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J M Blondeau

Publications and source records attributed to J M Blondeau.

At least 19 recordsLinked to original sources

Application of two methods to determine killing of Streptococcus pneumoniae by various fluoroquinolones.

Minimum inhibitory concentration (MIC) testing measures the lowest drug concentration that prevents microbial growth using an inoculum of 10(5) colony forming units/ml (cfu/ml) whereas the mutant prevention concentration (MPC) (inoculum approximately 10(10) cells) defines the antimicrobial drug concentration threshold that would require an organism to possess two simultaneous mutations for continued growth in the presence of the drug. The rates at which multidrug-resistant Streptococcus pneumoniae [MDRSP] were killed by the respiratory fluoroquinolones, gatifloxacin, gemfloxacin, levofloxacin and moxifloxacin, were compared based on the MIC and MPC drug concentrations and at inocula ranging from 10(6)-10(9) cfu/ml. The MIC drug concentration failed to eradicate all viable cells whereas the MPC drug concentration resulted in 99.9% to 100% cellular reduction following 12-24 hours of drug exposure. MPC values against S. pneumoniae were different for each fluoroquinolone. The MPC drug concentration prevents the selection of multidrug-resistant or fluoroquinolone-resistant S. pneumoniae. The value of dosing of antimicrobial agents based on MPC thresholds results in a rapid reduction in viable cells--even at higher inocula which are more reflective of organism burden in pneumonia. The rapid reduction in viable cells observed at MPC drug concentrations may not only have an impact on preventing the selection of resistant mutants but may also help explain the rapid symptom resolution seen with new fluoroquinolones since these agents lead to little or low release of cell contents which are known to drive the inflammatory response.

Anti-Bacterial Agents↗

Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric Gram-negative urinary tract infection pathogens.

Acute, uncomplicated urinary tract infections (UTIs) are among the most commonly encountered bacterial infections and management has been made more complicated in the last decade due to the trend toward increasing antimicrobial resistance to ampicillin and trimethoprim/sulfamethoxazole (TMP/SMX). Fluoroquinolones are suggested as alternative antimicrobials for the treatment of UTIs in communities for which TMP/SMX resistance is > or = 10%. The mutant-prevention concentration (MPC) is a novel susceptibility parameter designed to minimize the selection of first-step resistant mutants present in large, > or = 10(10) CFU/mL, heterogeneous bacterial populations and is a distinct measurement from minimum inhibitory concentration testing. We measured MPC results for 80 enteric Gram-negative and 20 Pseudomonas aeruginosa urinary isolates against ciprofloxacin, levofloxacin and garenoxacin. Ciprofloxacin, levofloxacin and garenoxacin MPC results for Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Klebsiella pneumoniae and P. aeruginosa respectively were 0.5, 1, 1, 1 and 4 mg/L; 1, 2, 4, 2 and 16 mg/L; 1, 8, >8, 4 and > or = 32 mg/L. By comparison, minimum inhibitory concentration (MIC)90 results for the Enterobacteriaceae organisms ranged from < or = 0.06-4 mg/L for the three drugs and 1-4 mg/L against P. aeruginosa. Similarly, MBC90 results ranged from < or = 0.06-4 mg/L and 2-8 mg/L respectively. For ciprofloxacin against E. coli, E. cloacae and K. pneumoniae and for levofloxacin against E. coli, C. freundii and K. pneumoniae, MPC results were below susceptible breakpoints and within clinically achievable and sustainable drug concentrations for >24 hours of the dosing interval against. For garenoxacin, urine drug concentrations are expected to be in excess of MPC results for the entire length of the dosing interval for E. coli. Application of MPCs to fluoroquinolones and management of UTIs represents a situation where high levels of in vitro activity, based on low MICs, is reflected in correspondingly low MPC values for most of the organisms tested. Incorporation of MPC strategies into current fluoroquinolone dosing in UTI represents a realistic approach for preventing the further selection of resistant organisms associated with UTIs.

Anti-Bacterial Agents↗

Comparison of minimal inhibitory and mutant prevention drug concentrations of 4 fluoroquinolones against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus.

