Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q29983 (MIC)
 21,138 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance patterns that are currently problematic in Europe can vary greatly within the same species over time, among various patient populations and among geographic regions on the same continent. The results from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program, which monitors carbapenem resistance rates in institutions using meropenem, were used to determine resistance differences among Proteus mirabilis. MIC results from 688 P. mirabilis strains were classified into 4 patient care groups: ICU (n=426), neutropenia patients (NP; n=145), general wards (n=97) and cystic fibrosis patients (CF; n=20). A total of 40 centers from 12 European countries have participated since 1997, divided into 3 geographic regions (East, North, South). All testing was performed by NCCLS reference methods and interpretive criteria, including screening of extended-spectrum beta-lactamase (ESBL) phenotypes. Over the monitored interval the resistance rates varied for each agent without a clear trend toward a greater rate. Rank order of susceptibility was: meropenem (99%) > piperacillin/tazobactam (TAZ; 96%) > cefepime (95%) > ceftazidime (CAZ; 94%) > imipenem (IPM; 92%). Ciprofloxacin (CIP) was the least active agent tested (MIC90 4 microg/ml; 86% susceptible). Unexpectedly, 3.6% of P. mirabilis were imipenem-resistant (MIC, > or = 16 microg/ml). Greater rates of resistance were found for strains from NP and CF patients, and from eastern or southern European sites, usually associated with epidemic clusters. Generally susceptible species such as P. mirabilis have recently emerged as therapeutic problems in European medical centers following mutations that compromise CIP, CAZ and aminoglycoside use. Imipenem also showed decreased susceptibility of greater than 7% compared to less than 1% for meropenem. Continued surveillance by the MYSTIC Program appears to be a prudent practice to focus effective empiric treatment regimens.
 ...
PMID:Emerging antimicrobial resistances among Proteus mirabilis in Europe: report from the MYSTIC Program (1997-2001). Meropenem Yearly Susceptibility Test Information Collection. 1212 Aug 79

The objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin against Burkholderia cepacia in a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 10(6) CFU of a very resistant strain of B. cepacia (strain BC 1368; MIC, 128 micro g/ml) to establish lung infection. A 1,200- micro g dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the beta phase (t(1/2beta)) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 micro g. h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with a t(1/2beta) and AUC of 12.9 h (CV, 31.4%) and 821 micro g. h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <10(3), 10(3) to 10(5), and >10(5). Differences in CFU data between formulations showed a statistical trend (P < 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P < 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy against B. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.
 ...
PMID:Pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin after intratracheal administration in rats with pulmonary Burkholderia cepacia infection. 1243 76

