Background: The prolonged treatment duration for multidrug-resistant (MDR) tuberculosis (TB) makes dosing linezolid difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid given different MIC values. Methods: Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used fAUC/MIC >119 as the pharmacokinetic/pharmacodynamic (PK/PD) target, and Cmin of 2 and 7 mg/L as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. Results: A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kilograms. 81% had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/L for a total daily dose of 300 mg, while the daily dose of 450-600 mg and 900-1200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/L, respectively. The probability of achieving Cmin ≤2 mg/L was higher when the dose was given at once versus dividing it to two doses. Conclusion: Linezolid daily dose of 300 mg may not be optimal. We predicted excellent and comparable efficacy of linezolid using total daily doses of 900 and 1200 mg for MICs ≤0.5 mg/L, but with a potential for more toxicity compared to 600 mg daily. The increase in Cmin was noticeable when the daily dose was divided and may incur greater toxicity.

Background In the ICU, early and appropriate antimicrobial therapy is important to lower infection-related mortality. Objectives Assess whether achieving early β-lactam free concentration above the MIC 100% of the time (fT>MIC) is associated with positive outcomes in the ICU. Methods This retrospective study was conducted in ICU patients admitted to UF Health Shands Hospital between 2016 and 2018. Adult patients who received β-lactam therapy and had drug concentration measured were included. Data collected included demographics, β-lactam regimens and concentrations, sources of infection, cultures and susceptibilities, mortality, length of stay, resistance acquisition for 30 days and clinical outcome at end of therapy. Multiple regression and time-to-event (TTE) analyses were performed. Results Two-hundred and six patients were included. Clinical cure occurred in 71%, microbial eradication occurred in 58% and new resistance to the β-lactam received developed in 8% of patients. Hospital and 30 day mortalities were 17% and 14%, respectively. fT>MIC and fT>4×MIC were associated with clinical cure (P = 0.0303), microbial eradication (P = 0.0476) and suppression of resistance (P = 0.0043). Delay in measuring β-lactam concentration was associated with clinical failure (P = 0.0072), longer ICU stay (P < 0.0001) and higher mortality (P = 0.0387). In the TTE analysis, patients with 100% fT>MIC had a significantly shorter ICU stay (P = 0.0297). Patients who had clinical cure and microbial eradication had drug concentrations measured earlier (P = 0.0025 and 0.0254, respectively). Conclusions This study highlights the importance of early measurement of β-lactam concentration and confirms the association between fT>MIC and clinical cure, microbial eradication and emergence of resistance.

According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited.

Background: The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin. Methods: Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined. Results: Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17–87) and the median (range) body mass index was 25.7 kg/m2 (14.7–74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (fu) was 62.5% (41.6–99.1) for meropenem, 61.4% (51.6–99.2) for cefepime, and 48.3% (39.4–71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the fu increased (r = 0.37, P = 0.045). A decrease in piperacillin fu was observed as the albumin concentration increased (r = −0.56, P = 0.005). Conclusions: The average fu values were lower than those reported in the literature. There was also a large variability in fu; hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.

The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is an inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues. Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding. Plasma samples from 22 patients were included, of which plasma proteins were measured for 18 patients. The median PB was determined for rifampin (88%; range, 72 to 91%), isoniazid (14%; range, 0 to 34%), pyrazinamide (1%; range, 0 to 7%), and ethambutol (12%; range, 4 to 24%). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration ( value = 0.0051). Conversely, isoniazid PB was negatively correlated with its plasma concentration ( value = 0.0417). Age was found to have a significant effect on isoniazid PB ( value = 0.0376). No correlations were observed in pyrazinamide or ethambutol. In conclusion, we have determined variable PB of rifampin, isoniazid, pyrazinamide, and ethambutol in patient plasma samples, with median values of 88, 14, 1, and 12%, respectively. In this small study, PB of rifampin and that of isoniazid are dependent on their plasma concentrations.

Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0–24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0–24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500–3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.

Tuberculosis (TB) and hepatitis C virus (HCV) infections are both major public health problems. Despite high rates of coinfection, there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs), and existing data preclude these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move cotreatment regimens forward for clinical use among patients coinfected with TB and HCV.