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 21,138 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pandoraea spp. are gram-negative, glucose nonfermenting rods detectable in blood cultures and sputa of cystic fibrosis patients. They are resistant to various antibiotic groups, with imipenem being the only active beta-lactam. We isolated an imipenem-resistant (MIC, 64 microg/ml) Pandoraea pnomenusa strain from a cystic fibrosis patient. Cloning and sequencing identified two beta-lactamases of Bush group 2d, namely, the known OXA-33, located on an integron, and the novel carbapenem-hydrolyzing oxacillinase OXA-62. OXA-62 is only distantly related to other oxacillinases (OXA-50 being closest with 43% amino acid identity). It hydrolyzes penicillins, oxacillin, imipenem, and meropenem but not expanded-spectrum cephalosporins. The blaOXA-62 gene is chromosome located. No transposable elements were found in its genetic neighborhood. With OXA-62-specific primers, blaOXA-62 could be identified in all P. pnomenusa strains and appears to be species specific. This additional mechanism of carbapenem resistance further complicates the treatment of infections caused by P. pnomenusa.
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PMID:Novel carbapenem-hydrolyzing oxacillinase OXA-62 from Pandoraea pnomenusa. 1656 48

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 +/- 7.8 kg) and 26 healthy volunteers (WT, 71.1 +/- 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (> or =90%) probability-of-target attainment (PTA) for MICs of < or =12 mg/liter in CF patients and < or =16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of < or =16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.
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PMID:Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers. 1748 5

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 +/- 17.1 versus 76.2 +/- 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 +/- 0.17 h [mean +/- the standard deviation]) and volume of distribution (0.20 +/- 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of < or =4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.
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PMID:Pharmacokinetics of aztreonam in healthy subjects and patients with cystic fibrosis and evaluation of dose-exposure relationships using monte carlo simulation. 1757 27

The pH at the site of infection is one of a number of factors that may significantly influence the in vivo activity of an antibiotic prescribed for treatment of infection and it may be of particular importance in the treatment of cystic fibrosis (CF) pulmonary infection, as acidification of the airways in CF patients has been reported. As Pseudomonas aeruginosa is the most frequent causative pathogen of CF pulmonary infection, this study determines the effect that growth at a reduced pH, as may be experienced by P. aeruginosa during infection of the CF lung, has on the susceptibility of clinical P. aeruginosa isolates, grown planktonically and as biofilms, to tobramycin and ceftazidime. Time-kill assays revealed a clear loss of tobramycin bactericidal activity when the isolates were grown under acidic conditions. MIC and MBC determinations also showed decreased tobramycin activity under acidic conditions, but this effect was not observed for all isolates tested. In contrast, growth of the isolates at a reduced pH had no adverse effect on the bacteriostatic and bactericidal activity of ceftazidime. When the isolates were grown as biofilms, the pH at which the biofilms were formed did not affect the bactericidal activity of either tobramycin or ceftazidime, with neither antibiotic capable of eradicating biofilms formed by the isolates at each pH. This was in spite of the fact that the concentrations of both antibiotics used were much higher than the concentrations required to kill the isolates growing planktonically. These results show that growth in an acidic environment may reduce the susceptibility of clinical P. aeruginosa isolates to tobramycin.
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PMID:Effect of pH on the antimicrobial susceptibility of planktonic and biofilm-grown clinical Pseudomonas aeruginosa isolates. 1791 Feb 77

Nontypeable Haemophilus influenzae (NTHi) commonly causes otitis media, chronic bronchitis in emphysema, and early airway infections in cystic fibrosis. Long-term, low-dose azithromycin has been shown to improve clinical outcomes in chronic lung diseases, although the mechanism of action remains unclear. The inhibition of bacterial biofilms by azithromycin has been postulated to be one mechanism mediating these effects. We hypothesized that subinhibitory concentrations of azithromycin would affect NTHi biofilm formation. Laboratory strains of NTHi expressing green fluorescent protein and azithromycin-resistant clinical isolates were grown in flow-cell and static-culture biofilm models. Using a range of concentrations of azithromycin and gentamicin, we measured the degree to which these antibiotics inhibited biofilm formation and persistence. Large biofilms formed over 2 to 4 days in a flow cell, displaying complex structures, including towers and channels. Subinhibitory concentrations of azithromycin significantly decreased biomass and maximal thickness in both forming and established NTHi biofilms. In contrast, subinhibitory concentrations of gentamicin had no effect on biofilm formation. Furthermore, established NTHi biofilms became resistant to gentamicin at concentrations far above the MIC. Biofilm formation of highly resistant clinical NTHi isolates (azithromycin MIC of > 64 microg/ml) was similarly decreased at subinhibitory azithromycin concentrations. Clinically obtainable azithromycin concentrations inhibited biofilms in all but the most highly resistant isolates. These data show that subinhibitory concentrations of azithromycin have antibiofilm properties, provide mechanistic insights, and supply an additional rationale for the use of azithromycin in chronic biofilm infections involving H. influenzae.
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PMID:Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and Diminish established biofilms. 1795 87