The intensive antibiotic treatment of cystic fibrosis (CF) patients with chronic lung infection with Pseudomonas aeruginosa has improved the survival rate and the clinical condition of Danish patients. Acquirement of resistance to anti-pseudomonal antibiotics is one of the main drawbacks of this therapeutic strategy and our results showed the development of resistance of P. aeruginosa to several antibiotics during 25 years of intensive antibiotic treatment. Our studies have been concentrating on the development of resistance to beta-lactam antibiotics. We have shown an association between the development of resistance to beta-lactam antibiotics and the occurrence of high beta-lactamase producing strains and between the MIC of the beta-lactams and the levels of beta-lactamase expression. Partially derepressed mutants, characterized by high basal levels of beta-lactamase with the possibility of induction to even higher levels during treatment with beta-lactam antibiotics, were the most frequent phenotype found among resistant Danish P. aeruginosa CF isolates. We have also shown that the high alginate producing P. aeruginosa isolates, that characterize the chronic lung infection in CF patients, are more susceptible to antibiotics and produce less beta-lactamase than the non-mucoid paired isolates. We propose that the non-mucoid isolates are exposed to a relatively higher antibiotic pressure than the mucoid isolates and therefore, they become easily antibiotic resistant and in consequence produce high levels of beta-lactamase. The beta-lactamase produced by the non-mucoid isolates might play a protective role in the biofilm, defending the mucoid isolates from the action of beta-lactam antibiotics and helping them to maintain their antibiotic susceptibility. We have also shown that beta-lactamase, which is a periplasmic enzyme, can be secreted extracellulary packed in membrane vesicles liberated by high beta-lactamase-producing P. aeruginosa. The continuos presence in the CF lungs of bacteria producing high basal levels of beta-lactamase (partial derepressed) induces a humoral immune response to beta-lactamase. We have shown that antibodies against the chromosomally encoded beta-lactamase (a beta ab) might be considered a marker of the development of resistance to beta-lactam antibiotics. We investigated the humoral immune response to beta-lactamase by quantifying a beta ab specific IgG and IgG subclass antibodies, by investigating the influence of the allotypes on the IgG subclass response and by measuring the avidity of the IgG a beta ab. We found that CF patients with good lung function had in the early stages of the chronic lung infection higher titers of a beta ab of good avidity than patients with poor lung function. Therefore, we raised the hypothesis that some of the a beta ab might have beta-lactamase neutralizing effect, playing a beta-lactamase inhibitor role and improving the effect of the treatment with beta-lactam antibiotics. Finally, we tested our hypothesis in the rat model of chronic lung infection by assessing the effect of a beta ab raised by vaccination with purified chromosomal beta-lactamase on the outcome of the treatment with ceftazidime of bacteria resistant to beta-lactam antibiotics. Our results showed that significantly lower bacterial load and better lung pathology were found in rats with neutralizing antibodies compared to non-immunized rats or rats without neutralizing antibodies. Our findings might be of potential importance for the improvement of the treatment with beta-lactam antibiotics of resistant P. aeruginosa hyperproducing chromosomal beta-lactamase that represent a threat especially for patients with CF and chronic lung infection.
 ...
PMID:Pseudomonas aeruginosa chromosomal beta-lactamase in patients with cystic fibrosis and chronic lung infection. Mechanism of antibiotic resistance and target of the humoral immune response. 1469 54

The pharmacokinetics of many drugs are altered in patients with cystic fibrosis (CF), often necessitating different dosage requirements than those used in non-CF patients. The objective of this study was to determine the pharmacokinetics of linezolid, an antibiotic with good activity against gram-positive organisms such as methicillin-resistant Staphylococcus aureus, in patients with CF so that dosage requirements could be established. Twelve adult patients (6 male) ranging in age from 22 to 39 years were studied. A single 600-mg dose was administered intravenously over 0.5 h, and plasma samples were collected at 0 (predose), 0.5, 0.75, 1, 2, 4, 8, and 24 h. Linezolid concentrations were determined with a validated high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using standard noncompartmental methods. Blood chemistry and hematologic indices were determined before and after the study for safety purposes. All patients completed the study without encountering any adverse reactions. The pharmacokinetic parameters, while variable, with half-lives varying from 1.76 to 8.36 h, were similar to those previously described in other populations. Mean (+/- standard deviation) values for pharmacokinetic parameters of interest were as follows: elimination rate constant, 0.21 (0.11) h(-1); half-life, 4.41 (2.43); volume of distribution at steady state, 0.87 (0.19) liters/kg of body weight; and total body clearance, 0.12 (0.06) liters/h/kg. No patient would have achieved the pharmacodynamic target of an area under the concentration-time curve/MIC ratio of 83 h for pathogens for which the MIC was 4 micro g/ml. Patients with inadequate clinical responses to linezolid may require more frequent dosing.
 ...
PMID:Linezolid pharmacokinetics in adult patients with cystic fibrosis. 1469 51

Serotyping is one of the most used techniques for typing Pseudomonas aeruginosa strains. During chronic infections, and especially in cystic fibrosis, the decrease of lipopolysaccharide production is responsible for difficulties in determining O antigens. The possibility of serotyping can be simply restored by using a primary culture broth containing amikacin (1/6 of the strain MIC for this antibiotic); this is due to the ability of this antibiotic to inhibit alginate production. This technique allowed us to determine the serotype of 108 non-serotypable strains of P. aeruginosa isolated in 14 different hospitals. Among these isolates, serotype O:1 and O:13, had a high prevalence; the origin is a deficiency in D-glucose and L-rhamnose, required for the synthesis of lipopolysaccharide. In contrast, these sugars are not present in lipopolysaccharide of O:12, and these strains are always serotypable. The main protein is Alg C; this bifunctional enzyme is required in the exopolysaccharide and lipopolysaccharide production, according stress conditions in the bacterial-cells' environment. Determination of the serotype, as Antibiogram, is essential for genotypic inquiries.
 ...
PMID:[Recovery method of serotypable character in non serotypable pseudomonas aeruginosa strains]. 1476 11

