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. Results Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. Conclusion The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.

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. Results Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with β-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-β-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence. Conclusions Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.

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. Methods have been developed to minimise the washout of bacteria. Bacteria are retained in the system either by centrifugation and resuspension, use of filters, a capillary unit, dialysis tubing or mathematical correction, versus systems with an unprotected outflow allowing a continuous washout of bacteria. None of these eight models has been directly compared with another. Therefore, an interlaboratory study was performed to address the question of whether or not washout matters. All laboratories used identical batches of media, bacteria, antibiotics and simulated pharmacokinetic profiles with a short or long half-life. Values of area under the bacterial kill–time curve (AUBKC), single-point kill rate and time to 3-log10 reduction of inoculum were calculated. These parameters did not differ significantly between the models. Differences were noted if the inoculum was prepared from the early logarithmic growth phase compared with the late logarithmic or stationary growth phase, resulting either in a pronounced or reduced antibacterial activity. Thus, preparation of inocula affects the results generated, whereas washout of bacteria has apparently a negligible impact on antibacterial activities.

ABSTRACT 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.] orally for uUTI and 800 mg once a day [q.d.] intravenously [i.v.] for cUTI/PN) and ciprofloxacin (250 mg b.i.d. orally for uUTI and 400 mg b.i.d. i.v. for cUTI/PN). The early response to the study medications was evaluated in the microbiological intent-to-treat population (mITT) at day 3. A total of 21% of the isolates were ciprofloxacin resistant, 13.7% were primed pathogens carrying a mutation(s) potentially fostering fluoroquinolone resistance development, and 7.1% produced extended-spectrum β-lactamases (ESBLs). Finafloxacin demonstrated very good early clinical activity, with microbiological eradication rates of 88.6% ( n = 132), compared to 78.7% ( n = 61) for ciprofloxacin, and 69.6% ( n = 23), compared to 35.7% ( n = 14) for ciprofloxacin, in patients with ciprofloxacin-resistant uropathogens; 94.1% ( n = 17), compared to 80.0% ( n = 10) for ciprofloxacin, in patients infected with uropathogens primed for fluoroquinolone resistance uropathogens; and 91.7% ( n = 11), compared to 0% for ciprofloxacin, in patients infected with ESBL producers. Finafloxacin demonstrated early and rapid activity against uropathogens, including fluoroquinolone-resistant and/or multiresistant pathogens or ESBL producers, while ciprofloxacin was less active against this subset of resistant pathogens. Susceptibilities of pathogens were quantitated by broth microdilution. Isolates were subgrouped according to their susceptibility patterns, in particular first-step quinolone resistance, quinolone resistance, and ESBL production. Eradication was defined as the elimination or reduction of study entry pathogens to <10 3 CFU/ml in urine culture. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT00722735 and NCT01928433.)

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, α1-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. It has been demonstrated that IgG and albumin permeabilized Gram-negative and Gram-positive bacteria and facilitated the uptake of poorly penetrating antibiotics. Alpha-1-acid-glycoprotein and pulmonary surfactant also exerted a permeabilizing activity, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum-antibiotic synergisms do not represent a general phenomenon but are limited to specific drug-bug associations only. Although evidence has been generated to support the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well-controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum-antibiotic synergisms, so these techniques have to be standardized; otherwise, contradictory data or even artifacts will be generated.

