Explorative Randomized Phase II Clinical Study of the Efficacy and Safety of Finafloxacin versus Ciprofloxacin for Treatment of Complicated Urinary Tract Infections.

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.).

Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections.

The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-ß-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 log10 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.

Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?

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.

Resistance surveillance studies: a multifaceted problem--the fluoroquinolone example.

INTRODUCTION: This review summarizes data on the fluoroquinolone resistance epidemiology published in the previous 5 years. MATERIALS AND METHODS: The data reviewed are stratified according to the different prescription patterns by either primary- or tertiary-care givers and by indication. Global surveillance studies demonstrate that fluoroquinolone- resistance rates increased in the past several years in almost all bacterial species except Staphylococcus pneumoniae and Haemophilus influenzae causing community-acquired respiratory tract infections (CARTIs), as well as Enterobacteriaceae causing community-acquired urinary tract infections. Geographically and quantitatively varying fluoroquinolone resistance rates were recorded among Gram-positive and Gram-negative pathogens causing healthcare-associated respiratory tract infections. One- to two-thirds of Enterobacteriaceae producing extended-spectrum ß-lactamases (ESBLs) were fluoroquinolone resistant too, thus, limiting the fluoroquinolone use in the treatment of community- as well as healthcare-acquired urinary tract and intra-abdominal infections. The remaining ESBL-producing or plasmid-mediated quinolone resistance mechanisms harboring Enterobacteriaceae were low-level quinolone resistant. Furthermore, 10-30 % of H. influenzae and S. pneumoniae causing CARTIs harbored first-step quinolone resistance determining region (QRDR) mutations. These mutants pass susceptibility testing unnoticed and are primed to acquire high-level fluoroquinolone resistance rapidly, thus, putting the patient at risk. The continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some current guidelines for the treatment of intra-abdominal infections or even precludes the use of fluoroquinolones in certain indications like gonorrhea and pelvic inflammatory diseases in those geographic areas in which fluoroquinolone resistance rates and/or ESBL production is high. Fluoroquinolone resistance has been selected among the commensal flora colonizing the gut, nose, oropharynx, and skin, so that horizontal gene transfer between the commensal flora and the offending pathogen as well as inter- and intraspecies recombinations contribute to the emergence and spread of fluoroquinolone resistance among pathogenic streptococci. Although interspecies recombinations are not yet the major cause for the emergence of fluoroquinolone resistance, its existence indicates that a large reservoir of fluoroquinolone resistance exists. Thus, a scenario resembling that of a worldwide spread of ß-lactam resistance in pneumococci is conceivable. However, many resistance surveillance studies suffer from inaccuracies like the sampling of a selected patient population, restricted geographical sampling, and undefined requirements of the user, so that the results are biased. The number of national centers is most often limited with one to two participating laboratories, so that such studies are point prevalence but not surveillance studies. Selected samples are analyzed predominantly as either hospitalized patients or patients at risk or those in whom therapy failed are sampled; however, fluoroquinolones are most frequently prescribed by the general practitioner. Selected sampling results in a significant over-estimation of fluoroquinolone resistance in outpatients. Furthermore, the requirements of the users are often not met; the prescribing physician, the microbiologist, the infection control specialist, public health and regulatory authorities, and the pharmaceutical industry have diverse interests, which, however, are not addressed by different designs of a surveillance study. Tools should be developed to provide customer-specific datasets. CONCLUSION: Consequently, most surveillance studies suffer from well recognized but uncorrected biases or inaccuracies. Nevertheless, they provide important information that allows the identification of trends in pathogen incidence and antimicrobial resistance.

A long journey from minimum inhibitory concentration testing to clinically predictive breakpoints: deterministic and probabilistic approaches in deriving breakpoints.

