Pharmacodynamics of moxifloxacin versus vancomycin against biofilms of methicillin-resistant Staphylococcus aureus and epidermidis in an in vitro model.

The aim of this study was to compare the activities of moxifloxacin and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) biofilms. The study was conducted using a novel in vitro pharmacodynamic model where the biofilms were treated with a simulated clinical dosing of vancomycin 1 g every 12 h or moxifloxacin 400 mg every 24 h. Vancomycin failed to produce a 2 log reduction in the biofilm embedded bacterial count against either of the tested organisms at any time. Moxifloxacin treatment, on the other hand, exhibited a superior anti-biofilm activity and resulted in a 2.5- and 3.7-log reduction in the MRSA and MRSE bacterial bioburdens, respectively, after 24 h of exposure. the results support the implementation of further in vivo and clinical studies aimed at demonstrating the efficacy of moxifloxacin in the treatment of MRSA and MRSE biofilm-associated infections.

Microbiological appraisal of levofloxacin activity against Pseudomonas aeruginosa biofilm in combination with different calcium chanel blockers in vitro.

Chronic multi-drug resistant Pseudomonas aeruginosa infections among hospitalized elderly patients are nearly epidemic in some institutions and biofilms are now recognized as the root cause of such chronic infections such as with cystic fibrosis patients. We address the potential risks and advantages of combining commonly prescribed calcium channel blockers (CCBs) with the fluoroquinolone levofloxacin in the treatment of P. aeruginosa biofilms by using in vitro real-time monitoring of biofilm growth/inhibition over time. while mibefradil and diltiazem appear to be strongly antagonistic toward antimicrobial activity of levofloxacin, amlodipine and bepridil appear to have significant synergistic effects.

Designing fluoroquinolone breakpoints for Streptococcus pneumoniae by using genetics instead of pharmacokinetics-pharmacodynamics.

We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.

Hepatitis B vaccination for patients with chronic renal failure.

BACKGROUND: Chronic renal failure patients are at particular risk of hepatitis B virus infection. Early studies have demonstrated that renal failure patients benefit from vaccination; however, not all studies have consistently shown benefit. OBJECTIVES: To determine the beneficial and harmful effects of hepatitis B vaccine and of a reinforced vaccination series in chronic renal failure patients. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Renal Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library (Issue 1, 2002),PubMed/MEDLINE (1966 to July 2003), EMBASE (1985 to November 2003), Current Clinical Practice Guidelines (Canadian Immunization Guide and Vaccine Preventable Diseases Surveillance Manual), and Science Citation Index as well as journals, published abstracts, and reference lists of articles. SELECTION CRITERIA: Randomised clinical trials comparing plasma vaccine with placebo, recombinant vaccine with placebo, recombinant vaccine with plasma vaccine, and a reinforced vaccination series (ie, more than three inoculations) with three inoculations of vaccine in chronic renal failure patients. DATA COLLECTION AND ANALYSIS: Primary outcome measures included incidence of patients developing hepatitis B virus antibodies and infections while secondary outcomes included adverse events, liver-related morbidity, and mortality. Random effects models were used and reported relative risks and 95% confidence intervals (RR and 95% CI). MAIN RESULTS: We included seven randomised clinical trials. None of them had high quality. Plasma vaccine was significantly more effective than placebo in achieving hepatitis B antibodies (RR 23.0, 95% CI 14.39 to 36.76, 3 trials). We found no statistically significant difference between plasma vaccine or placebo regarding hepatitis B virus infections (RR 0.50, 95% CI 0.20 to 1.24). We found no statistically significant differences between recombinant vaccine and plasma vaccine in achieving hepatitis B antibodies (RR 0.65, 95% CI 0.28 to 1.53, 2 trials). Heterogeneity was significant and appeared to be attributable to the dose of vaccine. Two trials examined a reinforced recombinant vaccine strategy, which was not statistically more effective than three inoculations of recombinant vaccine regarding development of hepatitis B antibodies (RR 1.36, 95% CI 0.85 to 2.16). REVIEWERS' CONCLUSIONS: Plasma derived vaccines are more effective than placebo in achieving hepatitis B antibodies, while no statistically significant difference was found between recombinant and plasma vaccines. No statistically significant difference of effectiveness was observed between a reinforced vaccination series versus routine vaccinations of three inoculations of recombinant vaccine.

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.

Pharmacokinetics and pharmacodynamics of the new fluoroquinolones: focus on respiratory infections.

High occurrence of penicillin-resistant and multidrug-resistant Streptococcus pneumoniae and reports of resistance with Haemophilus influenzae and Moraxella catarrhalis are influencing the empiric treatment of community-acquired respiratory infections and allowing the new fluoroquinolones to serve as important treatment alternatives. Recent analysis of the pharmacokinetic and pharmacodynamic properties of the new fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin) have shown high bioavailability (> or = 70%) and long serum half-lives (> or = 7 h), allowing for once-daily dosing. They concentrate in respiratory tract tissues and fluids at levels that exceed serum concentrations. Concentration-dependant killing is evident and the pharmacodynamic parameters that best correlate with bacteriological eradication, clinical efficacy and minimization of resistance have now been identified. The new fluoroquinolones display excellent pharmacokinetic and pharmacodynamic properties against community-acquired respiratory pathogens, making them ideal agents for the empirical treatment of community-acquired respiratory infections.

Hypersensitivity anaphylactoid reaction to pefloxacin in a patient with AIDS.

OBJECTIVE: To report a life-threatening anaphylactoid reaction to oral pefloxacin in a patient with AIDS and to review the pertinent literature. CASE SUMMARY: A 32-year-old woman with AIDS developed an anaphylactoid reaction following a second exposure to oral pefloxacin. This reaction was characterized by severe hypotension, dizziness, itching, and fever. DISCUSSION: Fluoroquinolones are broad-spectrum antimicrobial agents. They are used frequently in patients with AIDS for numerous indications, including treatment of Mycobacterium avium complex. Pefloxacin, a broad-spectrum fluoroquinolone, was introduced in France in 1985. Since then, many patients with AIDS have been treated with this drug. Several cases of anaphylactoid reactions to ciprofloxacin have been documented in patients with HIV infection. To our knowledge, this is the first reported case of an anaphylactoid reaction to pefloxacin in a patient with AIDS. CONCLUSIONS: There is a need for continued vigilance in the reporting of adverse drug reactions in patients with AIDS, especially with new drug. Also, care must be taken in introducing drugs, including fluoroquinolones, to this patient population.