ABSTRACT The broad-spectrum C-8-cyano-fluoroquinolone finafloxacin displays enhanced activity under acidic conditions. This phase II clinical study compared the efficacies and safeties of finafloxacin and ciprofloxacin in patients with complicated urinary tract infection and/or pyelonephritis. A 5-day regimen with 800 mg finafloxacin once a day (q.d.) (FINA05) had results similar to those of a 10-day regimen with 800 mg finafloxacin q.d. (FINA10). Combined microbiological and clinical responses at the test-of-cure (TOC) visit were 70% for FINA05, 68% for FINA10, and 57% for a 10-day ciprofloxacin regimen (CIPRO10) in 193 patients (64 for FINA05, 68 for FINA10, and 61 for CIPRO10) of the microbiological intent-to-treat (mITT) population. Additionally, the clinical effects of ciprofloxacin on patients with an acidic urine pH (80% of patients) were reduced, whereas the effects of finafloxacin were unchanged. Finafloxacin was safe and well tolerated. Overall, 43.4% of the patients in the FINA05 group, 42.7% in the FINA10 group, and 54.2% in the CIPRO10 group experienced mostly mild and treatment-emergent but unrelated adverse events. A short-course regimen of 5 days of finafloxacin resulted in high eradication and improved clinical outcome rates compared to those for treatment with ciprofloxacin for 10 days. In contrast to those of ciprofloxacin, the clinical effects of finafloxacin were not reduced by acidic urine pH. Hospitalized adults were randomized 1:1:1 to finafloxacin treatment (800 mg q.d.) for either 5 or 10 days or to ciprofloxacin treatment (400 mg/500 mg b.i.d.) for 10 days with an optional switch from intravenous (i.v.) to oral administration at day 3. The primary endpoint was the combined microbiological and clinical response at the TOC visit in the microbiological intent-to-treat population. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.)

ABSTRACT 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. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.)

Natamycin is approved almost worldwide as a food additive for surface treatment of cheese and sausages.Its use is considered to be safe as Natamycin is extremely sensitive to ultraviolet light and an acidic pH, so that products exposed to light in the retail industry and food stores are likely free from Natamycin.However, the use of an acid-, heat-and light stable Natamycin formulation in yoghurt has recently been authorized in the USA as well as in Australia and New Zealand.Furthermore, yoghurt is stored in sealed cups in refrigerated shelves, so it will not be exposed to light and thus not be inactivated during storage.Consequently, the resident flora will be exposed to Natamycin and it may exert a resistance selective pressure on faecal Candida spp.hypothetically selecting strains being resistant to Amphothericin B. In this review literature has been evaluated addressing the questions if Natamycin may foster emergence of polyene-resistance.This concern is supported by the facts that first, polyeneresistance could be elicited in vitro and in vivo.Second, as Azoles being used in agriculture and hospitals as well as polyenes share some common resistance mechanisms a polyene-resistance reservoir does exist in environmental and clinical fungal isolates.Third, Natamycin may amplify Amphothericin B resistance as fourth, resistance can in principal be spread amongst fungi by horizontal gene transfer.To preserve clinical efficacy of Amphothericin B for treatment of serious, life threatening infections, the use of Natamycin as a food-preservative should be limited to an absolute minimum.

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. Cross-resistance between agricultural and medical azoles and between azoles and amphotericin B (AMB) not being used in agriculture has been demonstrated in clinical and environmental isolates. Polyene resistance can be elicited in vitro by the use of subinhibitory polyene concentrations and a large number of transfers. This condition may mirror the exposure of faecal Candida spp. to natamycin following consumption of natamycin-containing food. A large number of environmental and clinical isolates are resistant to AMB, and strong evidence linking farm antibiotic use and multidrug resistance, including AMB resistance, in human infections has been provided. In contrast to the acquisition of resistant environmental strains, consumption of natamycin-containing food may expose the gastrointestinal fungal flora directly to resistance selective pressure. So far, whether natamycin itself may cause the emergence of polyene resistance in gastrointestinal fungal flora and/or may act as an AMB resistance selector is probable but speculative. Use of any anti-infective agent as a food preservative should be limited to an absolute minimum as the clinical efficacy of anti-infectives used to treat serious life-threatening infections has to be preserved.

