The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

https://www.tandfonline.com/doi/pdf/10.1080/14756360701425014

The role of fluorine in medicinal chemistry

Although the fluoroquinolones are presently used to treat tuberculosis primarily in cases involving resistance or intolerance to first-line antituberculosis therapy, these drugs are potential first-line agents and are under study for this indication However, there is concern about the development of fluoroquinolone resistance in Mycobacterium tuberculosis, particularly when administered as monotherapy or as the only active agent in a failing multidrug regimen Treatment failures as well as relapses have been documented under such conditions With increasing numbers of fluoroquinolone prescriptions and the expanded use of these broad-spectrum agents for many infections, the selective pressure of fluoroquinolone use results in the ready emergence of fluoroquinolone resistance in a diversity of organisms, including M tuberculosis Among M tuberculosis, resistance is emerging and may herald a significant future threat to the long-term clinical utility of fluoroquinolones Discussion and education regarding appropriate use are necessary to preserve the effectiveness of this antibiotic class against the hazard of growing resistance

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(03)00671-6.pdf

Fluoroquinolones, tuberculosis, and resistance

The fluoroquinolones are a class of compounds that comprise a large and expanding group of synthetic antimicrobial agents. Structurally, all fluoroquinolones contain a fluorine molecule at the 6-position of the basic quinolone nucleus. Despite the basic similarity in the core structure of these molecules, their physicochemical properties, pharmacokinetic characteristics and microbial activities can vary markedly across compounds. The first of the fluoroquinolones approved for use in animals, enrofloxacin, was approved in the late 1980s. Since then, five other fluoroquinolones have been marketed for use in animals in the United States, with others currently under investigation. This review focuses on the use of fluoroquinolones within veterinary medicine, providing an overview of the structure-activity relationship of the various members of the group, the clinical uses of fluoroquinolones in veterinary medicine, their pharmacokinetics and potential interspecies differences, an overview of the current understanding of the pharmacokinetic/pharmacodynamic relationships associated with fluoroquinolones, a summary of toxicities that have been associated with this class of compounds, their use in both in human and veterinary species, mechanisms associated with the development of microbial resistance to the fluoroquinolones, and a discussion of fluoroquinolone dose optimization. Although the review contains a large body of basic research information, it is intended that the contents of this review have relevance to both the research scientist and the veterinary medical practitioner.

Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals

Objective: This review seeks to identify original research articles that link antibiotic dosing and the development of antibiotic resistance for different antibiotic classes. Using this data, we seek to apply pharmacodynamic principles to assist clinical practice for suppressing the emergence of resistance. Concepts such as mutant selection window and mutant prevention concentration will be discussed. Data Sources: PubMed, EMBASE, and the Cochrane Controlled Trial Register. Study Selection: All articles that related antibiotic doses and exposure to the formation of antibiotic resistance were reviewed. Data Synthesis: The escalation of antibiotic resistance continues worldwide, most prominently in patients in intensive care units. Data are emerging from in vitro and in vivo studies that suggest that inappropriately low antibiotic dosing may be contributing to the increasing rate of antibiotic resistance. Fluoroquinolones have widely been researched and publications on other antibiotic classes are emerging. Developing dosing regimens that adhere to pharmacodynamic principles and maximize antibiotic exposure is essential to reduce the increasing rate of antibiotic resistance. Conclusions: Antibiotic dosing must aim to address not only the bacteria isolated, but also the most resistant subpopulation in the colony, to prevent the advent of further resistant infections because of the inadvertent selection pressure of current dosing regimens. This may be achieved by maximizing antibiotic exposure by administering the highest recommended dose to the patient.

Antibiotic resistance : What's dosing got to do with it?

Widespread, increasing antibiotic resistance amongst the major respiratory pathogens has compromised traditional therapy of the major infective respiratory syndromes, including bacterial pneumonia and acute exacerbations of chronic bronchitis. Guidelines for antibiotic prescribing dating from the 1980s to 1990s, which attempted to address such problems, were commonly too prescriptive and difficult to apply, and took little account of end-user practice or locally prevalent resistance levels. Further confusion was caused by conflicting recommendations emanating from differing specialty groups. The evidence that such guidelines benefited either clinical outcomes or treatment costs has been disputed. They have probably had little effect on resistance emergence. We report the recommendations of an independent, multi-national, inter-disciplinary group, which met to identify principles underlying prescribing and guideline formulation in an age of increasing bacterial resistance. Unnecessary prescribing was recognized as the major factor in influencing resistance and costs. Antibiotic therapy must be limited to syndromes in which bacterial infection is the predominant cause and should attempt maximal reduction in bacterial load, with the ultimate aim of bacterial eradication. It should be appropriate in type and context of local resistance prevalence, and optimal in dosage for the pathogen(s) involved. Prescribing should be based on pharmacodynamic principles that predict efficacy, bacterial eradication and prevention of resistance emergence. Pharmacoeconomic analyses confirm that bacteriologically more effective antibiotics can reduce overall management costs, particularly with respect to consequential morbidity and hospital admission. Application of these principles should positively benefit therapeutic outcomes, resistance avoidance and management costs and will more accurately guide antibiotic choices by both individuals and formulary/guideline committees.

