cefepime and Cystic-Fibrosis

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400 mg/kg/day divided every 6-8 hr, maximum 8-12 g/day, and 150-200 mg/kg/day divided every 6-8 hr, up to 6-8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600 mg/kg/day divided every 4 hr, maximum 18-24 g/day of piperacillin component, and 400-750 mg/kg/day divided every 6 hr, up to 24-30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Cefepime; Ceftazidime; Cephalosporins; Clavulanic Acids; Cystic Fibrosis; Disease Progression; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Penicillins; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Ticarcillin

The use of a continuous infusion of a β-lactam antibiotic in combination with high-dose, extended-interval amino-glycoside therapy for eradication of Pseudomonas aeruginosa in an adult patient with cystic fibrosis (CF) is reported.. Testing of an expectorated sputum sample taken during routine evaluation of a 32-year-old woman with CF isolated P. aeruginosa; the patient's medical record indicated no prior episodes of P. aeruginosa colonization. In an initial attempt to eradicate the organism, the woman received outpatient therapy with oral ciprofloxacin twice daily combined with an aminoglycoside (tobramycin solution) by nebulization twice daily. After a culture four weeks later again isolated P. aeruginosa, the patient was hospitalized, and i.v. antimicrobial therapy was initiated. The inpatient treatment regimen consisted of continuous-infusion cefepime 6 g (100 mg/kg/24 hr) and i.v. tobramycin 700 mg (12 mg/kg/24 hr), with both drugs administered via a peripherally inserted central catheter, for two weeks. A bronchoalveolar lavage fluid culture performed two months after completion of the i.v. antimicrobial regimen, as well as several sputum cultures obtained during the subsequent three years, tested negative for P. aeruginosa.. The administration of continuous-infusion cefepime and high-dose, extended-interval tobramycin led to the successful eradication of P. aeruginosa in an adult patient with CF.

Topics: Adult; Anti-Infective Agents; Cefepime; Cephalosporins; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients. The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be performed at least every 2-3 months in patients with well-established colonisation, and always during exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but with no clinical signs of colonisation, should be with oral ciprofloxacin (15-20 mg/kg twice-daily for 3-4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment can be used as an alternative), while patients with acute infection should be treated for 14-21 days with high doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection/colonisation (pathogenic colonisation) in stable patients (aged>6 years) should be with inhaled tobramycin (300 mg twice-daily) in 28-day cycles (on-off) or, as an alternative, colistin (1-3 million units twice-daily). Colistin is also a possible choice for patients aged<6 years. Treatment can be completed with oral ciprofloxacin (3-4 weeks every 3-4 months) for patients with mild pulmonary symptoms, or intravenously (every 3-4 months) for those with severe symptoms or isolates with ciprofloxacin resistance. Moderate and serious exacerbations can be treated with intravenous ceftazidime (50-70 mg/kg three-times-daily) or cefepime (50 mg/kg three-times-daily) plus tobramycin (5-10 mg/kg every 24 h) or amikacin (20-30 mg/kg every 24 h) for 2-3 weeks. Oral ciprofloxacin is recommended for patients with mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity are recommended and epidemiological control measures should be established.

Topics: Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Bronchopneumonia; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Inhalation; Injections, Intravenous; Lung Diseases; Pneumonia, Bacterial; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

This review is the fruit of multidisciplinary discussions concerning the continuous administration of beta-lactams, with a special focus on cefepime. Pooling of the analyses and viewpoints of all members of the group, based on a review of the literature on this subject, has made it possible to test the hypothesis concerning the applicability of this method of administering cefepime. Cefepime is a cephalosporin for injection which exhibits a broader spectrum of activity than that of older, third-generation cephalosporins for injection (cefotaxime, ceftriaxone, ceftazidime). The specific activity of cefepime is based on its more rapid penetration (probably due to its zwitterionic structure, this molecule being both positively and negatively charged) through the outer membrane of Gram-negative bacteria, its greater affinity for penicillin-binding proteins, its weak affinity for beta-lactamases, and its stability versus certain beta-lactamases, particularly derepressed cephalosporinases. The stability of cefepime in various solutions intended for parenteral administration has been studied, and the results obtained demonstrated the good compatibility of cefepime with these different solutions. These results thus permit the administration of cefepime in a continuous infusion over a 24-h period, using two consecutive syringes.

