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Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter , including multidrug-resistant (MDR) isolates. Although sulbactam is a β-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter , and has been used effectively in the treatment of susceptible Acinetobacter -associated infections. Increasing prevalence of β-lactamase–mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed β-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine β-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through β-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans. [ABSTRACT FROM AUTHOR]

Delamanid, a-first-in-class bicyclic nitroimidazole, was recently approved for multidrug-resistant tuberculosis treatment. Pitted against the hope for improving treatment outcomes is the threat of the rapid resistance emergence. This review provides information on the mechanisms of action, resistance emergence, and drug susceptibility testing (DST) for delamanid. Delamanid resistance has already been reported in both in vitro experiments and clinical settings. Although mutations conferring delamanid resistance have been identified in fbiA, fbiB, fbiC, ddn, and fgd1 genes of Mycobacterium tuberculosis , knowledge about the molecular resistance mechanisms is limited, and there remains no standardized DST method. The rapid acquisition of delamanid resistance emphasizes the need for optimal use of new drugs, the need for drug resistance surveillance, and a comprehensive understanding of drug resistance mechanisms. Further studies are necessary to investigate genetic and phenotypic changes that determine clinically relevant delamanid resistance to help develop a rapid delamanid DST. [ABSTRACT FROM AUTHOR]

A World Health Organization workshop systematically examined the evidence base for dosing second-line tuberculosis drugs, identifying knowledge gaps. To fill these in, pharmacokinetics/pharmacodynamics, Monte Carlo experiments, and artificial intelligence algorithms were used in hollow-fiber model studies and clinical data analyses. [ABSTRACT FROM AUTHOR]

Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration–time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background Linezolid exhibits remarkable sterilizing effect in tuberculosis; however, a large proportion of patients develop serious adverse events. The congener tedizolid could have a better side-effect profile, but its sterilizing effect potential is unknown. Methods We performed a 42-day tedizolid exposure-effect and dose-fractionation study in the hollow fiber system model of tuberculosis for sterilizing effect, using human-like intrapulmonary pharmacokinetics. Bacterial burden was examined using time to positivity (TTP) and colony-forming units (CFUs). Exposure-effect was examined using the inhibitory sigmoid maximal kill model. The exposure mediating 80% of maximal kill (EC80) was defined as the target exposure, and the lowest dose to achieve EC80was identified in 10000-patient Monte Carlo experiments. The dose was also examined for probability of attaining concentrations associated with mitochondrial enzyme inhibition. Results At maximal effect, tedizolid monotherapy totally eliminated 7.1 log10CFU/mL Mycobacterium tuberculosis over 42 days; however, TTP still demonstrated some growth. Once-weekly tedizolid regimens killed as effectively as daily regimens, with an EC80free drug 0- to 24-hour area under the concentration–time curve-to-minimum inhibitory concentration (MIC) ratio of 200. An oral tedizolid of 200 mg/day achieved the EC80in 92% of 10000 patients. The susceptibility breakpoint was an MIC of 0.5 mg/L. The 200 mg/day dose did not achieve concentrations associated with mitochondrial enzyme inhibition. Conclusions Tedizolid exhibits dramatic sterilizing effect and should be examined for pulmonary tuberculosis. A tedizolid dose of 200 mg/day or 700 mg twice a week is recommended for testing in patients; the intermittent tedizolid dosing schedule could be much safer than daily linezolid. [ABSTRACT FROM AUTHOR]

Background Children are often neglected during early development of antituberculosis agents, and most receive treatment after it is first tested in adults. However, very young children have tuberculosis that differs in many respects from adult cavitary pneumonia and could have different toxicity profiles to drugs. Linezolid is effective against intracellular tuberculosis, a common manifestation in young children. However, linezolid has considerable toxicity due to inhibition of mitochondrial enzymes. Tedizolid could be a replacement if it shows equal efficacy and reduced toxicity. Methods We performed tedizolid dose-effect studies in the hollow fiber system model of intracellular tuberculosis. We measured linezolid concentrations, colony-forming units (CFU), time-to-positivity, and monocyte viability and performed RNA sequencing on infected cells collected from repetitive sampling of each system. We also compared efficacy of tedizolid vs linezolid and vs tedizolid-moxifloxacin combination. Results There was no downregulation of mitochondrial enzyme genes, with a tedizolid 0–24 hour area under the concentration-time curve (AUC0-24) of up to 90 mg*h/L. Instead, high exposures led to increased mitochondrial gene expression and monocyte survival. The AUC0-24to minimum inhibitory concentration ratio associated with 80% of maximal bacterial kill (EC80) was 184 by CFU/mL (r2= 0.96) and 189 by time-to-positivity (r2= 0.99). Tedizolid EC80killed 4.0 log10CFU/mL higher than linezolid EC80. The tedizolid-moxifloxacin combination had a bacterial burden elimination rate constant of 0.27 ± 0.05 per day. Conclusions Tedizolid demonstrated better efficacy than linezolid, without the mitochondrial toxicity gene or cytotoxicity signatures encountered with linezolid. Tedizolid-moxifloxacin combination had a high bacterial elimination rate. [ABSTRACT FROM AUTHOR]

