brl-28500 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

To compare the minimum inhibitory concentrations (MIC) of the ceftazidime-avibactam (CZA) combination versus ceftazidime alone (TZ) for Stenotrophomonas maltophilia.. MIC comparison was performed by E-tests. We assumed that CZA was more effective in vitro than TZ alone when CZA led to a category change from "Resistant" with TZ alone to "Susceptible" or "Intermediate" with CZA, or if the MIC of CZA was at least 4-fold lower than the MIC of TZ for TZ-susceptible isolates.. Using CZA for empirical treatments in severe or polymicrobial infections with S. maltophilia seems appropriate.

Topics: Azabicyclo Compounds; Ceftazidime; Clavulanic Acids; Cystic Fibrosis; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Multicenter Studies as Topic; Stenotrophomonas maltophilia; Ticarcillin

While. To determine the risk and explanatory factors of acquiring. Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting. Cross-sectional analysis found that the number of. In young children with CF, completing

Topics: Anti-Bacterial Agents; Bronchoalveolar Lavage; Ceftazidime; Child, Preschool; Ciprofloxacin; Clavulanic Acids; Cross-Sectional Studies; Cystic Fibrosis; Female; Humans; Infant; Longitudinal Studies; Male; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Pulmonary Aspergillosis; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Ticarcillin; Tobramycin

Aztreonam, cefepime, and ceftazidime are anti-pseudomonal beta-lactam antibiotics which have been previously reported to be administered by continuous infusion (CI) in pediatric CF patients. We present two cases administering intravenous (IV) meropenem and ticarcillin-clavulanate by CI in pediatric CF patients. The delivery of beta-lactam antibiotics via CI should be considered in order to optimize the pharmacodynamics (PD) of beta-lactams in the treatment of acute pulmonary exacerbations (APE).

Topics: Adolescent; Anti-Bacterial Agents; Clavulanic Acids; Cystic Fibrosis; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Meropenem; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rhodospirillaceae; Thienamycins; Ticarcillin

The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)-approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen.. The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF).. This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses.. A total of 127 patients (age, 0-19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL.. The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 μg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

Topics: Adolescent; Anti-Bacterial Agents; Area Under Curve; Child; Child, Preschool; Clavulanic Acids; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Combinations; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Ticarcillin

The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400mg/kg/day divided every 6h, (maximum 24 g/day). This dosing strategy is higher than the Cystic Fibrosis Foundation (CFF) recommendations and the Food and Drug Administration (FDA) approved package labeling. The purpose is to determine the safety of this dosing regimen.. A retrospective study of pediatric cystic fibrosis (CF) patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Baseline and follow-up laboratory parameters were recorded. Statistical analysis was performed.. 127 patients met inclusion criteria. The mean (+ or - SD) ticarcillin dose was 3.5 g (+ or - 2.16) every 6 h; while the mean (+ or - SD) total ticarcillin dose was 13.5 g (+ or - 6.5) per day. No significant differences occurred in liver function tests, white blood count, and platelet count from baseline. Serum creatinine showed a statistically significant decrease from baseline.. Higher than FDA approved doses of ticarcillin-clavulanate may be safely used in the treatment of exacerbations in pediatric cystic fibrosis patients.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Clavulanic Acids; Creatinine; Cystic Fibrosis; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Humans; Infant; Leukocyte Count; Liver Function Tests; Platelet Count; Retrospective Studies; Ticarcillin

Earlier reports suggested that Pseudomonas aeruginosa frequent epidemic clones circulating in cystic fibrosis (CF) centres had increased virulence. However, recent data show no consistent associations with virulence, and suggest attenuation of virulence in chronic infection. Changes to infection control programmes in relation to frequent epidemic clones should be based on their frequency, virulence across all age groups and mode of acquisition. The Australian epidemic strain-1 (AES-1) (or the Melbourne epidemic strain) and AES-2 are common in CF clinics in mainland eastern Australia, but not in the environment. Both have shown increased virulence, but there are no data specifically in adults. This study examines the frequency and virulence of P. aeruginosa frequent epidemic clones in the adult CF clinic at Royal Prince Alfred Hospital, Sydney, Australia.. Two hundred and fifty-eight P. aeruginosa isolates from 112 participants were genotyped by pulsed field gel electrophoresis. Ninety-eight patients were followed up for 1 year and associations sought between infection with a frequent epidemic clone, clinical outcome and antibiotic resistance.. Four frequent P. aeruginosa epidemic clones (AES-1, AES-2, S-1, S-2) affected almost 50% of participants. AES-1 predominated (38%). AES-1, AES-2 and S-1 were associated with increased exacerbations and hospital-admission days. AES-1 showed increased resistance to aminoglycosides and ticarcillin-clavulanate.. This study supports the potential threat of frequent P. aeruginosa epidemic clones in adult CF populations.

Topics: Adolescent; Adult; Aminoglycosides; Anti-Bacterial Agents; Aspergillus fumigatus; Australia; Clavulanic Acids; Clone Cells; Comorbidity; Cystic Fibrosis; Female; Follow-Up Studies; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Sputum; Stenotrophomonas maltophilia; Ticarcillin; Young Adult

The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Topics: Adult; Anti-Bacterial Agents; Ceftazidime; Child, Preschool; Chronic Disease; Ciprofloxacin; Clavulanic Acids; Colistin; Cost of Illness; Cystic Fibrosis; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins; Ticarcillin; Tobramycin

Topics: Child, Preschool; Clavulanic Acids; Cystic Fibrosis; Desensitization, Immunologic; Drug Therapy, Combination; Female; Humans; Infusions, Parenteral; Pneumococcal Infections; Pseudomonas Infections; Sinusitis; Ticarcillin