Topics: Bacterial Infections; Cefepime; Cephalosporins; Clinical Trials as Topic; Cystic Fibrosis; Drug Administration Schedule; Humans; Infusions, Intravenous; Microbial Sensitivity Tests; Treatment Outcome

Cefepime is a 'fourth' generation cephalosporin that has a broader spectrum of antibacterial activity than the third generation cephalosporins and is more active in vitro against Gram-positive aerobic bacteria. The fact that cefepime is stable to hydrolysis by many of the common plasmid- and chromosomally-mediated beta-lactamases, and that it is a poor inducer of type I beta-lactamases, indicates that cefepime may be useful for treatment of infections resistant to earlier cephalosporins. In comparative trials, cefepime 1 to 2 g, usually administered intravenously twice daily, was as effective as ceftazidime 1 to 2 g, usually administered 3 times daily, for treatment of bacteraemia and infections of the lower respiratory tract, urinary tract, pelvis and skin and skin structures. Furthermore, cefepime was as effective as ceftazidime and piperacillin or mezlocillin in combination with gentamicin when administered as empirical treatment for fever in patients with neutropenia. A limited number of trials have found cefepime to be as effective as cefotaxime for the treatment of gynaecological and lower respiratory tract infections. Similarly, cefepime 2 g twice daily intravenously (alone or in combination with metronidazole) was as effective as gentamicin in combination with mezlocillin or clindamycin, respectively, for the treatment of intra-abdominal infection. Cefepime has a linear pharmacokinetic profile, an elimination half-life of approximately 2 hours and is primarily excreted by renal mechanisms as unchanged drug. Cefepime has a tolerability profile similar to that of other parenteral cephalosporins; adverse events are primarily gastrointestinal in nature. A total of 1.4 and 2.9% of patients receiving cefepime < or = 2 g/day and > 2 g/day, respectively, required treatment withdrawal as a result of any adverse event. Thus, cefepime has the advantage of an improved spectrum of antibacterial activity, and is less susceptible to hydrolysis by some beta-lactamases, compared with third generation cephalosporins. Despite these advantages, cefepime has not been found to be more effective than ceftazidime and cefotaxime in clinical trials, although most trials selected patients with organisms sensitive in vitro to both comparator agents. Further trials, particularly in areas of widespread bacterial resistance, are required to confirm the positioning of cefepime for treatment of serious infection, and in particular to further explore whether its potential advantag

Topics: Aging; Animals; Bacteria; Bacterial Infections; Cefepime; Cephalosporins; Clinical Trials as Topic; Cystic Fibrosis; Drug Administration Schedule; Humans; Microbial Sensitivity Tests; Renal Insufficiency

Topics: Adult; Anti-Bacterial Agents; Cefepime; Cephalosporins; Cystic Fibrosis; Humans; Infusions, Intravenous; Metabolic Clearance Rate; Pilot Projects; Time Factors