Staphylococcus aureus remains an important human pathogen affecting both outpatients and those hospitalized. Increasing antimicrobial resistance is global but prevalence rates are variable for different geographical areas. Fluoroquinolones have been used to treat S. aureus infections and the newer quinolones have enhanced in vitro activity against this organism. The mutant prevention concentration (MPC) defines the antimicrobial drug concentration threshold that would require an organism to simultaneously possess two mutations for growth in the presence of the drug. We tested clinical isolates of methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) S. aureus by minimum inhibitory concentration (MIC) and MPC against gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin. For MSSA strains, the rank order of potency based on MIC(90) values were gemifloxacin (0.063 mg/l) = moxifloxacin (0.063 mg/l) > gatifloxacin (0.05 mg/l) = levofloxacin (0.25 mg/l) and by MPC values moxifloxacin (0.25 mg/l) > gemifloxacin (0.5 mg/l) > gatifloxacin (1 mg/l) = levofloxacin (1mg/l). For 87% of the isolates the MPC value was 0.5 mg/l for gatifloxacin. The rank order of potency based on the time the serum drug concentration exceeded the MPC(90), was as follows: moxifloxacin (>24 h) > levofloxacin (>18 h) > gatifloxacin (12 h) > gemifloxacin (9 h). Serum drug concentration remained in excess of the MPC(87) for 24 h for gatifloxacin. Both MIC(90) and MPC(90) values were higher against MRSA strains and the time above the MPC(90) was significantly shorter for all agents.

Anti-Infective Agents↗

The role of PK/PD parameters to avoid selection and increase of resistance: mutant prevention concentration.

The continuing escalation of antimicrobial resistant human pathogens and the limited number of new antimicrobial agents under development has dictated that our knowledge on the emergence of resistance and any potential strategies to slow the rate at which resistance occurs is of paramount importance. Investigations with fluoroquinolones resulted in the mutant prevention concentration (MPC) concept which represents a novel in vitro measurement of fluoroquinolone potency. In essence, the MPC defines the antimicrobial drug concentration threshold that would require an organism to simultaneously possess two resistance mutations for growth in the presence of the drug. An alternative definition is the drug concentration that prevents the growth of first-step resistant mutants or the minimal inhibitory concentration of the most resistant organism present in the heterogeneous bacterial population when tested against > or =10(9) organisms. From in vitro investigations, the new fluoroquinolones (gatifloxacin, gemifloxacin, moxifloxacin) were all found to have lower MPC values than did levofloxacin against clinical isolates of Streptococcus pneumoniae. Ciprofloxacin was found to have lower MPC values than levofloxacin against clinical isolates of Pseudomonas aeruginosa. When MPC data is applied to achievable and sustainable serum drug concentrations in the body, estimation of the time the serum drug concentration exceed both MIC and MPC values can be determined. This data along with kill data allows for an estimate of the amount of time drug concentration needs to exceed MIC/MPC values to not only result in significant kill but also to minimize resistance development. To date, MPC measurements have been determined in in vitro microbiological and pharmacological models and animal and human data are being investigated. The data summarized in this overview detail resistance issues for P. aeruginosa, S. pneumoniae and other pathogens. Also presented is a summary of the MPC concept and investigations completed to date. A brief summary of fluoroquinolone mechanisms of action and resistance is presented. Finally, some preliminary investigations with other classes of compounds are discussed. To date, very limited data is available to conclude if the MPC concept does or does not apply to other classes of antimicrobial agents.

Drug Resistance↗

In vitro susceptibility of 4903 bacterial isolates to gemifloxacin--an advanced fluoroquinolone.

