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Biomedical subjects

M D Kitzis

Publications and source records attributed to M D Kitzis.

At least 19 recordsLinked to original sources
PubMed2006

Monitoring of vancomycin serum levels for the treatment of staphylococcal infections.

Vancomycin serum concentrations were determined for 1,737 patients treated with either 2 x 1 g of vancomycin or 4 x 500 mg daily (780 patients), according to current nomograms, or by continuous infusion (957 patients) with a loading dose (1 g) and a total of 2-6 g daily. Trough serum concentrations were determined after 36-48 h. Adequate serum levels for the treatment of a normal methicillin-resistant Staphylococcus aureus (MRSA) and a glycopeptide-intermediate S. aureus (GISA) were observed in 81% and 20.9% of patients, respectively. The data support theoretical arguments that higher and more sustained serum levels of vancomycin, obtained by continuous infusion, may enhance clinical efficacy.

Anti-Bacterial Agents↗
PubMed2004

False synergy between vancomycin and beta-lactams against glycopeptide-intermediate Staphylococcus aureus (GISA) caused by inappropriate testing methods.

The combination of vancomycin and beta-lactams is often considered synergistic and has been recommended for the treatment of glycopeptide-intermediate Staphylococcus aureus (GISA) infections. In this study, the combination of vancomycin or teicoplanin with different beta-lactams was tested. When using NaCl 4% w/v, for better expression of heterogeneous resistance to beta-lactams, with a longer (48-h) incubation period and a higher (10(7) CFU/mL) inoculum, the association of vancomycin with beta-lactams was antagonistic. However, a synergistic effect was observed for teicoplanin under the same conditions.

Anti-Bacterial Agents↗
PubMed2003

Vancomycin-resistant Staphylococcus aureus: no apocalypse now.

The number of reports concerning vancomycin-resistant Staphylococcus aureus is much higher than the number of true resistant strains or unexpected clinical failures. Many confounding factors, including inadequate serum levels, severely ill patients, foreign devices or undrained abscesses, are more likely to be responsible for the clinical failures than resistance to vancomycin.

Drug Therapy, Combination↗
PubMed2001

New mutation in parE in a pneumococcal in vitro mutant resistant to fluoroquinolones.

For an in vitro mutant of Streptococcus pneumoniae selected on moxifloxacin four- to eightfold-increased MICs of new fluoroquinolones, only a twofold-increased MIC of ciprofloxacin, and a twofold-decreased MIC of novobiocin were observed. This phenotype was conferred by two mutations: Ser81Phe in GyrA and a novel undescribed His103Tyr mutation in ParE, outside the quinolone resistance-determining region, in the putative ATP-binding site of topoisomerase IV.

Adenosine Triphosphate↗
PubMed1999

In vitro exchange of fluoroquinolone resistance determinants between Streptococcus pneumoniae and viridans streptococci and genomic organization of the parE-parC region in S. mitis.

Transfer of fluoroquinolone (FQ) resistance determinants between Streptococcus pneumoniae and viridans streptococci was explored by transformation in vitro. One-step FQ-resistant parC mutants were selected, and resistance could be transferred from DNA from S. oralis, S. mitis, S. sanguis, and S. constellatus to S. pneumoniae, with frequencies of 10(-3) to <10(-7) in correlation with the homologies of their quinolone resistance determining region sequences (95%, 91%, 85%, and 81%, respectively). Reciprocal transfers of mutated parC from DNA from S. pneumoniae to S. mitis and S. oralis were also observed. Simultaneous transfer of mutated parC and gyrA genes from S. mitis to S. pneumoniae yielded high-level-resistant pneumococcal transformants in one step at low frequencies. The parE-parC region of the type strain S. mitis 103335T had >90% homology with that of S. pneumoniae. The efficient interspecific transfer of quinolone resistance determinants in vitro leads us to anticipate their dissemination in the clinical setting.

Anti-Infective Agents↗
PubMed1999

In-vitro activity of levofloxacin, a new fluoroquinolone: evaluation against Haemophilus influenzae and Moraxella catarrhalis.