The purposes of this study were to determine and compare the single- and multiple-dose pharmacokinetics of cefepime in patients with and without cystic fibrosis. Twelve patients with cystic fibrosis hospitalized for treatment of acute pulmonary exacerbations were studied. In addition, pharmacokinetic data for seven of the patients with cystic fibrosis were compared with those for seven age-matched control patients. The cefepime dose was 50 mg/kg of body weight (maximum, 2 g) administered as a 30-min intravenous infusion every 8 h for a minimum of 8 days. Serial plasma and urine samples, obtained after the first and last doses, were analyzed for cefepime content by a validated high-pressure liquid chromatographic assay. By standard noncompartmental analysis, the pharmacokinetic parameters ascertained were area under the concentration in plasma-time curve, elimination half-life, total body clearance, renal clearance, and volume of distribution at steady state. In addition, the maximum concentration in plasma was recorded. Mean (+/- standard deviation) results of the first dose analysis in patients with cystic fibrosis were as follows: maximum concentration in plasma, 142.6 (+/- 26.07) micrograms/ml; area under the concentration in plasma-time curve, 265.3 (+/- 114.31) micrograms.h/ml; elimination half-life, 1.8 (+/- 0.53) h; total body clearance, 127.2 (+/- 50.94) ml/min; renal clearance, 91.1 (+/- 38.86) ml/min/kg; volume of distribution at steady state, 14.1 (+/- 4.31) liters. Analysis for the last dose in patients with cystic fibrosis did not vary appreciably from these values, nor did those from the controls. Thus, it appears that the first-dose pharmacokinetics of cefepime are predictive of those at steady state. In order to consistently exceed the MIC for Pseudomonas aeruginosa for the entire dosing interval in patients with cystic fibrosis, a higher dose and/or different dosing interval compared with those used in this study may be necessary.

Topics: Adolescent; Adult; Cefepime; Cephalosporins; Child; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged

To measure first-dose and steady-state plasma, urine, and sputum concentrations of cefepime and make preliminary assessments of the clinical efficacy of cefepime in patients with cystic fibrosis.. Open noncomparative clinical trial.. Memorial Miller Children's Hospital of Long Beach, Calif.. Twelve patients, aged 4 to 41 years, with a confirmed diagnosis of cystic fibrosis and chronic bronchopulmonary infections.. Patients received cefepime at 50 mg/kg per dose (maximum dose, 2 g per dose) given intravenously every 8 hours. Clinical evaluations, pulmonary function tests, quantitative sputum cultures, and sensitivity testing were performed before, at the end of, and 2 weeks after therapy.. Mean (+/- SD) peak plasma concentrations after the first dose were 148.2 (36.6) mg/L; the following other values were included: half-life, 1.59 (0.46) hours; area under the curve, 292 (94) microgram/h per milliliter; total-body clearance, 3.01 (1.46) mL/min per kilogram; volume of distribution at steady state, 0.32 (0.10) L/kg; and percent of dose recovered in urine, 52% (27%). Steady-state and first-dose values were similar. Trough levels varied from 6.4 to 7.2 mg/L. Mean (+/- SD) sputum concentrations at steady state varied from 6.3 (5.4) to 4.8 (2.3) mg/L. At completion of therapy, nine of 10 patients' conditions were improved as indicated by clinical scores (greater than 10 points), forced vital capacity (greater than 10%), and a greater than or equal to 1 log decrease in sputum bacterial concentration. Cefepime was well tolerated in 10 patients, but rash and light-headedness developed in two patients. Pseudomonas aeruginosa minimum inhibitory concentration90 increased from the start (64 mg/L) to the end of therapy (256 mg/L) and was unchanged 2 weeks later.. Based on these data and the potential advantage of a single agent for the treatment of mixed infections (Staphylococcus aureus and P aeruginosa), comparative clinical trials of cefepime and standard therapy for bronchopulmonary exacerbations in patients with cystic fibrosis appear to be warranted.

Topics: Adolescent; Adult; California; Cefepime; Cephalosporins; Child; Child, Preschool; Chronic Disease; Cystic Fibrosis; Female; Hospitals, Pediatric; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Microbial Sensitivity Tests; Respiratory Tract Infections; Severity of Illness Index; Sputum; Tissue Distribution; Vital Capacity