The in vitro activity of gemifloxacin against over 4900 bacterial isolates was determined by microbroth dilution with interpretation in accordance with NCCLS guidelines. Susceptibility results were compared with those for ciprofloxacin, gatifloxacin, levofloxacin and moxifloxacin. Gemifloxacin and the other fluoroquinolones were not affected by either beta-lactamase production or penicillin-resistance in Streptococcus pneumoniae. The MIC90 values for gemifloxacin were: S. pneumoniae 0.063 mg/l; Haemophilus influenzae 0.016 mg/l; Moraxella catarrhalis 0.008 mg/l, methicillin-susceptible Staphylococcus aureus 0.063 mg/l; methicillin-susceptible Streptococcus pyogenes 0.031 mg/l; Enterobacteriaceae 0.031-0.16 mg/l; Pseudomonas aeruginosa 4 mg/l; Neisseria meningitidis 0.008 mg/l. The MIC90 for gemifloxacin was lower than those for the other quinolones tested against S. pneumoniae (ciprofloxacin 2-4 mg/l, gatifloxacin 0.5 mg/l, levofloxacin 1-2 mg/l, moxifloxacin 0.25 mg/l). This study confirms the enhanced potent activity of gemifloxacin against Gram-positive pathogens, its broad-spectrum, Gram-negative activity and indicates that gemifloxacin is likely to have an important role in treating patients with Gram-positive and/or Gram-negative infections.

Anti-Infective Agents↗

Susceptibility of Canadian isolates of Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae to oral antimicrobial agents.

We measured the susceptibility of Canadian isolates of three respiratory tract pathogens (Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae) to several currently approved antimicrobial agents by two different methods. We also measured the susceptibility of isolates to seven fluoroquinolones. Beta-lactamase was produced by 123/566 (21.7%) of H. influenzae isolates compared with 178/200 (89%) of M. catarrhalis isolates. For S. pneumoniae 83/374 (22.2%) isolates were penicillin resistant and of these 2.1% (8/374) showed high level resistance (MIC > or = 2 mg/l). Regardless of methodology, all fluoroquinolones were highly active against H. influenzae (MIC(90) < or = 0.031 mg/l) and M. catarrhalis (MIC(90) < or = 0.064 mg/l) isolates. Susceptibility of H. influenzae to cefuroxime and amoxycillin/clavulanic acid was 99-100% whereas 84-85.5% were susceptible to cefaclor and cefprozil. Azithromycin susceptibility ranged from 82.6 to 99.2% depending on the method. M. catarrhalis isolates were uniformly susceptible to all agents tested except amoxycillin. Cross-resistance in S. pneumoniae to all non-quinolone agents was concurrent with increasing penicillin resistance as shown by increasing MIC90 values. For the fluoroquinolones tested, the rank order of potency based on MIC(90) values was as follows: gemifloxacin (0.031-0.063 mg/l), trovafloxacin (0.125 mg/l), moxifloxacin (0.125-0.25 mg/l), grepafloxacin (0.125-0.25 mg/l), gatifloxacin (0.5 mg/l), levofloxacin (1 mg/l) and ciprofloxacin (2 mg/l). Our study confirms either a high or increasing prevalence of antimicrobial resistant respiratory pathogens in Canada and also compares the new and old fluoroquinolones and their potential role as therapy for community-acquired infections. The prevalence of beta-lactamase positive H. influenzae may have decreased from levels reported in previous studies.

Administration, Oral↗

Extended-spectrum beta-lactamases.

Extended-spectrum beta lactamase (ESBL) producing gram-negative bacilli are a growing concern, especially because the species of organisms producing these enzymes are increasing. Bacteria possessing these enzymes are resistant to third-generation cephalosporins--antimicrobial agents important for inpatient therapy. These resistant organisms are clinically important because they result in increased morbidity and mortality. Additionally, some laboratories may have difficulty detecting ESBL-producing organisms. These and other issues are discussed in this article.

Anti-Bacterial Agents↗

Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae.

The mutant prevention concentration (MPC) represents a threshold above which the selective proliferation of resistant mutants is expected to occur only rarely. A provisional MPC (MPC(pr)) was defined and measured for five fluoroquinolones with clinical isolates of Streptococcus pneumoniae. Based on their potential for restricting the selection of resistant mutants, the five fluoroquinolones, in descending order, were found to be moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. For several compounds, 90% of about 90 clinical isolates that lacked a known resistance mutation had a value of MPC(pr) that was close to or below the serum levels that could be attained with a dosing regimen recommended by the manufacturers. Since MPC(pr) overestimates MPC, these data identify moxifloxacin and gatifloxacin as good candidates for determining whether MPC(pr) can be used as a guide for choosing and eventually administering fluoroquinolones to significantly reduce the development of resistance.