The in-vitro activity of levofloxacin was studied against 10 beta-lactamase-negative and 93 beta-lactamase-positive Moraxella catarrhalis isolates, and 65 beta-lactamase-negative and 35 beta-lactamase-positive Haemophilus influenzae isolates. The MICs of levofloxacin were determined by agar dilution on Mueller-Hinton agar (with the addition of 5% horse blood for M. catarrhalis) or on Haemophilus Test Medium for H. influenzae, and were compared with those of ofloxacin, ciprofloxacin and sparfloxacin, as well as pefloxacin and D-ofloxacin for M. catarrhalis. The fluoroquinolones showed similar activity against isolates of H. influenzae and M. catarrhalis, irrespective of beta-lactamase production. Levofloxacin (MIC50/90 0.06 mg/L) was 64 times more active against M. catarrhalis than D-ofloxacin (MIC50/90 4/8 mg/L) and twice as active as ofloxacin (MIC50/90 0.125 mg/L). Ciprofloxacin had an MIC50/90 of 0.03/0.06 mg/L and sparfloxacin showed an MIC50/90 of 0.015 mg/L against M. catarrhalis irrespective of the resistance phenotype of the isolates. Against H. influenzae, levofloxacin was twice as active as ofloxacin (MIC90 values 0.03 mg/L versus 0.06 mg/L), while the MIC90s of ciprofloxacin and sparfloxacin were both 0.015 mg/L. Our results therefore suggest that levofloxacin has potential for treating respiratory tract infections caused by H. influenzae and M. catarrhalis.

Anti-Infective Agents↗
PubMed1999

In-vitro antibacterial activity of levofloxacin against hospital isolates: a multicentre study.

The objective of this study was to evaluate the activity of the fluoroquinolone, levofloxacin, against hospital isolates of bacteria. MICs of levofloxacin were determined for 2154 strains by agar dilution. Breakpoints for susceptibility testing were calculated using the agar diffusion technique with 5 micrograms discs. The activity of levofloxacin against nalidixic acid- and pefloxacin-susceptible Enterobacteriaceae (n = 668) was higher (MIC50/90 0.06-0.12 mg/L) than previously reported for ofloxacin. As seen with other fluoroquinolones, this activity was reduced against nalidixic acid-resistant and pefloxacin-intermediate and -resistant strains (MIC 1-8 mg/L). MICs for Pseudomonas aeruginosa (n = 104) were between 0.12 and 128 mg/L. Levofloxacin had good activity against nalidixic acid- and pefloxacin-susceptible Acinetobacter baumannii (n = 12; MIC 0.06-0.25 mg/L), but the activity was reduced against nalidixic acid- and pefloxacin-resistant strains (n = 80; MIC 1-32 mg/L). Haemophilus influenzae (n = 70), Haemophilus parainfluenzae (n = 47) and Moraxella catarrhalis (n = 64) were inhibited by low concentrations of levofloxacin (MICs 0.016-0.03 mg/L, 0.03-0.12 mg/L) and 0.03-0.12 mg/L, respectively). Clostridium perfringens (n = 23; MIC 0.25-1 mg/L) was more susceptible than Bacteroides fragilis (n = 60; MIC 0.5-4 mg/L). Levofloxacin showed superior activity compared with ofloxacin against methicillin-susceptible staphylococci (n = 107; MIC 0.03-0.5 mg/L); the resistant strains (MICs 2-32 mg/L) were usually also resistant to methicillin. Levofloxacin was less effective against enterococci (n = 105; MIC 1-32 mg/L), but streptococci (n = 192) and pneumococci (n = 129), including 58 penicillin-non-susceptible strains, were inhibited by low concentrations (MICs 0.5-2 mg/L). According to the regression curve, zone diameters were usually 20-22 mm, 17-19 mm and 15-16 mm for MICs of 1, 2 and 4 mg/L, respectively. In conclusion, this study, performed on a large number of strains, confirms the superior anti-bacterial activity of levofloxacin compared with ofloxacin, especially against pathogens isolated from respiratory tract infections.

Acinetobacter↗
PubMed1999

ParC and GyrA may be interchangeable initial targets of some fluoroquinolones in Streptococcus pneumoniae.