Since the origin of an "'International Collaborative Study on Antibiotic Sensitivity Testing'" in 1971, considerable advancement has been made to standardize clinical susceptibility testing procedures of antimicrobial agents. However, a consensus on the methods to be used and interpretive criteria was not reached, so the results of susceptibility testing were discrepant. Recently, the European Committee on Antimicrobial Susceptibility Testing achieved a harmonization of existing methods for susceptibility testing and now co-ordinates the process for setting breakpoints. Previously, breakpoints were set by adjusting the mean pharmacokinetic parameters derived from healthy volunteers to the susceptibilities of a population of potential pathogens expressed as the mean minimum inhibitory concentration (MIC) or MIC90%. Breakpoints derived by the deterministic approach tend to be too high, since this procedure does not take the variabilities of drug exposure and the susceptibility patterns into account. Therefore, first-step mutants or borderline susceptible bacteria may be considered as fully susceptible. As the drug exposure of such sub-populations is inadequate, resistance development will increase and eradication rates will decrease, resulting in clinical failure. The science of pharmacokinetics/pharmacodynamics integrates all possible drug exposures for standard dosage regimens and all MIC values likely to be found for the clinical isolates into the breakpoint definitions. Ideally, the data sets used originate from patients suffering from the disease to be treated. Probability density functions for both the pharmacokinetic and microbiological variables are determined, and a large number of MIC/drug exposure scenarios are calculated. Therefore, this method is defined as the probabilistic approach. The breakpoints thus derived are lower than the ones defined deterministically, as the entire range of probable drug exposures from low to high is modeled. Therefore, the amplification of drug-resistant sub-populations will be reduced. It has been a long journey since the first attempts in 1971 to define breakpoints. Clearly, this implies that none of the various approaches is right or wrong, and that the different approaches reflect different philosophies and mirror the tremendous progress made in the understanding of the pharmacodynamic properties of different classes of antimicrobials.

Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle.

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.

Synergy between acylureidopenicillins and immunoglobulin G in experimental animals.

The interaction of a commercially available 7S modified immunoserumglobulin and beta-lactam antibiotics was studied in animal experiments (granuloma pouch model) as well as an ex vivo system (rat polyvinyl sponge model). Infections of the pouches were caused by gram-negative rods and gram-positive cocci, respectively. Therapy of pouches being infected with beta-lactamase-producing strains with beta-lactam antibiotics and immunoserumglobulin was as effective as beta-lactam antibiotic monotherapy of beta-lactamase-negative strains. This synergistic effect between immunoserumglobulin and beta-lactam antibiotics against beta-lactamase-producing bacteria is due to inactivation of enzymic beta-lactamase activity by specific antibodies against beta-lactamases. Immune phagocytosis was studied by adopting the in vivo and ex vivo models, respectively. Immune phagocytosis was most effectively stimulated by immunoserumglobulin whereas a pepsin-degraded product or a preparation obtained by pH4 treatment caused only minor effects. Furthermore, immunoserumglobulin stimulated phagocytosis and intracellular killing of gram-negative bacteria even in the absence of specific antibodies against these strains. Analogous effects were obtained with spermidine and albumin. These results indicate that immunoserumglobulin may stimulate phagocytosis nonspecifically, too. Thus, immunoserumglobulin may play a dual role in host defense mechanisms; in addition immunoserumglobulin acts as a beta-lactamase inhibitor, thus protecting beta-lactam antibiotics from hydrolysis.

Penetration of ciprofloxacin into gynecologic tissues.

Penetration of ciprofloxacin into gynecologic tissues has been studied after administration of the following: a single oral dose of 500 mg; a single injection of 100 mg; single intravenous infusions of 200 mg and 300 mg, respectively; and repeated oral doses of 500 mg followed by an infusion of 200 mg. In general, tissue concentrations of ciprofloxacin exceeded the corresponding serum concentrations on average twofold to fivefold, irrespective of the route of administration or the size of the dose. For example, mean tissue and serum concentrations of ciprofloxacin determined 12 hours after administration of a single oral dose of 500 mg were as follows: serum, 0.09 mg/liter; ovary, 0.28 mg/kg; uterus, 0.49 mg/kg; endometrium, 0.23 mg/kg; myometrium, 0.34 mg/kg; and fallopian tube, 0.36 mg/kg. Repeated drug administration did not result in an accumulation of ciprofloxacin in either serum or the tissues studied.

Treatment of chronic bacterial prostatitis with ciprofloxacin. Results of a one-year follow-up study.

In a one-year follow-up study, short-term therapy with ciprofloxacin proved to be beneficial in the treatment of chronic bacterial prostatitis, particularly in cases of Escherichia coli prostatitis. Ciprofloxacin therapy of E. coli prostatitis was a complete success in five of 12 patients, a probable success in two, and in one patient the outcome cannot be judged. Ciprofloxacin treatment failed in three men, and therapy was discontinued in one patient because of side effects. Enterobacter aerogenes prostatitis was cured. Ciprofloxacin treatment was insufficient in three patients with Streptococcus faecalis prostatitis and in one patient with Pseudomonas aeruginosa prostatitis.

Impact of different classes antimicrobial agents on plasma endotoxin activity.