/pdf/antibiotic-therapy-of-community-respiratory-tract-infections-41ds1gboic.pdf

Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence

Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100-125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.

Application of fluoroquinolone pharmacodynamics

An in vitro pharmacodynamic investigation was conducted to explore whether the area under the concentration time curve from 0 to 24 h (AUC0–24)/MIC ratio could predict fluoroquinolone performance against Bacteroides fragilis. An in vitro model was used to generate kill curves for trovafloxacin (TVA) and levofloxacin (LVX) at AUC0–24/MIC ratios of 1 to 406 against three strains of B. fragilis (ATCC 25285, ATCC 23745, and clinical isolate M97-117). TVA and LVX were bolused prior to the start of experiments to achieve the corresponding AUC0–24/MIC ratio. Experiments were performed in duplicate over 24 h and in an anaerobic environment. Analyses of antimicrobial performance were conducted by comparing the rates of bacterial kill (K) using nonlinear regression analysis with 95% confidence intervals. Statistical significance was defined as a lack of overlap in the 95% confidence limits generated from the slope of each kill curve. For both TVA and LVX, K was maximized once an AUC0–24/MIC ratio of ≥40 was achieved and was not further increased despite a 10-fold increase in AUC0–24/MIC from approximately 40 to 400 against all three strains of B. fragilis. No significant differences were found in K between AUC0–24/MIC ratios of approximately 40 to 200. In experiments where AUC0–24/MIC ratios that were ≥ 5 and ≤ 44 were conducted, 64% demonstrated regrowth at 24 h. Resistant strains were selected in 50% of those experiments, demonstrating regrowth, which resulted in increased MICs of two- to 16-fold for both TVA and LVX. Regrowth did not occur, nor were resistant strains selected in any studies with an AUC/MIC that was > 44. Our findings suggest that fluoroquinolones provide antibacterial effects against B. fragilis in a concentration-independent manner associated with an AUC0–24/MIC ratio of ≥40. Also, the potential for the selection of resistant strains of B. fragilis may increase with an AUC0–24/MIC ratio of ≤44.

Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model

Recent world events refocused attention on the possibility of nations engaging in biologic warfare, including an attack with Bacillus anthracis. The single available anthrax vaccine in the United States for human use, formerly known as MDPH-PA, has decreased ability to protect laboratory animals against virulent B. anthracis strains, especially compared with new vaccines being developed. Studies with these vaccines, however, have several shortcomings. The pathogenesis, diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the implications that an attack with B. anthracis would place on the health care system.

Bacillus anthracis: medical issues of biologic warfare.

Cyclospora is a parasite traditionally associated with diarrhea in travelers to endemic countries. Recently, several cases of cyclosporiasis were reported in nontravelers in the United States and Canada, implicating various fruits and vegetables as vehicles of infection. The life cycle of cyclospora is not fully known, but is believed to involve both asexual and sexual stages of proliferation. Food- and water-borne transmission of infection have been implicated. Patients infected with Cyclospora cayetanensis have protracted watery diarrhea. Various generalized symptoms are also present, making cyclosporiasis indistinguishable from infectious diarrhea caused by other microorganisms. Diagnosis depends on identifying the organism by microbiologic examination of stool samples. Treatment consists of supportive care, maintenance of fluid and electrolyte status, symptomatic relief, and antibiotic therapy. Trimethoprim-sulfamethoxazole is the only antibiotic available that is effective in eradicating the organism.

Gigi H. Brown

Papers

Application of fluoroquinolone pharmacodynamics

Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model

Bacillus anthracis: medical issues of biologic warfare.

Cyclospora: review of an emerging parasite.

Gram-positive infections: pharmacy issues and strategy for quinupristin/dalfopristin.