Anti-Infective Agents↗

Clinical utility of the new fluoroquinolones for treating respiratory and urinary tract infections.

Increasing antimicrobial resistance among most common urinary and respiratory tract pathogens has been the catalyst for the development of fluoroquinolones that are effective against these prevalent resistant organisms. Important attributes of the newly developed fluoroquinolones include once-daily dosing, maintained extensive tissue penetration and high oral bioavailability added to targeted antibacterial activities, all pharmacodynamic characteristics that may reduce the need for parenteral therapy or prevent patients being hospitalised. Some fluoroquinolones also offer same-dose bioequivalency between iv. and oral formulations, a feature that allows iv.-to-oral dosing (step-down or 'switch' therapy) without the need for dosage adjustments. These features suggest that the newer fluoroquinolones may be near-ideal agents for the empirical treatment of many common infections. This review discusses the efficacy and clinically relevant antimicrobial and pharmacokinetic qualities of the fluoroquinolones in comparison with other agents traditionally used to treat patients with urinary and respiratory tract infections.

Anti-Infective Agents↗

Moxifloxacin: a review of the microbiological, pharmacological, clinical and safety features.

Antimicrobial agents are used to treat patients with infectious diseases. Initial antimicrobial compounds originated from natural sources and were generally deemed to be narrow in spectrum. Today, we are in the era of designer drugs that have been specifically developed with current issues in infectious diseases in mind. For example, some new compounds require once daily dosing, have minimal side effects, are active against resistant pathogens and, for some, have a lower propensity for selecting for antimicrobial resistance during patient therapy.

Anti-Infective Agents↗

In vitro activity of 19 antimicrobial agents against 3513 nosocomial pathogens collected from 48 Canadian medical centres. The Canadian Antimicrobial Study Group.

Antimicrobial resistance is a global concern. Differentiation between susceptibility rates for nosocomial versus community pathogens is important epidemiologically because it impacts on the appropriate empirical selection of antimicrobial therapy for infected patients. We studied resistance rates for 3513 nosocomial pathogens from 48 Canadian medical centres tested against 19 antimicrobial agents. The following are percent susceptibility for ceftazidime, ceftriaxone, ciprofloxacin, imipenem, netilmicin, and ticarcillin/clavulanic acid, respectively: Enterobacteriaceae 95, 95, 97, 99 98, 89; Escherichia coli, all 99 except ticarcillin/clavulanic acid (91); Enterobacter spp. 78, 78, 96, 99, 99, 71; Citrobacter spp. 79, 80, 89, 100, 94, 73; Proteus spp. 99, 88, 99, 88, 99, 98; Pseudomonas aeruginosa 88, 20, 82, 88, 81, 36; Staphylococcus aureus, all > 95; Enterococcus spp. 4, 9, 62, 95, 43, 38. Susceptibility rates for other species of microorganisms and agents tested varied considerably. Some institutions had higher than average resistance rates for some pathogens (i.e. P. aeruginosa) and some agents. Detection and continued surveillance of antimicrobial resistance amongst nosocomial pathogens is vital to patient care and health care resources. The control of antimicrobial resistance can help maintain antibiotic usage and costs associated with the use of ever more potent drugs and the treatment of increasingly resistant infections.

Canada↗

Comparative in vitro activity of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin against 4151 Gram-negative and Gram-positive organisms.