Pediatric cystic fibrosis (CF) patients possess unique pharmacokinetics and may benefit from prolonged beta-lactam infusions to optimize pharmacodynamics. This study compared adverse drug event (ADE) rates with cefepime prolonged (PI) and standard infusions (SI).. This retrospective study included pediatric patients treated with cefepime for CF exacerbations between 2009 and 2019. One encounter per patient was analyzed with prioritization of SI encounters given sample size limitations. Baseline lab abnormalities, seizure disorders, and bleeding were exclusion criteria. The primary outcome was a composite safety endpoint (acute kidney injury [AKI], hepatotoxicity, hematologic toxicity, neurotoxicity, and hypersensitivity).. Of 188 patients, 135 received PI and 53 received SI. Baseline characteristics were similar between groups. More PI patients used CF transmembrane conductance regulator (CFTR) modulators (25% vs. 0%, p < 0.01) or had antibiotic allergies (62% vs. 38%, p = 0.02). Difference in rates of composite safety endpoint was not statistically significant between PI and SI (21 [15.6%] vs. 6 [11.3%] p = 0.46) nor was incidence of AKI (16 [11.8%] vs. 6 [11.3%], p = 0.92). Other ADEs were rarely observed. Length of stay (12.2 vs. 10.1 days, p = 0.06), change in discharge ppFEV1 from admission (13 vs. 12, p = 0.91) or from baseline (-4 vs. -6.5, p = 0.33), and time to next exacerbation (249.7 vs. 192.5 days, p = 0.93) were similar.. No difference in risk of ADEs including AKI was seen with cefepime PI in pediatric CF patients. Clinical outcomes were not significantly different between groups, but sample size may have limited comparison. PI cefepime may be considered in pediatric CF patients to optimize pharmacodynamics.

Topics: Acute Kidney Injury; Cefepime; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Incidence; Male; Retrospective Studies

Pulmonary exacerbations of infectious cause are one of the major complications in patients with cystic fibrosis (CF). These are associated with a progressive increase in morbidity and mortality. The treatment depending on the isolated microorganism. The β-lactam antibiotics are generally used which are not exempt from adverse reactions. Next, two report of neutropenia cases are described after prolonged use of cefepime in CF patients.

Topics: Anti-Bacterial Agents; Cefepime; Child, Preschool; Cystic Fibrosis; Female; Humans; Leukocyte Count; Male; Neutropenia; Risk Factors; Time Factors

Cystic fibrosis (CF) patients often receive prolonged courses of broad spectrum antibiotics, such as piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin. The objective of this study was to determine the difference in AKI for pediatric CF patients receiving piperacillin-tazobactam or cefepime in combination with vancomycin and tobramycin.. IRB approval from a single CF center was obtained for this retrospective cohort study. Charts were evaluated from December 1, 2008 to June 30,2015. Patients were included if they had a diagnosis of CF, age 30 days to 18 years, and received intravenous vancomycin, tobramycin, and piperacillin-tazobactam or cefepime. The primary outcome was difference of AKI incidence in patients receiving piperacillin-tazobactam or cefepime, as defined by modified pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria.. Seventy-one patients were included with a median (interquartile range) age 11 years (7-16) and weight 36.2 kg (22.7-50). AKI was identified in 54.5% (18/33) of patients receiving piperacillin-tazobactam and 13.2% (5/38) of patients receiving cefepime (P ≤ 0.0001). One patient receiving piperacillin-tazobactam experienced acute renal failure. There was a slight difference in length of admission (13 vs 10 days, P = 0.042), but no difference in days to maximum SCr (6 vs 3, P = 0.127) nor FEV1 percent predicted on admission (69% vs 65%, P = 1.00).. AKI occurred in nearly 55% of patients with piperacillin-tazobactam therapy versus 13% of patients with cefepime therapy, which suggests cefepime may be preferred in combination with vancomycin and tobramycin for pediatric CF patients.