ABSTRACT The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae isolates were compared. Since quinolones lose activity in acidic media, and particularly in urine, their activities were tested in parallel under conventional conditions and in acidic artificial urine. For this purpose, TEM- and SHV-type ESBL-producing Escherichia coli and Klebsiella pneumoniae strains and their wild-type counterparts were exposed in a modified Grasso model to simulated concentrations of drugs in serum and urine following oral doses of either finafloxacin at 800 mg once a day (q.d.), immediate-release ciprofloxacin at 500 mg twice a day (b.i.d.), extended-release ciprofloxacin at 1,000 mg q.d., or levofloxacin at 500 or 750 mg q.d. The concentrations of the drugs in urine were fitted by compartmental modeling. Bacteria were cultivated in Mueller-Hinton broth (MHB) at pH 7.2 or 5.8 or in artificial urine at pH 5.8. Bacteria were counted every 2 h until 10 h and at 24 h; the areas under the bacterial-count–versus–time curves were calculated. It was found that finafloxacin eliminated all strains within 2 h under all the conditions studied. At all doses studied, ciprofloxacin and levofloxacin were highly active against wild-type strains in MHB at pH 7.2 but lost activity in MHB, and particularly in urine, at pH 5.8. Viable counts of ESBL producers were reduced for 6 to 8 h by 3 log 10 titers, but the bacteria regrew thereafter. Ciprofloxacin and levofloxacin were almost inactive against the SHV producer grown in artificial urine. We conclude that pharmacodynamic models using artificial urine may mirror the physiology of urinary tract infections more closely than those using conventional media. In contrast to ciprofloxacin and levofloxacin, finafloxacin gained activity in this model at an acidic pH, maintained activity in artificial urine, and was active against TEM and SHV producers.

Objectives: Protein binding decreases antibacterial activities as the free fraction only crosses membranes thus reaching intracellular targets. However, serum components may also increase antibacterial activities. Therefore, the effect of serum proteins on activities of ß-lactams, macrolides, and fluoroquinolones was examined. Several preparation- and cultivation-conditions were examined as some preparative methods like freeze-thawing of sera may cause artifacts. Furthermore, previous studies have indicated that data may vary depending on the endpoints studied. Therefore, the aim of this study was to avoid an impact of methodological factors on the data generated and to analyse the activities of the study drugs by examining different static- or dynamic endpoints. Methods: Bacteria were grown in Brain Heart Infusion Broth (BHI), plus 50% of either fresh inactivated, pH 7.2, or fresh inactivated- , pH 7.2 or 8.2, frozen inactivated-serum, pH 8.2 as compared to BHI without any supplementations, pH 7.2 or 8.2, and BHI plus 45 g/L albumin. MICs of faropenem, amoxicillin, clarithromycin, azithromycin, moxifloxacin, and levofloxacin were determined and kill-kinetics were recorded following exposure to constant or fluctuating drug concentrations simulating serum pharmacokinetics of the agents. Kill-rates and areas under the bacterial kill curves were calculated. Results: Albumin and inactive serum increased MICs and reduced kill-rates of the agents studied in conformity with their protein binding, whereas active serum increased the activities of the agents. MICs and kill-rates did not change in parallel. The impact of protein binding in decreasing order was: MICs>kill-rates in time-kill experiments>kill-rates in kinetic-simulations. Macrolides and fluoroquinolones but not ß-lactams were more active at an alkaline- than neutral pH. Use of frozen sera caused alkalinization of media, thus generating artifacts. Conclusions: The impact of serum proteins on antibacterial activities is strongly dependent from three factors: the methods applied to prepare the serum pool, the incubation conditions, and the enpoints studied.

Objectives: Protein binding decreases antibacterial activities as the free fraction only crosses membranes thus reaching intracellular targets. However, serum components may increase antibacterial activities. Therefore, the effect of serum proteins on activities of ß-lactams and macrolides was examined. Methods: Strains with defined resistance genotypes were selected; MRSA, ermB-, mefA-, gyrA Ser81-Phemutants of S. pneumoniae, and TEM-1 or TEM-3 ß-lactamase producing E. coli were used. Ten antibiotics known to penetrate into bacteria either well or poorly and/or known to be labile or stable to inactivation by ß-lactamases were used. Strains were incubated in Brain Heart Infusion Broth (BHI), BHI +50% heat inactivated human serum or active serum, or 45 g/L albumin. MICs were determined and Kill-kinetics was recorded following exposure to constant or fluctuating drug concentrations. Kill constants and areas under the bacterial kill curves were calculated. Results: Albumin and inactive serum increased MICs and reduced kill rates of the agents studied in conformity with their protein binding. However, active serum increased the activities of such agents known to penetrate poorly into strains with permeation barriers. In addition, active as well as inactive serum restored the activities of ß-lactams against ß-lactamase producing strains due to enzyme inhibition. Conclusions: Serum proteins permeabilized bacteria and inhibited ß-lactamase activity. The impact of serum proteins on antibacterial activities against specific drug-bug associations is more than predicted by considering the numerical value of protein binding alone.