To evaluate the role of known topoisomerase IV and gyrase mutations in the fluoroquinolone (FQ) resistance of Streptococcus pneumoniae, we transformed susceptible strain R6 with PCR-generated fragments encompassing the quinolone resistance-determining regions (QRDRs) of parC or gyrA from different recently characterized FQ-resistant mutants. Considering the MICs of FQs and the GyrA and/or ParC mutations of the individual transformants, we found three levels of resistance. The first level was obtained when a single target, ParC or GyrA, depending on the FQ, was modified. An additional mutation(s) in a second target, GyrA or ParC, led to the second level. The highest increases in resistance levels were seen for Bay y3118 and moxifloxacin with the transformant harboring a double mutation in both ParC and GyrA. When a single modified target was considered, only the ParC mutation(s) led to an increase in the MICs of pefloxacin and trovafloxacin. In contrast, the GyrA or ParC mutation(s) could lead to increases in the MICs of ciprofloxacin, sparfloxacin, grepafloxacin, Bay y3118, and moxifloxacin. These results suggest that the preferential target of trovafloxacin and pefloxacin is ParC, whereas either ParC or GyrA may both be initial targets for the remaining FQs tested. The contribution of the ParC and GyrA mutations to efflux-mediated FQ resistance was also examined. Active efflux was responsible for two- to fourfold increases in the MICs of ciprofloxacin for the transformants, regardless of the initial FQ resistance levels of the recipients.

Anti-Infective Agents↗
PubMed1998

In vitro activity of sanfetrinem and affinity for the penicillin-binding proteins of Streptococcus pneumoniae.

Against penicillin-susceptible pneumococci, the activity of sanfetrinem was similar to those of penicillin, amoxicillin, cefotaxime, imipenem, and meropenem, while against penicillin-resistant strains, sanfetrinem and the carbapenems exhibited superior activity (MICs at which 90% of strains are inhibited, < or =1 microg/ml). PBP 1a in the penicillin-susceptible strain and PBP 1a and PBP 2b in the more resistant isolates seemed to be the essential penicillin-binding proteins for imipenem and sanfetrinem.

Anti-Bacterial Agents↗
PubMed1998

[Antibacterial activity of ofloxacin in urine for 4 days after a single oral dose of 400 mg].

Antibacterial activity of ofloxacin in urine after a single oral dose of 400 mg was evaluated in ten healthy female volunteers. Urine was collected over six periods, i.e., 0-6 h, 6-12 h, 12-24 h, 24-48 h, 48-72 h, and 72-96 h postdose. Ofloxacin levels were assayed in all samples using a microbiological method and HPLC. Urinary ofloxacin MICs were determined for five bacterial strains recovered from urine, two E. coli strains of which one was susceptible and the other resistant to nalidixic acid (Nal-A), one Klebsiella pneumoniae resistant to nalidixic acid (Nal-B), one Staphylococcus saprophyticus strain, and one Enterococcus faecalis strain; MICs were 0.06, 0.25, 1, 0.25, and 2 mg/L, respectively. Mean urinary ofloxacin levels by the microbiological method during the six collection periods were 193.3 +/- 30.3, 138.1 +/- 31, 53.2 +/- 7.3, 8.3 +/- 0.8, 1.4 +/- 0.2, and 0.6 +/- 0.1 mg/L, respectively. HPLC provided similar results: 216.7 +/- 31.6, 130.7 +/- 20.5, 56.5 +/- 7.1, 8.3 +/- 0.9, 1.5 +/- 0.3, and 0.5 +/- 0.05 mg/L, respectively. Mean urinary ofloxacin excretion over 96 h was 67.4 +/- 3.6% of the dose by the microbiological method was 72.5 +/- 2.5% of the dose by HPLC. On the first day, bacteriostatic activity of urine against enterobacteria exceeded 32 and was greater than 8192 for the nalidixic acid-susceptible E. coli strain; on the next day, overall values were equal or greater than 8 for the nalidixic acid-resistant E. coli and K. pneumoniae strains. Bacteriostatic activity was equal to or greater than 32 for the S. saprophyticus strain during the first two days and equal to 8 on the first day and 4 on the second day for the E. faecalis strain.

Administration, Oral↗
PubMed1997

Active efflux as a mechanism of resistance to ciprofloxacin in Streptococcus pneumoniae.