Topics: Acute Kidney Injury; Adolescent; Anti-Bacterial Agents; Cefepime; Cephalosporins; Child; Cystic Fibrosis; Drug Therapy, Combination; Female; Hospitalization; Humans; Incidence; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Tobramycin; Vancomycin

Organisms belonging to the Streptococcus milleri group (SMG) are known for their role in pyogenic infections but have recently been implicated as etiological agents of pulmonary exacerbation in adult patients with cystic fibrosis (CF). The prolonged exposure of CF patients to antibiotics prompted us to investigate the susceptibility profiles of 118 SMG isolates from the airways of CF patients to 12 antibiotics compared to 43 SMG isolates from patients with invasive infections. We found that approximately 60% of all isolates failed to grow using the standard medium for disc diffusion, Mueller-Hinton blood agar (MHBA), so we explored the usefulness of brain heart infusion (BHI) agar for susceptibility testing. Zone-of-inhibition comparisons between BHI and MHBA showed strong correlations for six antibiotics, and interpretations were similar for both medium types. For ceftriaxone and cefepime, both groups of isolates were highly susceptible. Tetracycline resistance levels were comparable between the two groups (22% in CF isolates and 17.4% in invasive isolates). However, more than half of the CF isolates were not susceptible to azithromycin, erythromycin, and clindamycin, compared to 11%, 13%, and 6.5% of invasive isolates, respectively. There were 5-fold and 8-fold increased risks of azithromycin and clindamycin resistance, respectively, for the isolates from the airways of CF patients relative to the invasive isolates. Macrolide resistance was strongly linked to chronic azithromycin therapy in CF patients. This study shows that BHI agar is a suitable alternative for antimicrobial susceptibility testing for the SMG and that SMG isolates from the airways of CF patients are more resistant to macrolides and clindamycin than strains isolated from patients with invasive infections.

Topics: Anti-Bacterial Agents; Azithromycin; Clindamycin; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Erythromycin; Humans; Macrolides; Streptococcus milleri Group; Tetracycline

Azithromycin (AZM) has shown promising results in the treatment of Pseudomonas aeruginosa chronic lung infections such as those occurring in cystic fibrosis (CF) patients. We evaluated the effect of hypermutation and alginate hyperproduction on the bactericidal activity and resistance development to AZM in P. aeruginosa biofilms. Strains PAO1, its microcA mutant (PAOMA), and their respective mutS-deficient hypermutable derivatives (PAOMS and PAOMSA) were used. Biofilms were incubated with several AZM concentrations for 1, 2, 4, or 7 days, and the numbers of viable cells were determined. During the first 2 days, AZM showed bactericidal activity for all the strains, but in extended AZM incubation for strain PAOMS and especially strain PAOMSA, a marked increased in the number of viable cells was observed, particularly at 4 microg/ml. Biofilms formed by the lineages recovered from the 7-day experiments showed enhanced AZM resistance. Furthermore, most of the independent lineages studied, including those obtained from biofilms treated with AZM concentrations as low as 0.5 microg/ml, showed MexCD-OprJ hyperexpression and mutations in nfxB. The role of nfxB mutation in AZM resistance was further confirmed through the characterization of nfxB and mexD knockout mutants. Results from this work show that, although AZM exhibits bactericidal activity against P. aeruginosa biofilms, resistant mutants are readily selected and that, furthermore, they frequently show cross-resistance to other unrelated antipseudomonal agents such as ciprofloxacin or cefepime but hypersusceptibility to others such as imipenem or tobramycin. Therefore, these results should help guide the selection of appropriate antipseudomonal therapies in CF patients under AZM maintenance treatment.