Respiratory tract infection, most often involving opportunistic bacterial species with broad-spectrum antibiotic resistance, is the primary cause of death in persons with cystic fibrosis (CF). Species within the Burkholderia cepacia complex are especially problematic in this patient population. We investigated a novel surfactant-stabilized oil-in-water nanoemulsion (NB-401) for activity against 150 bacterial isolates recovered primarily from CF respiratory tract specimens. These specimens included 75 Burkholderia isolates and 75 isolates belonging to other CF-relevant species including Pseudomonas, Achromobacter, Pandoraea, Ralstonia, Stenotrophomonas, and Acinetobacter. Nearly one-third of the isolates were multidrug resistant, and 20 (13%) were panresistant based on standard antibiotic testing. All isolates belonging to the same species were genotyped to ensure that each isolate was a distinct strain. The MIC(90) of NB-401 was 125 microg/ml. We found no decrease in activity against multidrug-resistant or panresistant strains. MBC testing showed no evidence of tolerance to NB-401. We investigated the activity of NB-401 against a subset of strains grown as a biofilm and against planktonic strains in the presence of CF sputum. Although the activity of NB-401 was decreased under both conditions, the nanoemulsion remained bactericidal for all strains tested. These results support NB-401's potential role as a novel antimicrobial agent for the treatment of infection due to CF-related opportunistic pathogens.
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PMID:In vitro activities of a novel nanoemulsion against Burkholderia and other multidrug-resistant cystic fibrosis-associated bacterial species. 1895 31

The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.
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PMID:Using chemical probes to investigate the sub-inhibitory effects of azithromycin. 1897 42

Retrospective analysis of 189 nonredundant strains of Pseudomonas aeruginosa sequentially recovered from the sputum samples of 46 cystic fibrosis (CF) patients over a 10-year period (1998 to 2007) revealed that 53 out of 189 (28%) samples were hypersusceptible to the beta-lactam antibiotic ticarcillin (MIC < or = 4 microg/ml) (phenotype dubbed Tic(hs)). As evidenced by trans-complementation and gene inactivation experiments, the mutational upregulation of the efflux system MexXY was responsible for various degrees of resistance to aminoglycosides in a selection of 11 genotypically distinct strains (gentamicin MICs from 2 to 64 microg/ml). By demonstrating for the first time that the MexXY pump may evolve in CF strains, we found that a mutation leading to an F1018L change in the resistance-nodulation-cell division (RND) transporter MexY was able to increase pump-promoted resistance to aminoglycosides, cefepime, and fluoroquinolones twofold. The inactivation of the mexB gene (which codes for the RND transporter MexB) in the 11 selected strains showed that the Tic(hs) phenotype was due to a mutational or functional loss of function of MexAB-OprM, the multidrug efflux system known to contribute to the natural resistance of P. aeruginosa to beta-lactams (e.g., ticarcillin and aztreonam), fluoroquinolones, tetracycline, and novobiocin. Two of the selected strains synthesized abnormally low amounts of the MexB protein, and 3 of 11 strains expressed truncated MexB (n = 2) or MexA (n = 1) polypeptide as a result of mutations in the corresponding genes, while 7 of 11 strains produced wild-type though nonfunctional MexAB-OprM pumps at levels similar to or even higher than that of reference strain PAO1. Overall, our data indicate that while MexXY is necessary for P. aeruginosa to adapt to the hostile environment of the CF lung, the MexAB-OprM pump is dispensable and tends to be lost or inactivated in subpopulations of P. aeruginosa.
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PMID:Efflux unbalance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. 1925 80

The pharmacokinetics and pharmacodynamics of a novel liposomal amikacin for inhalation were evaluated in cystic fibrosis patients with chronic pseudomonas infection. Twenty-four patients from two studies received 500 mg of liposomal amikacin by inhalation once daily for 14 days. Serum, sputum, and 24-h urine samples were collected on days 1 and 14 of therapy; pulmonary function tests (PFT) and sputum for quantitative microbiology were assessed at baseline and serially for 14 days. Relationships between amikacin exposure in serum and sputum and absolute change in PFT endpoints and log10 CFU of Pseudomonas aeruginosa from baseline on days 7 and 14 of therapy were assessed. On days 7 and 14, absolute change from baseline in forced expiratory volume in 1 s (FEV1), percent predicted forced expiratory volume in 1 s (FEV1 % predicted), and forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75%)) increased by 0.24 (P = 0.002) and 0.13 (P = 0.10) liters, 7.49 (P < 0.001) and 4.38 (P = 0.03), and 0.49 (P < 0.001) and 0.42 (P = 0.02) liters/s, respectively. In addition, relative change from baseline in FEV1 % predicted was 10.8% (P < 0.001) and 5.62% (P = 0.073) on days 7 and 14, respectively. While significant relationships between absolute change in PFT endpoints and the ratio of serum or sputum area under the concentration-time curve to the MIC (AUC/MIC) were not observed, relationships between change in log10 CFU and serum AUC/MIC ratio and change in log10 CFU and absolute changes in all PFT endpoints were significant. Together, these findings likely represent drug effect and warrant the further development of liposomal amikacin for inhalation.
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PMID:Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infection. 1945 Dec 81

Our objectives were to compare the pharmacokinetics (PK) of carumonam, a monobactam, between cystic fibrosis (CF) patients and healthy volunteers and assess its pharmacodynamic profile. We studied 10 adult CF patients and 18 healthy volunteers of similar body size (dose: 2.166 g of carumonam as 15-min intravenous infusion). High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for drug analysis and NONMEM (ICON, Ellicot City, MD) for population PK and Monte Carlo simulation with targets between > or =20% and 100% free time above MIC (fT > MIC). Unscaled renal clearance was 24% higher in CF patients. Lean body mass and creatinine clearance explained the difference in average clearance and volume of distribution between both subject groups. For a daily dose of 6 g per 70 kg of total body weight, 15-min infusions q8h achieved robust (>90%) probabilities of target attainment (PTAs) (target, 60% fT > MIC) for MICs < or =3 mg/L in CF patients and < or =6 mg/L in healthy volunteers. At the same dose, 4-h infusions q8h achieved robust PTAs up to markedly higher MICs < or =8 to 12 mg/L in CF patients and < or =16 mg/L in healthy volunteers.
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PMID:Comparison of the pharmacokinetics and pharmacodynamic profile of carumonam in cystic fibrosis patients and healthy volunteers. 1974 23


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