Gatifloxacin, grepafloxacin, moxifloxacin and trovafloxacin are fluoroquinolones with enhanced Gram-positive activity while retaining broad-spectrum activity against Gram-negative pathogens. Levofloxacin and ciprofloxacin are older quinolones with broad activity against Gram-negative pathogens and borderline activity against some Gram-positive organisms. We compared the in vitro activity of these compounds against 4151 Gram-negative and -positive organisms. Gatifloxacin, grepafloxacin, moxifloxacin and trovafloxacin were highly active against penicillin sensitive and resistant Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Streptococcus agalactiae. Ciprofloxacin and levofloxacin were active but less potent. All compounds were highly active (overall) against Gram-negative pathogens with ciprofloxacin being the most active agent against Pseudomonas aeruginosa. Our data indicate that the advanced fluoroquinolones will be important compounds for treating infections caused by Gram-positive and Gram-negative pathogens.

Anti-Infective Agents↗

Antimicrobial susceptibility patterns of respiratory pathogens--a global perspective.

Antimicrobial resistance among respiratory tract pathogens poses a major challenge for the ongoing use of antimicrobial agents for treating infected patients. Global antimicrobial susceptibility data has documented the existence of widespread resistance issues. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis constitute the principal community-acquired respiratory tract bacterial pathogens. For H. influenzae, resistance to ampicillin varies from less than 5% in some European countries to greater than 30% in North America and Southeast Asia. For H. influenzae, resistance to trimethoprim/sulfamethoxazole has been shown to range from less than 5% in North America and Europe to greater than 25% in Europe, the Middle East, and India. For M. catarrhalis, 85% to 100% of isolates worldwide are beta-lactamase positive and, therefore, ampicillin and amoxicillin resistant. Penicillin-resistant S. pneumoniae shows considerable variability worldwide ranging from 6% to 80% whereas macrolide resistance among the pneumococci range from 0% to 90%. Clearly, documenting and understanding the emergence, dissemination, and infection with pathogens resistant to antimicrobial agents is essential for developing strategies to deal with this global problem. This article highlights the frequency of antimicrobial resistance among the respiratory pathogens from a global perspective. Also, mechanisms of resistance and factors associated with the emergence, dissemination, and colonization of resistant organisms are discussed.

Drug Resistance, Microbial↗

A review of clinical trials with fluoroquinolones with an emphasis on new agents.

This review aims to provide a comparison between the antimicrobial spectra, pharmacokinetics and clinical efficacy of the newer fluoroquinolones with older agents in this class, as well as other antibiotics used to treat lower respiratory and urinary tract infections (LRTIs and UTIs) respectively. Increasing antimicrobial resistance among common uro- and respiratory pathogens has focused attention on the development of fluoroquinolones, which have a broad spectrum of activity and improved tissue penetration. The new and developmental quinolones can be administered on a once-daily basis and exhibit high oral bioavailability, which reduces the need for parenteral therapy in hospitalised patients and may therefore potentially reduce the need for hospitalisation. These attributes, coupled with their expanded spectrum suggest that the newer fluoroquinolones are so far the most ideal agents for the empirical treatment of many common infections.

Anti-Infective Agents↗

Gatifloxacin: a new fluoroquinolone.

Gatifloxacin is a new 8-methoxy-fluoroquinoline antimicrobial agent. It has enhanced activity against Gram-positive and atypical agents, while retaining broad-spectrum antiGram-negative activity. For example, the MIC(90) values for respiratory tract pathogens are < or = 0.5 microg/ml for organisms such as Streptococcus pneumoniae (regardless of penicillin susceptibility), Haemophilus influenzae (beta-lactamase positive or negative), Moraxella catarrhalis (beta-lactamase positive or negative), Legionella species, Mycoplasma pneumoniae, methicillin-sensitive Staphylococcus aureus, beta-haemolytic Streptococci (macrolide sensitive or resistant), Neisseria species, most Enterobacteriaceae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella species, Vibrio species and Yersinia enterocolitica. For methicillin-resistant S. aureus, ciprofloxacin-resistant S. aureus, Citrobacter freundii, Providencia species, Serratia species, Pseudomonas aeruginosa and other non-fermentative Gram-negative bacilli, the MIC(90) are elevated. Gatifloxacin is bactericidal and exhibits a post-antibiotic effect against Gram-positive and -negative bacteria. The standard dose is 400 mg once daily and is available in both oral and iv. formulation. Gatifloxacin appears to have a low propensity for the selection of resistant mutants. Clinical trial data supports the use of gatifloxacin for treatment of patients with respiratory tract, urinary tract, skin and soft tissue infections. The side effect profile for gatifloxacin is similar to that with other agents.