Topics: Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Biofilms; Cefepime; Cephalosporins; Ciprofloxacin; Cystic Fibrosis; DNA-Binding Proteins; Humans; Membrane Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; MutS DNA Mismatch-Binding Protein; Pseudomonas aeruginosa; Transcription Factors

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.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactams; Cystic Fibrosis; Gene Expression Regulation, Bacterial; Humans; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

During investigation of susceptibility testing methods for polymyxins, 24 multidrug-resistant clinical isolates of Pseudomonas aeruginosa were observed to have a distinct, reproducible phenotype in which skipped wells were observed during broth microdilution testing for polymyxin B. Possible mechanisms underlying this phenotype were investigated. The effects of various concentrations of polymyxin B on growth, the expression of resistance genes, and outer-membrane permeability were observed. Real-time PCR was performed to compare the expression, in response to selected concentrations of polymyxin B, of genes related to the PhoP-PhoQ and PmrA-PmrB two-component regulatory systems in polymyxin B-susceptible isolate PAO1, polymyxin B-resistant isolate 9BR, and two isolates (19BR and 213BR) exhibiting the skipped-well phenotype. 19BR and 213BR appeared to have similar basal levels of expression compared to that of PAO1 for phoQ, arnB, and PA4773 (from the pmrAB operon), and in contrast, 9BR had 52- and 280-fold higher expression of arnB and PA4773, respectively. The expression of arnB and PA4773 increased in response to polymyxin B in a concentration-dependent manner for 9BR but not for 19BR and 213BR. For these isolates, expression was significantly increased for arnB and PA4773, as well as phoQ, only upon exposure to 2 mug/ml polymyxin B but not at a lower concentration of 0.125 microg/ml. The sequencing of the pmrAB and phoPQ operons for all three isolates revealed a number of unique mutations compared to that for PAO1. 1-N-phenylnaphthylamine (NPN) was used to study the effect of preincubation with polymyxin B on the self-promoted uptake of polymyxin B across the outer membrane. The preincubation of cells with 2 microg/ml polymyxin B affected baseline membrane permeability in 19BR and 213BR and also resulted in a reduced rate of NPN uptake in these isolates and in PAO1 but not in 9BR. The results presented here suggest that the skipped-well isolates have the ability to adapt to specific concentrations of polymyxin B, inducing known polymyxin B resistance genes involved in generating alterations in the outer membrane.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Genotype; Microbial Sensitivity Tests; Polymyxin B; Promoter Regions, Genetic; Pseudomonas aeruginosa; Transcription Factors

Susceptibility (18 antimicrobial agents including high-dose tobramycin) and checkerboard synergy (23 combinations) studies were performed for 2,621 strains of Burkholderia cepacia complex isolated from 1,257 cystic fibrosis patients. Minocycline, meropenem, and ceftazidime were the most active, inhibiting 38%, 26%, and 23% of strains, respectively. Synergy was rarely noted (range, 1% to 15% of strains per antibiotic combination).

Topics: Anti-Bacterial Agents; Burkholderia cepacia complex; Burkholderia Infections; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Microbial Sensitivity Tests

Clinicobacteriological effect of cefepime (in combination with amikacin) was studies in 25 pediatric patients of the age of 7 to 17 years with a mixed form of mucoviscidosis at the stage of the bronchopulmonary infection exacerbation. The basic pathogens isolated from the sputum were: Pseudomonas aeruginosa sm., P. aeruginosa muc. (67.5%) and Staphylococcus aureus (29.1%). The 2-week treatment course resulted in a marked clinical effect with improvement of the lung functional indices and eradication of the majority of the S. aureus strains (81.2%) and half of the P. aeruginosa strains (49.6%). The only side effect was moderate diarrhea not requiring discontinuation of the drug use.

Topics: Adolescent; Anti-Bacterial Agents; Bronchial Diseases; Cefepime; Cephalosporins; Child; Cystic Fibrosis; Female; Humans; Lung Diseases; Male; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Staphylococcal Infections; Staphylococcus aureus

