A Pharmacology Perspective of Simultaneous Tuberculosis and Hepatitis C Treatment.

Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection 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 precludes 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 co treatment regimens forward for clinical use among patients coinfected with TB and HCV.

Discovery of quinoline small molecules with potent dispersal activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis biofilms using a scaffold hopping strategy.

Staphylococcus aureus and Staphylococcus epidermidis are recognized as the most frequent cause of biofilm-associated nosocomial and indwelling medical device infections. Biofilm-associated infections are known to be highly resistant to our current arsenal of clinically used antibiotics and antibacterial agents. To exacerbate this problem, no therapeutic option exists that targets biofilm-dependent machinery critical to Staphylococcal biofilm formation and maintenance. Here, we describe the discovery of a series of quinoline small molecules that demonstrate potent biofilm dispersal activity against methicillin-resistant S. aureus and S. epidermidis using a scaffold hopping strategy. This interesting class of quinolines also has select synthetic analogues that demonstrate potent antibacterial activity and biofilm inhibition against S. aureus and S. epidermidis.

Experience with Implementing a Beta-lactam Therapeutic Drug Monitoring Service in a Burn Intensive Care Unit: A Retrospective Chart Review.

Thermal injuries alter pharmacokinetics, complicating the prediction of standard antibiotic dose effectiveness. Therapeutic drug monitoring (TDM) has been proposed to prevent subtherapeutic dosing of antibiotic therapy, but remains scarcely studied in the burn patient population. A retrospective chart review of burn patients receiving beta-lactam TDM from 2016 to 2019 was conducted. Adult patients with thermal injury receiving cefepime, piperacillin/tazobactam, or meropenem for ≥48 hours were included. Between February 2016 and July 2017, we utilized selective TDM based on clinical judgement to guide treatment. From October 2018 until July 2019, TDM was expanded to all burn patients on beta-lactams. The primary endpoint was achievement of therapeutic concentration, and the secondary endpoints were clinical cure, culture clearance, new resistance, length of stay, and mortality. The selective (control) group included 19 patients and the universal (study) group reviewed 23 patients. In both groups, skin and lungs were the most common primary infection sources, with Pseudomonas aeruginosa as the most common species. In the universal cohort, patients were older with higher risk factors, but more frequently achieved the target drug concentration, required less days to start TDM (p < .0001), and had more frequent measurements and beta-lactam dose adjustments. Positive clinical outcome was reported in 77%, and microbial eradication in 82% of all patients. All clinical outcomes were similar between the groups. The implementation of beta-lactam TDM protocol shortened the time, increased the probability of appropriate target attainment, and individualized beta-lactam therapy in burn patients.

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems.

INTRODUCTION: Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation. AREAS COVERED: This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver impairment, patients co-infected with HIV or hepatitis, and special patient populations - children and pregnant women. EXPERT OPINION: TB treatment has a long history of using 'one size fits all.' This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB.

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV.

PURPOSE: The updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women. METHODS: Ghanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared. FINDINGS: Of 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The Cmax, Cmin, AUC0-24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV Cmax, Cmin, AUC0-24, and CL/F were 1.10 (95% CI, 0.93-1.31), 0.88 (95% CI, 0.67-1.17), 0.84 (95% CI, 0.71-0.98), and 1.20 (95% CI, 1.02-1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission. IMPLICATIONS: We found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Recent Progress in Natural-Product-Inspired Programs Aimed To Address Antibiotic Resistance and Tolerance.

Bacteria utilize multiple mechanisms that enable them to gain or acquire resistance to antibiotic therapies during the treatment of infections. In addition, bacteria form biofilms which are surface-attached communities of enriched populations containing persister cells encased within a protective extracellular matrix of biomolecules, leading to chronic and recurring antibiotic-tolerant infections. Antibiotic resistance and tolerance are major global problems that require innovative therapeutic strategies to address the challenges associated with pathogenic bacteria. Historically, natural products have played a critical role in bringing new therapies to the clinic to treat life-threatening bacterial infections. This Perspective provides an overview of antibiotic resistance and tolerance and highlights recent advances (chemistry, biology, drug discovery, and development) from various research programs involved in the discovery of new antibacterial agents inspired by a diverse series of natural product antibiotics.

A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis.

Unlike individual, free-floating planktonic bacteria, biofilms are surface-attached communities of slow- or non-replicating bacteria encased within a protective extracellular polymeric matrix enabling persistent bacterial populations to tolerate high concentrations of antimicrobials. Our current antibacterial arsenal is composed of growth-inhibiting agents that target rapidly-dividing planktonic bacteria but not metabolically dormant biofilm cells. We report the first modular synthesis of a library of 20 halogenated phenazines (HP), utilizing the Wohl-Aue reaction, that targets both planktonic and biofilm cells. New HPs, including 6-substituted analogues, demonstrate potent antibacterial activities against MRSA, MRSE and VRE (MIC = 0.003-0.78 µM). HPs bind metal(II) cations and demonstrate interesting activity profiles when co-treated in a panel of metal(II) cations in MIC assays. HP 1 inhibited RNA and protein biosynthesis while not inhibiting DNA biosynthesis using 3H-radiolabeled precursors in macromolecular synthesis inhibition assays against MRSA. New HPs reported here demonstrate potent eradication activities (MBEC = 0.59-9.38 µM) against MRSA, MRSE and VRE biofilms while showing minimal red blood cell lysis or cytotoxicity against HeLa cells. PEG-carbonate HPs 24 and 25 were found to have potent antibacterial activities with significantly improved water solubility. HP small molecules could have a dramatic impact on persistent, biofilm-associated bacterial infection treatments.

Structure-Activity Relationships of a Diverse Class of Halogenated Phenazines That Targets Persistent, Antibiotic-Tolerant Bacterial Biofilms and Mycobacterium tuberculosis.

Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC < 10 µM), MRSE (MBEC = 2.35 µM), and VRE (MBEC = 0.20 µM) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 µM). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.