OBJECTIVE: To investigate the influence of different classes and doses of antibiotics on endotoxin release in gram-negative infection in a rat model of intra- abdominal infection. DESIGN: Immediately after intraperitoneal inoculation of Escherichia coli (5 x 10(7) colony-forming units/kg), anesthetized Wistar rats were treated with a single intravenous dose of an antimicrobial agent: cefotaxime (40 mg/kg), ciprofloxacin (3 mg/kg or 6 mg/kg), imipenem (7 mg/kg or 14 mg/kg), or gentamicin (5 mg/kg). An untreated control group received 0.9% sodium chloride instead of antibiotic. Plasma endotoxin activity, blood bacteria count, and mean arterial pressure were monitored at 60-minute intervals for 5 hours. At the end of the experiment, lavage was performed to determine the bacteria count in the peritoneal cavity. RESULTS: In the untreated group, the blood bacteria count increased rapidly. Five hours after therapy, the plasma endotoxin activity in the cefotaxime group was higher by a factor of 3.6 than in the untreated group. Compared with the cefotaxime group, endotoxin activity was approximately 26% lower in the ciprofloxacin (3 mg/kg) group, 35% lower in the imipenem groups, and 38% lower in the gentamicin group. The lowest endotoxin levels were in the high-dose ciprofloxacin group. Bacteria counts in the peritoneal cavity were lowest in the gentamicin and high-dose ciprofloxacin groups. Except in the high-dose ciprofloxacin group, the endotoxin increase in the therapy groups was associated with a significant (P < .05) decrease in mean arterial pressure. CONCLUSIONS: In the early phase of therapy, antibiotic-induced endotoxin release is influenced by the mode of action of the agent class. This is not the sole influence in every class. With quinolones, this effect is also influenced considerably by dosage, ie, by pharmacodynamics.

Spectrum and antibiotic resistance of uropathogens from hospitalized patients with urinary tract infections: 1994-2000.

During the period 1994-2000 all uropathogens cultured from urine of hospitalized urological patients were identified and susceptibility was tested against 11 antibacterials. Duplicated isolates were eliminated. There was no general trend of increased of resistance apart from E. coli to ciprofloxacin (10.4% in 2000). Vancomycin-resistant staphylococci or enterococci was not significant. The lowest overall rates of resistance were found with piperacillin/tazobactam followed by ciprofloxacin and trimethoprim/sulphamethoxazole. Ciprofloxacin was the best oral antibiotic for the empirical treatment of urinary tract infection (UTI) due to Gram-negative rods and ampicillin/sulbactam for the treatment of UTI with Gram-positive cocci.

Electrically evoked potentials in the rat hippocampus slice in the presence of aminophylline alone and in combination with quinolones.

The excitability of brain matter was tested bt electrically evoked field potentials in the CA1 region of the rat hippocampus in vitro. In contrast to the quinolones which only increased the amplitudes of electrically evoked potentials, aminophylline induced spontaneous firing in the pyramidal cell layer without stimulation in addition to its dose-dependent effects on the amplitudes of the evoked potentials. Threshold doses of the quinolones tested (0.25 microM) increased the amplitudes of evoked potentials in the presence of an otherwise ineffective concentration of aminophylline (0.5 microM) to different degrees, ranging from 135.3% for ciprofloxacin to 223.8% for nalidixic acid. The rank order of potency of CNS side effects reported in the literature correlates very well with the increase of the population spike amplitude in the hippocampus slice preparation. This feature could be important during the development of new chemical analogues of quinolones.

Ticarcillin: pharmacokinetics in man according to different administration schedules.

The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were studied. Following a rapid intravenous infusion of 1 g, 2 g, 5 g and 10 g ticarcillin respectively the serum half-life was 72-4 minutes independent of the dosage administered. If ticarcillin is administered under steady-state conditions, e.g. continuous infusion of either 2g/hr or 1g/hr following a loading dose of 1g (total dose 5 g) the average steady-state serum concentrations are 125 microgram/ml and 105 microgram/ml respectively.

Prospective clinical trial on the efficacy of amoxycillin administered twice or four times daily in children with respiratory tract infections.

Thirty-four children with upper or lower respiratory tract infections were randomly allocated to receive either a twice daily or four times daily dose of 50 mg amoxycillin/kg body-weight/day. Mean duration of therapy was identical in both groups. Peak and trough antibiotic concentrations were determined. Eradication of bacteria, clinical improvement and side-effects were comparable in both groups.