Background: MCB3681, a novel quinolonyl-oxazolidinone antibacterial, is active against quinolone- and/or linezolidresistant Gram-positive bacteria. Thus, MCB3681 may interact with other targets than quinolones and oxazolidinones. Methods and Findings: Protein expression in S. aureus following short-term exposure to MCB3681 was analyzed using 2D-gel electrophoresis and MALDI-TOF-MS/MS. Synthesis of 13 and 16 proteins was induced or repressed, respectively. Among the induced proteins are four ribosomal proteins. Repressed are proteins from different amino acid synthesis pathways, two aminoacyl-tRNAsynthetases, and methicillin-resistance-factor-protein FemB. Conclusion: Our findings demonstrate that the impact of MCB3681 on the proteome signature of treated S. aureus cells is different from that of either ciprofloxacin or linezolid.

The water-soluble prodrug MCB3837 is rapidly converted to MCB3681, active against Gram-positive bacterial species, after intravenous infusion. The aim of this study was to prove the principle that MCB3681 is efficacious in vivo by demonstrating its effect on the resident microflora or colonizers of the human skin, nose, oropharynx and intestine. MCB3837 was infused at a daily dose of 6 mg/kg for 5 days. MCB3681 was active against clostridia, bifidobacteria, lactobacilli, enterococci and Staphylococcus aureus, thus proving the principle that MCB3681 is antibacterially efficacious in vivo without affecting the Gram-negative microflora.

This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well. Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations. This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations. Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections. Well-designed clinical studies should be performed to substantiate these findings.

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. This practice leads to high drug exposures exceeding the safety level. Apart from the definition of an acceptable daily dietary exposure to natamycin, its effect on the faecal flora as a reservoir for resistance has to be examined. Consumption of food to which natamycin has been added and mixed homogeneously, such as yoghurt, and in particular the addition of cyclodextrin inclusion complexes to beverages and wine generates high faecal natamycin concentrations resulting in high drug exposures of faecal Candida spp. Development of natamycin resistance has been observed in Candida spp. colonising the intestinal tract of patients following natamycin treatment of fungal infections. Horizontal gene transfer among different Candida spp. and within Aspergillus fumigatus spreads resistance. Therefore, it cannot be denied that use of natamycin for preservation of yoghurt and beverages may foster development of resistance to polyenes in Candida spp.

ABSTRACT 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. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program.

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. The MICs of the isolates were determined against MCB3681 and nine other antimicrobial agents by the agar dilution method. All isolates were positive for toxin B as well as for toxin A and B genes. In addition, 13 isolates were positive for the binary toxin genes. Thirty-two different ribotypes were identified. No strain of ribotype 027 was found. All 114 isolates were sensitive to MCB3681 (0.008-0.5 mg/l), cadazolid (0.064-0.5 mg/l), fidaxomicin (0.008-0.125 mg/l), metronidazole (0.125-2 mg/l), vancomycin (0.125-1 mg/l) and tigecycline (0.032-025 mg/l). Three isolates were resistant to linezolid (8 mg/l), 12 isolates were resistant to moxifloxacin (8-32 mg/l), 87 isolates were resistant to clindamycin (8-256 mg/l) and 107 isolates were resistant to ciprofloxacin (8-256 mg/l). No association between toxins A, B and binary toxin, ribotypes and the sensitivity to MCB3681 could be found. MCB3681 has a potent in vitro activity against C difficile. (C) 2014 Published by Elsevier Ltd.

SUMMARY 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. However, reductions of the bacterial load in sputum and improvements in lung function were within the same ranges following aerosolized and conventional therapies. Furthermore, the use of conventional pharmacokinetic/pharmacodynamic (PK/PD) surrogates correlating pharmacokinetics in serum with clinical cure and presumed or proven eradication of the pathogen as a basis for PK/PD investigations in CF patients is irrelevant, as minimization of systemic exposure is one of the main objectives of aerosolized therapy; in addition, bacterial pathogens cannot be eradicated, and chronic infection cannot be cured. Consequently, conventional PK/PD surrogates are not applicable to CF patients. It is nonetheless obvious that systemic exposure of patients, with all its sequelae, is minimized and that the burden of oral treatment for CF patients suffering from chronic infections is reduced.