Hypermutable bacterial pathogens exist at surprisingly high prevalence and benefit bacterial populations by promoting adaptation to selective environments, including resistance to antibiotics. Five hundred Haemophilus influenzae isolates were screened for an increased frequency of mutation to resistance to rifampicin, nalidixic acid and spectinomycin: of the 14 hypermutable isolates identified, 12 were isolated from cystic fibrosis (CF) sputum. Analysis by enterobacterial repetitive intergenic consensus (ERIC)-PCR and ribotyping identified eight distinct genetic fingerprints. The hypermutable phenotype of seven of the eight unique isolates was associated with polymorphisms in conserved sites of mutS. Four of the mutant mutS alleles were cloned and failed to complement the mutator phenotype of a mutS : : TSTE mutant of H. influenzae strain Rd KW20. Antibiotic susceptibility testing of the hypermutators identified one beta-lactamase-negative ampicillin-resistant (BLNAR) isolate with two isolates producing beta-lactamase. Six isolates from the same patient with CF, with the same genetic fingerprint, were clonal by multilocus sequence typing (MLST). In this clone, there was an evolution to higher MIC values for the antibiotics administered to the patient during the period in which the strains were isolated. Hypermutable H. influenzae with mutations in mutS are prevalent, particularly in the CF lung environment, and may be selected for and maintained by antibiotic pressure.
 ...
PMID:Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum. 1534 53

The MexZ-MexX-MexY multidrug efflux system in Pseudomonas aeruginosa was studied to determine its contribution to aminoglycoside resistance. Amikacin-resistant (AR) mutants were generated from P. aeruginosa strain PAO1, and clinical isolates of P. aeruginosa were collected from cystic fibrosis patients. The regulatory gene mexZ and the intergenic region (mexOZ) between mexZ and mexX were investigated for mutation by PCR and DNA sequence analysis. The results showed that 14 of 15 AR clinical isolates and one of ten laboratory mutants had at least one mutation in mexZ and/or mexOZ. To study the effect of mexZ and mexOZ mutations, the production of MexY mRNA was investigated quantitatively by real-time PCR. Seven of ten AR mutants (MIC 4-8 mg/L) produced 8-21-fold more MexY mRNA than PAO1. These isolates were sensitive to fluoroquinolones, carbapenems and ceftazidime. One AR mutant (MIC 64 mg/L) that produced > 200-fold more MexY mRNA than PAO1 was also resistant to fluoroquinolones, carbapenems and ceftazidime. Thirteen of 15 AR clinical isolates produced 3.4-727-fold more MexY mRNA. No evidence was found for the aminoglycoside-modifying enzymes 6'-N-acetyltransferase type Ib, 4'-O-nucleotidyltransferase type IIb or aminoglycoside 3'-phosphotransferase IIps in these strains. Nine AR mutants overproduced MexY without mutations in mexZ or mexOZ, suggesting that MexXY efflux is also regulated by gene(s) other than mexZ.
 ...
PMID:Expression of the MexXY efflux pump in amikacin-resistant isolates of Pseudomonas aeruginosa. 1537 80