The accumulation of fluoroquinolones (FQs) was studied in a FQ-susceptible laboratory strain of Streptococcus pneumoniae (strain R6). Uptake of FQs was not saturable, was rapidly reversible, and appeared to occur by passive diffusion. In the presence of glucose, which energizes bacteria, the uptake of FQs decreased. Inhibitors of the proton motive force and ATP synthesis increased the uptake of FQs in previously energized bacteria. Similar results were observed with the various FQs tested and may be explained to be a consequence simply of the pH gradient that exists across the cytoplasmic membrane. From a clinical susceptible strain (strain SPn5907) we isolated in vitro on ciprofloxacin an FQ-resistant mutant (strain SPn5929) for which the MICs of hydrophilic molecules were greater than those of hydrophobic molecules, and the mutant was resistant to acriflavine, cetrimide, and ethidium bromide. Strain SPn5929 showed a significantly decreased uptake of ciprofloxacin, and its determinant of resistance to ciprofloxacin was transferred by transformation to susceptible laboratory strain R6 (strain R6tr5929). No mutations in the quinolone resistance-determining regions of the gyrA and parC genes were found. In the presence of arsenate or carbonyl cyanide m-chlorophenylhydrazone, the levels of uptake of ciprofloxacin by the two resistant strains, SPn5929 and R6tr5929, reached the levels of uptake of their susceptible parents. These results suggest an active efflux of ciprofloxacin in strain SPn5929.

4-Quinolones↗
PubMed1996

In vitro selection of one-step mutants of Streptococcus pneumoniae resistant to different oral beta-lactam antibiotics is associated with alterations of PBP2x.

Many oral penicillins and cephalosporins are used to treat clinical infections caused by Streptococcus pneumoniae. Therefore, using different beta-lactams as selectors, we estimated the frequencies of one-step mutations leading to resistance. Resistant mutants were obtained from penicillin-susceptible, intermediately resistant, and penicillin resistant strains. For cefixime, cefuroxime, cefpodoxime, cefotaxime, and ceftriaxone, the frequencies of mutation ranged from 10(-6) to 10(-8) when resistant mutants were selected at 2- to 8-fold the MIC, and the MICs increased 2- to 16-fold. For ampicillin, ampicillin-sulbactam, amoxicillin, amoxicillin-clavulanic acid, cefaclor, and loracarbef, the frequencies of mutation were about 10(-7) to 10(-8), and the MICs increased twofold at most. One to three resistance profiles of the resulting mutants were selected for each of the selecting antibiotics. Among those, some showed resistance to the cephalosporins associated with a 2- to 32-fold increase in susceptibility to the penicillins. Competition experiments showed a decreased affinity of PBP2x for cefpodoxime in all mutants. In some mutants that were more susceptible to amoxicillin, a decreased affinity of PBP2x for cefpodoxime was associated with an increased affinity for amoxicillin and a particular substitution of alanine for threonine at position 550 just after the KSG triad. From these results we infer (i) that among the beta-lactams tested the penicillins, cefaclor, and loracarbef selected one-step resistant mutants less frequently and that they achieved a lower level of resistance, and (ii) that mutants with different profiles may have acquired different point mutations in PBP2x.

Amino Acid Sequence↗
PubMed1996

High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA.

The mechanism of high-level fluoroquinolone resistance was studied in strains of Streptococcus pneumoniae, either selected in vitro or isolated from clinical samples. By using DNA from these high-level-resistant strains, low-level-resistant transformants (MIC of pefloxacin, > or = 32 micrograms/ml; MIC of ciprofloxacin, 4 micrograms/ml; MIC of sparfloxacin, 0.50 micrograms/ml) were obtained at high frequencies (ca.10(-2)), while high-level-resistant transformants (MIC of pefloxacin, > or = 64 micrograms/ml; MIC of ciprofloxacin, 16 to 64 micrograms/ml; MIC of sparfloxacin, > or = 8 micrograms/ml) were obtained only at low frequencies (ca.10(-4)). This suggested that mutations in at least two unlinked genes were necessary to obtain high-level resistance. Low-level resistance was associated with ParC mutations (change from Ser to Tyr at position 79 [Ser79Tyr], Ser79Phe, or Asp83Gly). ParC mutations were associated, in high-level-resistant strains and transformants, with alterations in the quinolone resistance-determining region of GyrA (Ser84Tyr, Ser84Phe, and/or Glu88Lys). Low-level resistance was shown to be necessary for expression of the gyrA mutations. No mutation in the region corresponding to the quinolone resistance-determining region of GyrB and no alteration of drug accumulation were found.

4-Quinolones↗
PubMed1996

[Comparative study of the performance and ergonomics of nebulizers in cystic fibrosis].