Background Amikacin has been used for over 40 years in multidrug resistant tuberculosis (MDR-TB), but there is still debate on the right dose. The aim of this review was to search relevant pharmacokinetic (PK) and pharmacodynamic (PD) literature for the optimal dose and dosing frequency of amikacin in MDR-TB regimens trying to optimize efficacy while minimizing toxicity. Methods A systematic review on the value of amikacin as second-line drug in the treatment of MDR-TB was performed. Results Five articles were identified with data on PK, hollow-fiber system model for TB and or early bactericidal activity of amikacin. Despite the long period in which amikacin has been available for the treatment of MDR-TB, very little PK data is available. This highlights the need for more research. Conclusions Maximum concentration (Cmax) of amikacin related to MIC proved to be the most important PK/PD index for efficacy. The target Cmax/MIC ratio should be 10 at site of infection. Cumulative area under the concentration-time curve (AUC) corresponding with cumulative days of treatment was associated with an increased risk of toxicity. [ABSTRACT FROM AUTHOR]

Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0–24). Methods. To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. Results. The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r2 = 0.89). Linezolid efficacy was linked to the AUC0–24 to minimum inhibitory concentration (MIC) ratio (r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC0–24/MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC0–24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r2 = 0.98). Conclusions. We identified the linezolid AUC0–24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0–24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis. [ABSTRACT FROM AUTHOR]

Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children. First, target drug concentrations for optimal efficacy are derived from preclinical models of disseminated tuberculosis that recapitulate pediatric pharmacokinetics, starting with monotherapy. Second, 2-drug combinations were examined for zones of synergy, antagonism, and additivity based on a whole exposure–response surface. Exposures associated with additivity or synergy were then combined and the regimen was compared to standard therapy. Third, several exposures of the third drug were added, and a 3-drug regimen was identified based on kill slopes in comparison to standard therapy. Fourth, computer-aided clinical trial simulations are used to identify clinical doses that achieve these kill rates in children in different age groups. The proposed program led to the development of a 3-drug combination regimen for children from scratch, independent of adult regimens, in <2 years. The regimens and doses can be tested in animal models and in clinical trials. [ABSTRACT FROM AUTHOR]

The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximum-tolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that the concentration will persist above minimum inhibitory concentrations of Candida species for several days. Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each other, is not only logical, but might even lead to faster clearance of Candida. [ABSTRACT FROM AUTHOR]

Background. The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/ pharmacodynamics (PK/PD) experiments, and hence the design of optimal doses and dose schedules for the treatment of tuberculosis. To determine if this model is useful for deriving PK/PD data relevant to clinical outcomes, we compared its quantitative output to that from clinical trials. Methods. We performed a PubMed search to identify clinical studies performed with antituberculosis therapy in which PK/PD data and/or parameters were documented or a dose-scheduling study design was employed. The search period was from January 1943 to December 2012. All clinical studies were published prior to HFS-TB experiments. Bias minimization was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical publications were scored for quality of evidence, with 1 as the highest score (randomized controlled trials or meta-analyses of such studies), and 4 as the lowest score. Results. We identified 17 studies that examined the same parameters as in 8 HFS-TB studies. Fifteen of 17 studies had a quality-of-evidence score of 1. The sterilizing and bactericidal effect rates for isoniazid, rifampin, pyrazinamide, and ethambutol were the same in the HFS-TB as in patients. Time to emergence of resistance for monotherapy was the same as in patients. The PK/PD indices associated with efficacy were the same in HFS-TB as in patients for all drugs examined. Conclusions. The HFS-TB model is highly accurate at identifying optimal drug exposures, doses, and dosing schedules for use in the clinic. [ABSTRACT FROM AUTHOR]

The author discusses strategies for usage of colistin, a polymyxin antibiotic. Topics discussed include use of colistin for treatment of carbapenem-resistant gram-negative bacilli, lack of information regarding dosing and administration of colistin, complications in dosage of colistin due to nephrotoxicity which limits dose and duration of therapy, identification of risk factors of acute kidney injury (AKI) with colistin.