Pseudomonas aeruginosa is an opportunistic pathogen, and this organism is a major cause of pulmonary damage and mortality in patients with cystic fibrosis (CF), diffuse panbronchiolitis (DPB) and other forms of bronchiectasis. A break-through in the treatment of DPB and associated chronic P. aeruginosa pulmonary infection was realized when a patient with DPB improved dramatically after treatment with erythromycin for years. Now, long-term macrolide therapy has become a first line of treatment in DPB patients, and the immunomodulatory properties have now been extended to other clinical settings, including CF. An important factor in the pathogenesis of chronic P. aeruginosa infection is a bacterial cell-to-cell signaling mechanism, referred to as "quorum sensing", which enables bacteria to coordinately turn on and off specific virulence genes through the production of autoinducer molecules. Interference or blocking of quorum-sensing systems has been considered an attractive therapeutic strategy. Clinical and basic science data suggests the potential of macrolides as relevant inhibitors of the Pseudomonas quorum-sensing system. In fact, certain macrolides strongly suppressed quorum-sensing associated genes and autoinducer production, in addition to inhibition of a variety of virulence factors. In this review, clinical efficacy of macrolides on DPB and CF patients will be briefly summarized. Additionally, the mechanisms of action of macrolides will be discussed from the standpoint of sub-MIC macrolide effects on P. aeruginosa, particularly the ability of this antibiotic to suppress quorum-sensing systems, which may be crucial in the pathogenesis of chronic P. aeruginosa infection.
 ...
PMID:Regulatory effects of macrolides on bacterial virulence: potential role as quorum-sensing inhibitors. 1554 97

The aim of this study was to compare a commercially available automated broth microdilution system (Merlin; Micronaut, Germany) with the standard agar dilution method for susceptibility testing of pulmonary isolates from cystic fibrosis patients. Accurate susceptibility testing of bacterial isolates from cystic fibrosis patients is known to pose problems. Although commercially available automated test systems could facilitate susceptibility testing of such isolates in routine diagnostics, these systems have not been recommended thus far. However, a pilot study recently indicated that the Merlin system, which is based on an endpoint measurement rather than on growth curves, might be applicable in the susceptibility testing of isolates from cystic fibrosis patients. In the present study, the Merlin system was further evaluated using an extended panel of nonmucoid and mucoid Pseudomonas aeruginosa isolates. The results showed that the MICs obtained with the Merlin system tended to be lower than those obtained with the agar dilution method, a finding that became increasingly apparent when mucoid Pseudomonas aeruginosa strains were tested. The correlation coefficients (r values) of the MIC results for all strains tested were between 0.6 and 0.8 for five of the seven antimicrobial agents, with r values exceeding 0.8 for only meropenem and ciprofloxacin. However, since the overall rate of serious discrepancies was within an acceptable range, the Merlin system appears to be applicable for routine clinical use in susceptibility testing of P. aeruginosa isolates from cystic fibrosis patients.
 ...
PMID:Comparison of the Micronaut Merlin automated broth microtiter system with the standard agar dilution method for antimicrobial susceptibility testing of mucoid and nonmucoid Pseudomonas aeruginosa isolates from cystic fibrosis patients. 1560 83

Relationships between pharmacodynamic indices (PI), such as the area under the concentration-time curve (AUC)/MIC ratio and time > MIC (T(>MIC)), and efficacy have been described for antimicrobial drugs. The use of these quantitative relationships may increase the power to demonstrate significant effects of drugs, obviating the need to include large numbers in comparative trials. Patients with cystic fibrosis (CF) hospitalized for treatment of an infectious exacerbation due to Pseudomonas aeruginosa were eligible for the study. They received tobramycin 3.3 mg/kg tid as initial therapy in combination with ticarcillin 125 mg/kg qid. Blood samples were drawn at t = 0-8 h after infusion. Pharmocokinetic parameters and PI were calculated for every individual and correlated to the relative improvement in forced expiratory volume during the first second (FEV1) and forced vital capacity (FVC) between pretreatment and days 9-11 as a measure of efficacy. The 3 PI fAUC/MIC, f Peak/MIC, and T(>MIC) of tobramycin showed a significant correlation with effect and was the highest for the fAUC/MIC relationships with FEV1 and FVC as determined both by the Emax model as well as Spearman correlations (r = 0.77, P = 0.002 and 0.58, P = 0.036 for FEV1 and FVC). Pharmacokinetic parameters AUC and Peak as such showed no significant correlation with effect, nor did the MIC values. There is a significant relationship between PI of aminoglycosides and efficacy parameter (increase in FEV1 and FVC) in patients with CF. This study demonstrates the applicability of pharmacodynamic relationships in determining efficacy of antimicrobial therapy, by demonstrating a strong PI-effect relationship in a group of only 13 patients.
 ...
PMID:Pharmacodynamics of tobramycin in patients with cystic fibrosis. 1596


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>