This study had, as its aim, to test twelve nebulizers (6 jet, 6 ultrasonic) which are used in the treatment of cystic fibrosis. Devices were connected to a respirator in order to mimic the ventilation of a child and of an adult suffering from cystis fibrosis. Three medications: tobramycine, colistine and amiloride were nebulised. The volume of the recommended solution varied between 1.5 and 13 ml according to the manufacturer. During a session of ten minutes the ultrasonic nebulizer delivered an inhaled volume which was significantly greater than the jet (2.72 +/- 0.98 ml vs 1.22 +/- 0.59 ml, p < 0.0001) for the three drugs. Regarding granulometry, the fraction of particles between 0.5 and 5 microns, was higher with ultrasonic than with pneumatic nebulizer for tobramycine (67.1 +/- 10.7 vs 55.5 +/- 11.5%, p < 0.001) and amiloride (66.4 +/- 9.2% vs 58.1 +/- 15%, p < 0.05%). The variation of concentration due to nebulisation were independent of the type of apparatus but influenced by the drug since concentration was increased for tobramycine (+10.5 +/- 18.6%) and amiloride (+13.4 +/- 8/9%). In summary the effective fraction resulting from the inhalable fraction, from granulometry and from changes in concentration was significantly greater for ultrasonic than for jet nebrulizer (17.3 +/- 6.7% vs 9.7 +/- 9.6%, p < 0.001). This study underlines the great variability of the performance of aerosols generators and therefore the need for an accurate evaluation of nebulizer performances in order to prescribe the best nebulizer/drug association in clinical practice.

Administration, Inhalation↗
PubMed1996

[In vitro antibacterial activity of a new fluoroquinolone, sparfloxacin, against nosocomial bacteria, and concordance curve].

Minimal inhibitory concentrations (MICs) of sparfloxacin (SFX) were determined by agar dilution for 3,164 bacterial strains isolated in 10 university hospitals; in addition, antibiograms by agar diffusion were performed with 5 micrograms disks. Activity of SFX against nalidixic acid (NAL) susceptible (S) Enterobacteriaceae was close to that of other fluoroquinolones (FQ) (MIC 50 and 90: 0.06-0.5 microgram/ml); like for other FQ, this activity was reduced against NAL intermediate and resistant (R) Enterobacteriaceae (2-16). MICs of SFX against P. aeruginosa were between 0.12 and 16 (1-32). SFX had also a good activity against NAL-S A. baumannii (CMI < or = 0.25) but this activity is reduced against NAL-R Acinetobacter (16). SFX was highly active against Haemophilus (0.016-0.06) gonococci (0.008), meningococci (0.008) and B. catarrhalis (0.008-0.03). SFX showed activity superior to the currently available FQ against methicillin susceptible staphylococci (0.06); the resistant strains [8] are usually methicillin resistant. SFX is more effective against enterococci (0.5), streptococci (0.25-0.5) and particularly pneumococci (0.25-0.5) including penicillin-resistant strains. The coefficient correlation of the regression curve is 0.876; for MIC breakpoints of 1 and 2 micrograms/ml, zone diameter breakpoints should be 20 and 16 mm.

Anti-Infective Agents↗
PubMed1995

Comparison of different beta-lactam-glycopeptide-gentamicin combinations for an experimental endocarditis caused by a highly beta-lactam-resistant and highly glycopeptide-resistant isolate of Enterococcus faecium.

A synergistic bactericidal effect between penicillin, vancomycin, and gentamicin has been described against enterococci highly resistant to beta-lactams and glycopeptides. Since such a synergy was also observed in vitro between ceftriaxone, teicoplanin, and gentamicin against Enterococcus faecium 70/90, the efficacy of different combinations including penicillin or ceftriaxone, vancomycin or teicoplanin, and gentamicin was compared in vivo in experimental endocarditis. In vitro, all four triple combinations provided a bactericidal effect. In rabbits, after a 5-day treatment, the ceftriaxone-vancomycin-gentamicin combination was the most effective, both in reducing the total bacterial titers and in eradicating the subpopulation resistant to the synergy. Compared with the 5-day regimen, 10- and 20-day regimens of ceftriaxone-vancomycin-gentamicin, each followed by a 3-day antibiotic-free period, increased the number of sterilized animals but failed to avoid the emergence of resistant bacteria, which occurred in 10%-20% of animals.

Animals↗