Animals↗

A review of antimicrobial resistance in Canada.

Antimicrobial resistance is a global concern. Over the past 10 years, considerable efforts and resources have been expended to detect, monitor, and understand at the basic level the many different facets of emerging and increasing resistance. This review summarizes our current understanding of bacterial antimicrobial resistance issues in Canada with particular emphasis given to the Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus, Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Streptococcus pyogenes. In addition, future concerns and programs for ongoing surveillance are discussed.

Anti-Bacterial Agents↗

Expanded activity and utility of the new fluoroquinolones: a review.

In general, the fluoroquinolones developed over the past few years have greater potency, a broader spectrum of antimicrobial activity, greater in vitro efficacy against resistant organisms, and a better safety profile than other antimicrobial agents, including the older quinolones. The present review focuses on 4 new quinolones that are commercially available (levofloxacin, trovafloxacin, grepafloxacin, and sparfloxacin) and 3 that are currently undergoing clinical trials (gatifloxacin, moxifloxacin, and clinafloxacin). Examination of the minimum inhibitory concentrations of these drugs against gram-positive, gram-negative, anaerobic, and atypical organisms demonstrates their increased potency in vitro. The available clinical evidence, although sparse, suggests the potential enhanced efficacy of these drugs in the treatment of various community-acquired and nosocomial infections (eg, respiratory, urinary tract, and skin infections and sexually transmitted diseases). Compared with ciprofloxacin, their pharmacokinetic profiles demonstrate equivalent or greater bioavailability, higher plasma concentrations, and increased tissue penetration, as reflected in greater volume of distribution. Adverse events seen with most quinolones are mild. Serious adverse effects that may occur are phototoxicity (particularly with sparfloxacin) and prolongation of the QTc interval (seen with sparfloxacin and grepafloxacin). Drug interactions are possible between multivalent cation-containing compounds and all quinolones and between theophylline and both ciprofloxacin and grepafloxacin. Drugs that prolong the QTc interval should not be coadministered with sparfloxacin and grepafloxacin. Step-down therapy, a therapeutic and cost-saving advantage possible with gatifloxacin, levofloxacin, and moxifloxacin, allows the switching of patients from intravenous to oral therapy without having to change the dosage regimen or class of antibiotics. In addition to shortening the hospital stay and reducing the risk of venous complications, step-down therapy has been shown to cut hospital drug costs by 40% and hospitalization costs by 20%.

Animals↗

In vitro evaluation of G1: a novel antimicrobial compound.

G1 (1-[5-bromofur-2-il]-2-bromo-2-nitroethene) is a novel antimicrobial compound developed in Cuba with reported broadspectrum activity against Gram-positive and -negative bacteria, yeasts and fungi. A compound of this nature may have considerable therapeutic potential. We tested the in vitro activity of this novel compound against 3595 organisms using microbroth dilution. The following are MIC50, MIC90 and range respectively for some of the microorganisms tested: E. coli 16, 16, 4 32; Klebsiella sp. 16, 16, 8 32; Citrobacter sp. 16, 16, 8 16; Enterobacter sp. 16, 16, 8-16; Proteus sp. 16, 16, 8-16; Coagulase-negative staphylococci 16, 32, 4-32; Enterococcus sp. 16, 32, 2-32; Staphylococcus aureus 8, 16, 4-16; Streptococcus agalactiae 4, 8, 4 8; Streptococcus pyogenes 4, 8, 0.25-16; Candida albicans 2, 2, 1-4; Candida tropicalis 4, 4, 2-4; Candida sp. 2,4, 1-4. MIC values appear lower for Gram-positive microorganisms and yeasts. G1 appears to be a novel antimicrobial agent with broad spectrum activity against bacterial and fungal pathogens. Defining the activity of this compound against multi-resistant bacteria is a priority.

Anti-Bacterial Agents↗