Cefepime has been examined for stability, potential liberation of degradation products and compatibility with other drugs under conditions mimicking its potential use by continuous infusion in cystic fibrosis and intensive care patients (5-12% w/v solutions; temperatures from 20 to 37 degrees C; 1 h contact at 25 degrees C with other drugs frequently co-administered by intravenous route to these types of patients). Ceftazidime was used as a comparator based on a previous normative study with this antibiotic for the same indications. Based on a limit of max. 10% degradation, cefepime can be considered stable for a maximum of 24 h at 25 degrees C, but for only approximately 14 h at 30 degrees C, and for <10 h at 37 degrees C. Cefepime released so far unidentified degradation products if maintained at >30 degrees C for >12 h as shown from a marked increase in pH and from the development of a strong red-purple colour. Incompatibilities were observed with erythromycin, propofol, midazolam, phenytoin, piritramide, theophylline, nicardipine, N-acetylcysteine and a concentrated solution of dobutamine. We conclude that: (i) cefepime cannot be used safely by continuous infusion if containers are kept for more than a few hours at 37 degrees C (as will be the case for cystic fibrosis patients if using portable pumps carried under clothes); (ii) caution must be exercised in intensive care patients if the temperature and co-administration of other drugs is not kept under tight control. The nature and safety of the cefepime degradation products need to be studied further.

Topics: Ambulatory Care; Cefepime; Ceftazidime; Cephalosporins; Chemical Precipitation; Cystic Fibrosis; Drug Incompatibility; Drug Stability; Drug Storage; Drug Therapy, Combination; Infusions, Intravenous; Intensive Care Units

Pulmonary infectious exacerbations with Pseudomonas aeruginosa are the major problem for patients with cystic fibrosis. Emergence of multi-resistant mucoid strains leads to complicate the choice of antibiotherapy. Therefore, synergic and bactericidal treatment must be used. Then, it is interesting to estimate the bactericidal activity of antibiotics associations in order to optimise the treatment. The aim of this work is to describe a new method of bactericidal antibiotics combinations by superimposing 2 E-test strips and to compare results with those obtained with a broth bactericidal method chosen as reference method.. Twenty strains of P. aeruginosa (13 mucoïd and 7 non mucoïd) were selected from expectorants of cystic fibrosis children. Four antibiotics combinations were tested (ceftazidime/tobramycine, cefepime/tobramycine, ceftazidime/amikacine, cefepime/amikacine). Two antibiotics combinations by superimposing E-test strips techniques were used: maximal concentration on maximal concentration (C(max)/C(max)) and minimal inhibitory concentration on minimal inhibitory concentration (MIC/MIC). The comparison of results between killing curves and superposition of E-test strips (C(max)/C(max)) show 88% agreements, 4% major discrepancies specially with mucoid strains and 8% minor discrepancies. The Cmax/Cmax method seems to give better results than MIC/MIC method.. The superposition of E-test strips method is an attractive method: it is rapid, easy to use and well correlated to broth bactericidal method.

Topics: Amikacin; Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

An isolate of Pseudomonas aeruginosa from cystic fibrosis was highly resistant to beta-lactams and beta-lactamase inhibitors. The resistant determinants of clinical isolate to imipenem, ceftazidim, cefriaxone and cefepime were conjugally nontransferable. The slow or nonenzymically mediated breakdown of imipenem and other broad-spectrum beta-lactams suggested the resistance of P. aeruginosa isolate to these drugs which may be attributed to both permeability and efflux. Impaired penetration of imipenem and other beta-lactams through the membrane was detected by a diminished expression of outer-membrane proteins of approximate molar mass of 46 and 39 kDa, matched to OprD and OprF, respectively. Efflux resistance mechanism for meropenem and beta-lactams has been ruled out since the isolate failed to express outer-membrane protein of approximately 50 kDa which is matched to the OprM protein channel. Thus, reduced permeability in the clinical isolate is the main mechanism conferring resistance against beta-lactams including imipenem.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Biological Transport, Active; Cefepime; Ceftazidime; Ceftriaxone; Cell Membrane Permeability; Cephalosporins; Conjugation, Genetic; Cystic Fibrosis; Drug Resistance, Multiple, Bacterial; Electrophoresis, Polyacrylamide Gel; Genes, Bacterial; Humans; Imipenem; Membrane Transport Proteins; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa

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.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Critical Care; Cystic Fibrosis; Data Collection; Drug Resistance, Bacterial; Europe; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Neutropenia; Penicillanic Acid; Piperacillin; Population Surveillance; Proteus Infections; Proteus mirabilis; Tazobactam; Thienamycins

To compare the susceptibility of respiratory cultures of Pseudomonas aeruginosa obtained from patients with cystic fibrosis to cefepime versus ceftazidime. The pattern of cumulative resistance of P aeruginosa to cefepime in patients who had received at least one treatment course of cefepime between two sputum cultures was also characterized.. Prospective consecutive data collection.. University-affiliated cystic fibrosis clinic and medical center.. Eighty patients with cystic fibrosis who had at least one sputum culture positive for P aeruginosa with reported microbiologic susceptibilities to cefepime and ceftazidime.. Patient data was collected and analyzed. Measurements and Main Results. Two hundred and thirty-one P aeruginosa isolates were collected over 6 months. A total of 16.4% and 8.7% of the isolates were nonsusceptible to cefepime and ceftazidime, respectively (p=0.01). In eight patients who had not received cefepime before the study period, nonsusceptibility was 11.8% and 27.2% before and after exposure to cefepime, respectively.. Susceptibility of P. aeruginosa isolates in patients with cystic fibrosis was lower with cefepime than with ceftazidime. Follow-up surveillance to determine changes in susceptibility of P aeruginosa isolates to cefepime is warranted.

Topics: Adolescent; Adult; Cefepime; Ceftazidime; Cephalosporins; Chi-Square Distribution; Child; Child, Preschool; Cystic Fibrosis; Drug Resistance, Bacterial; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Pseudomonas aeruginosa

We studied 67 Pseudomonas aeruginosa isolates from cystic fibrosis patients, and compared their in vitro susceptibility to two carbapenems (meropenem and imipenem) and two cephalosporins (cefepime and ceftazidime). The carbapenems were more effective in vitro than the cephalosporins: 92.5% of isolates were susceptible to the former and 77.6% to the latter. Essentially no difference was found between meropenem and imipenem. More discrepancies were seen between cefepime and ceftazidime: four of 67 isolates (6.0%) were more susceptible to cefepime than to ceftazidime, while eight (11. 9%) were more susceptible to ceftazidime than to cefepime.

Topics: Carbapenems; Cefepime; Ceftazidime; Cephalosporins; Cystic Fibrosis; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Thienamycins

The comparative in vitro activity and synergy of cefepime were evaluated with clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. The activity of cefepime, both alone and in combination, was comparable to those of other antibiotics. The clinical efficacy of cefepime in cystic fibrosis patients merits investigation.

Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Pseudomonas; Pseudomonas aeruginosa; Sputum

The antibacterial activity of BMY-28142, a new aminothiazole cephalosporin, was measured by standardized broth microdilution and agar dilution methods against 450 gram-positive and gram-negative bacteria isolated from pediatric infections, including acute pulmonary exacerbations of cystic fibrosis. BMY-28142 activity was compared with that of aminoglycosides, beta-lactams, chloramphenicol, trimethoprim-sulfamethoxazole, vancomycin, and clindamycin. The activity of BMY-28142 in combination with other antimicrobial agents against Pseudomonas aeruginosa was also determined. Furthermore, the effects of inoculum and pH on BMY-28142 activity were evaluated. BMY-21842 was active against most of the gram-positive and gram-negative isolates, with the exception of methicillin-resistant Staphylococcus aureus and Pseudomonas cepacia. The combination of BMY-28142 with tobramycin was often synergistic, and combinations of BMY-28142 with either polymyxin B or imipenem were usually antagonistic. BMY-28142 antibacterial activity could be adversely affected at extremes of medium pH and by high inoculum densities.

Topics: Bacteria; Cefepime; Cephalosporins; Child; Cystic Fibrosis; Drug Interactions; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Sputum; Staphylococcus aureus; Streptococcus pneumoniae