Contribution of immunocompetence to the antibacterial activities of ciprofloxacin and moxifloxacin in an in vitro pharmacodynamic model.

Traditional in vitro models used to simulate human pharmacokinetics and to characterize the pharmacodynamics of antibacterial agents represent a totally immunosuppressed condition. However, host defense mechanisms contribute to the elimination of the pathogen from the infectious site in most of the patients suffering from infectious diseases. Therefore, the attempt was made to introduce immunocompetence into an in vitro pharmacodynamic model. Immunocompetence was added either by using J774 macrophages growing as adherent monolayers in cell culture flasks, or by using a newly developed ex vivo model. This ex vivo model consists of sponges which have been implanted into rats for 24 h. After 24 h the sponges are explanted; at this point in time the sponges are soaked with an inflammatory exudate to which the bacteria to be tested are added. Into a slightly modified one-compartment model according to Grasso the explanted sponges which are entrapped in dialysis tubings are added. Neither the bacteria nor the inflammatory proteins nor the immunocompetent cells escape from the explants. Thus, it is possible to simulate antibiotic kinetics without diluting bacteria, the polymorphonuclear cells (PMN) or the inflammatory exudates. This ex vivo model and the J774 cell culture model were used to compare the antibacterial effects of ciprofloxacin against Pseudomonas aeruginosa and moxifloxacin against Streptococcus pneumoniae either in the absence or presence of any immunocompetence. In general, the presence of J774 macrophages resulted in an increased reduction of viable counts by 1 log10 titer. However, an increased killing of the bacteria studied by 3 to 4 log10 titers was seen in the presence of PMN and an inflammatory exudate. This increase in bacterial clearance is very well in agreement with the data obtained in animal models of infection in immunocompetent animals as compared to immunocompromised animals. Thus, it is possible to introduce immunocompetence into an in vitro model in order to simulate pharmacokinetics of antibacterial agents in the presence of an inflammatory exudate and immunocompetent cells. The use of this more complex model may complement the well-established in vitro kinetic simulation models.

Immunomodulatory activities of fluoroquinolones.

A review of published data on the in vitro, ex vivo, in vivo and clinical effects of fluoroquinolones on the synthesis of cytokines is provided. Fluoroquinolones (FQs) were found to affect both cellular and humoral immunity. In general, FQs exert their modulating effects only when used together with a co-stimulant. The in vitro studies generated heterogeneous data because of inhomogeneous effects triggered by different types of co-stimulants and differing responses of various cell lines on the stimuli. However, there is the general trend that FQs decrease the synthesis of pro-inflammatory cytokines. Studies in experimental animals generated homogenous data. All the FQs studied exerted significant clinical effects by attenuating cytokine responses in vivo. The FQs were found to be effective in vivo either in infections caused by organisms against which these are inactive or when dosed suboptimally, so that serum levels were lower than the susceptibilities of the causative pathogens. These in vivo effects were correlated with a significant decrease in pro-inflammatory cytokines like Il-1 and TNF. In addition, FQs were found to upregulate hematopoiesis. These immunomodulatory effects can be attributed in particular to those FQs with a cyclopropyl-moiety at the position N1 of the quinolone core structure, i. e. ciprofloxacin, moxifloxacin, grepafloxacin, sparfloxacin. The immunomodulatory effects of the FQs are due to their effects on intracellular cyclic AMP and phosphodiesterases, on transcription factors such as NF-kappa B, activator protein 1 and a triggering effect on the eucaryotic equivalent of bacterial SOS response. All these studies indicate that FQs exert immunomodulatory activities in particular in latent or chronic infections.

The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints.

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).

Effect of pH on the in vitro activity of and propensity for emergence of resistance to fluoroquinolones, macrolides, and a ketolide.

Antibiotic activity against common respiratory pathogens can be affected by the pH of the medium (in vitro) or the bodily fluid (in vivo) in which bacteria are present. The ionized fraction of an antibiotic is not able to efficiently penetrate bacterial or mammalian membranes, reducing the quantity of molecules able to exert their antibacterial effect resulting in elevated MIC values This study shows that the activity of macrolide antibiotics is particularly sensitive to acidic conditions, whereas a ketolide and fluoroquinolones are much less affected. Furthermore, induction of spontaneous and multistep macrolide resistance is greatly increased in acidic medium. In contrast, telithromycin and moxifloxacin did not induce resistance at any pH. Antibiotics which are less likely to induce resistance in vitro may also be less likely to induce the development of resistance in patients with respiratory tract infections.