynamics simulations were performed to uncover the resistance mechanism of rifampin due to S456L and D441V mutations at the atomic level. The binding free energy analysis revealed that the reduction in the ability of two mutants to bind rifampin is mainly due to a decrease in electrostatic interaction, specifically, a decrease in the energy contribution of the R454 residue. R454 acts as an anchor and forms stable hydrogen bond interaction with rifampin, allowing rifampin to be stably incorporated in the center of the binding pocket. However, the disappearance of the hydrogen bond between R454 and the mutated residues increases the flexibility of the side chain of R454. The conformation of R454 changes, and the hydrogen bond interaction between it and rifampin is disrupted. As result, the rifampin molecule moves to the outside of the pocket, and the binding affinity decreases. Overall, these findings can provide useful information for understanding the drug resistance mechanism of rifampin and also can give theoretical guidance for further design of novel inhibitors to overcome the drug resistance.

Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Molecular Dynamics Simulation; Mutation; Mycobacterium tuberculosis; Point Mutation; Rifampin

PubMed: 32393493
DOI: 10.1128/AAC.02476-19

Observational Study

Authors: Mark Beldman, Claudia Löwik, Alex Soriano...

BACKGROUND

Rifampin is generally advised in the treatment of acute staphylococcal periprosthetic joint infections (PJI). However, if, when, and how to use rifampin remains a matter of debate. We evaluated the outcome of patients treated with and without rifampin, and analyzed the influence of timing, dose and co-antibiotic.

METHODS

Acute staphylococcal PJIs treated with surgical debridement between 1999 and 2017, and a minimal follow-up of 1 year were evaluated. Treatment failure was defined as the need for any further surgical procedure related to infection, PJI-related death or the need for suppressive antimicrobial treatment.

RESULTS

A total of 669 patients were analyzed. Treatment failure was 32.2% (131/407) in patients treated with rifampin and 54.2% (142/262) in whom rifampin was withheld (P < .001). The most prominent effect of rifampin was observed in knees (treatment failure 28.6% versus 63.9%, respectively, P < .001). The use of rifampin was an independent predictor of treatment success in the multi-variate analysis (OR 0.30, 95% CI 0.20 - 0.45). In the rifampin group, the use of a co-antibiotic other than a fluoroquinolone or clindamycin (OR 10.1, 95% CI 5.65 - 18.2) and the start of rifampin within 5 days after surgical debridement (OR 1.96, 95% CI 1.08 - 3.65) were predictors of treatment failure. The dosing of rifampin had no effect on outcome.

CONCLUSIONS

Our data supports the use of rifampin in acute staphylococcal PJIs treated with surgical debridement, particularly in knees. Immediate start of rifampin after surgical debridement should probably be discouraged, but requires further investigation.

Topics: Anti-Bacterial Agents; Debridement; Humans; Prosthesis-Related Infections; Retrospective Studies; Rifampin; Staphylococcal Infections; Staphylococcus; Treatment Outcome

PubMed: 33970214
DOI: 10.1093/cid/ciab426