Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?

Background: Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes.

Methods And Objective: This review summarizes data describing multiple modes of action of antibiotics in eukaryotes.

Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?

Purpose: Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins.

Methods: This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets.

Comparative evaluation of eight in vitro pharmacodynamic models of infection: Activity of moxifloxacin against Escherichia coli and Streptococcus pneumoniae as an exemplary example.

Use of pharmacodynamic in vitro models provides more clinically relevant information about the activities of antibiotics than static endpoints. Several models are used to simulate pharmacokinetics by dilution of the medium. It is discussed whether this procedure would result in a washout of bacteria, particularly if profiles with a short half-life are simulated.

Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections.

Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally ( = 77) or intravenously ( = 50), and 139 patients with cUTI received finafloxacin intravenously.

Early Clinical Assessment of the Antimicrobial Activity of Finafloxacin Compared to Ciprofloxacin in Subsets of Microbiologically Characterized Isolates.

Two phase II studies were performed with patients with uncomplicated urinary tract infections (uUTIs) and complicated urinary tract infections (cUTIs) or acute pyelonephritis (PN) to compare finafloxacin (300 mg twice a day [b.i.d.

Seventy-Five Years of Research on Protein Binding.

This review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifaceted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters, as the free fraction only is antibacterially active and governs pharmacokinetics. Several studies have indicated that independent from protein binding of immunoglobulin G, albumin, α-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum-antibiotic synergisms.

Does the use of antifungal agents in agriculture and food foster polyene resistance development? A reason for concern.

Environmental fungicides are used in agriculture to reduce fungal spoilage of crops to a minimum, and the polyene macrolide natamycin is used as a food preservative. The use of natamycin in yoghurt has recently been authorised in the USA and some other countries. However, resistance development is a serious risk associated with the use of antimicrobials as food additives and environmental fungicides.

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers.

Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo.

Does use of the polyene natamycin as a food preservative jeopardise the clinical efficacy of amphotericin B? A word of concern.

Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety concern. However, highly soluble natamycin-cyclodextrin inclusion complexes have been developed for the protection of beverages.

Pharmacokinetics and pharmacodynamics of aerosolized antibacterial agents in chronically infected cystic fibrosis patients.

Bacteria adapt to growth in lungs of patients with cystic fibrosis (CF) by selection of heterogeneously resistant variants that are not detected by conventional susceptibility testing but are selected for rapidly during antibacterial treatment. Therefore, total bacterial counts and antibiotic susceptibilities are misleading indicators of infection and are not helpful as guides for therapy decisions or efficacy endpoints. High drug concentrations delivered by aerosol may maximize efficacy, as decreased drug susceptibilities of the pathogens are compensated for by high target site concentrations.

In vitro activity of MCB3681 against Clostridium difficile strains.

One hundred fourteen Clostridium difficile strains were collected from 67 patients and analyzed for the presence of C. difficile toxin B by the cell cytotoxoicity neutralization assay, genes for toxin A, toxin B, binary toxin and TcdC deletion by PCR. All strains were also PCR-ribotyped.

Ecological impact of MCB3837 on the normal human microbiota.

MCB3837 is a novel, water-soluble, injectable prodrug that is rapidly converted to the active substance MCB3681 in vivo following intravenous (i.v.) administration.

Alternative strategies for proof-of-principle studies of antibacterial agents.

The proof that a new antibacterial agent is not only active in vitro but also effective in vivo under clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals.

Global fluoroquinolone resistance epidemiology and implictions for clinical use.

This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species except S. pneumoniae and H.

Activity of moxifloxacin, imipenem, and ertapenem against Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, and Bacteroides fragilis in monocultures and mixed cultures in an in vitro pharmacokinetic/pharmacodynamic model simulating concentrations in the human pancreas.

The activities of moxifloxacin, imipenem, and ertapenem against pathogens causing severe necrotizing pancreatitis were studied in an in vitro pharmacokinetics/pharmacodynamics (PK/PD) model. Escherichia coli, Enterobacter cloacae, Enterococcus faecalis, and Bacteroides fragilis were exposed in monocultures and mixed cultures to concentrations of the three agents comparable to those in the human pancreas. Moxifloxacin was more active than the two carbapenems in monocultures and mixed cultures, reducing the numbers of CFU more drastically and more rapidly.

Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg) in healthy volunteers receiving a single oral dose.

Background: Finafloxacin is a novel 8-cyano-fluoroquinolone under investigation for treatment of urinary tract infection.

Methods: Urinary concentrations and urinary bactericidal titers (UBT) of finafloxacin 200- and 800-mg single doses in 6 healthy volunteers were measured up to 48 h. UBT were determined for a reference strain and 9 selected clinical uropathogens at the pH of native, acidified (pH 5.

Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine.

Kill kinetics and MICs of finafloxacin and ciprofloxacin against 34 strains with defined resistance mechanisms grown in cation-adjusted Mueller-Hinton broth (CAMHB) at pH values of 7.2 and 5.8 and in synthetic urine at pH 5.

German multicentre survey of the antibiotic susceptibility of Bacteroides fragilis group and Prevotella species isolated from intra-abdominal infections: results from the PRISMA study.

Objectives: To determine the susceptibility of Gram-negative anaerobic bacteria of the family Bacteroidaceae from hospitalized patients with intra-abdominal infections (IAIs) to moxifloxacin and other antimicrobial agents with known activity against anaerobes.

Methods: Four hundred and thirty anaerobic bacterial isolates of the family Bacteroidaceae obtained from patients with IAIs were collected from 32 centres in Germany in 2007. MICs were determined using microbroth dilution for the following antimicrobials: ampicillin/sulbactam; ertapenem; meropenem; levofloxacin; moxifloxacin; clindamycin; and metronidazole.

Dichotomous selection of high-level oxacillin resistance in Staphylococcus aureus by fluoroquinolones.

The objective of this study was to determine whether exposure of Staphylococcus aureus to early (ciprofloxacin or levofloxacin) and a recent fluoroquinolone (moxifloxacin) has differential potential as a mutator or selector for meticillin resistance. The potential of fluoroquinolones to act as mutators or selectors was studied in 24 strains each of healthcare-associated meticillin-susceptible S. aureus (MSSA) and meticillin-resistant S.

Susceptibility patterns of bacterial isolates from hospitalised patients with respiratory tract infections (MOXIAKTIV Study).

The objective of this study was to determine: (i) the prevalence of resistance in current clinical isolates of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis and Klebsiella pneumoniae; (ii) the prevalence of production of extended-spectrum beta-lactamases (ESBLs) and methicillin resistance in S. aureus; and (iii) regional differences in the prevalence of ESBL production and clonality of K. pneumoniae isolates.

Redefining penems.

The antimicrobial class of penems has the potential to address most of the relevant resistance issues associated with beta-lactam antibiotics because of their exceptionally broad spectrum of antibacterial activity and their intrinsic stability against hydrolytic attack by many beta-lactamases including ESBL and AmpC enzymes. The subclass of carbapenems covers the spectrum of hospital pathogens whereas the subclass of penems covers community pathogens. The only currently available penem, faropenem, has a low propensity for resistance development, beta-lactamase induction and selection of carbapenem-resistant Pseudomonas aeruginosa.

Pharmacokinetics of ciprofloxacin XR (1000 mg) versus levofloxacin (500 mg) in plasma and urine of male and female healthy volunteers receiving a single oral dose.

The new extended-release formulation of ciprofloxacin (ciprofloxacin XR) was designed for once-daily administration in the treatment of urinary tract infection (UTI). The aim of this study was to compare concentrations in plasma, urinary excretion (UE) and pharmacokinetic parameters of ciprofloxacin XR (1000 mg) versus those of levofloxacin (500 mg) in healthy volunteers receiving a single oral dose. In this randomised crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 1000 mg ciprofloxacin XR or 500 mg levofloxacin to assess the concentrations (by high-pressure liquid chromatography) in plasma up to 32 h and the UE at intervals up to 36 h.

Moxifloxacin and azithromycin but not amoxicillin protect human respiratory epithelial cells against streptococcus pneumoniae in vitro when administered up to 6 hours after challenge.

We determined the protective effect of moxifloxacin, azithromycin, and amoxicillin against Streptococcus pneumoniae infection of respiratory cells. Moxifloxacin and azithromycin effectively killed intracellular S. pneumoniae strains and protected respiratory epithelial cells significantly even when given 6 h after S.