Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations.

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised "population, intervention, comparison, and outcome" questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

Drug-induced acne with elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ELX-TEZ-IVA) is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator shown to improve lung function and reduce sweat chloride in people with Cystic Fibrosis (CF). The only commonly reported dermatologic adverse effect with CFTR modulators including ELX-TEZ-IVA is rash. In this case series, we describe 19 patients who reported new onset or worsening of acne after initiation of this drug to their CF pharmacist or another member of their CF care team. The mechanism and frequency of this adverse effect is unknown.

Defining the Importance of Age-Related Changes in Drug Clearance to Optimizing Aminoglycoside Dosing Regimens for Adult Patients with Cystic Fibrosis.

BACKGROUND AND OBJECTIVE: The number of adults living with cystic fibrosis (CF) has increased and will continue to do so with the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Because systemic aminoglycosides are commonly administered for CF pulmonary exacerbations, we sought to define optimized dosing regimens using a population pharmacokinetic modeling and simulation approach. METHODS: Adult CF patients admitted for pulmonary exacerbation, receiving at least 72 h of systemic gentamicin, tobramycin, or amikacin, with measured concentrations were included. Covariates [e.g., age, weight, creatinine clearance (CRCL)] were screened. Population modeling was completed using Monolix, and simulations were conducted in R. Simulated exposures were calculated using noncompartmental analysis. Once-daily fixed (10 mg/kg) and exposure-matched dosing (i.e., 15, 10, 7.5, 6 mg/kg for ages 20, 30, 40, and 50 years, respectively) strategies were compared. First-24 h exposures were evaluated for each strategy according to the probability of target attainment (PTA) (ratio of peak plasma concentrations relative to the minimum inhibitory concentration [Cmax/MIC] or ratio of the area under the concentration-time curve to MIC [AUC/MIC]) and the probability of toxic exposure (PTE) (trough concentration, Ctrough > 2 mg/l). RESULTS: Forty-eight adult patients (55% female) were included. A one-compartment model best fit the data. Estimates for volume of distribution (V) and clearance (CL) were 22 l and 5.57 l/h, respectively. Weight significantly modified CL and V. Age significantly modified CL and was more influential than CRCL. PTA was > 90% at MICs ≤ 1 mg/l for fixed doses of 10 mg/kg and for exposure-matched doses at MIC ≤ 1 mg/l. Exposure-matched dosing reduced PTE roughly 50% in patients aged 40 and 50 years vs. fixed dosing. CONCLUSIONS: Exposure-matching maintained PTA at MICs ≤ 1 mg/l while reducing toxicity risk in older patients compared to fixed dosing. Confirmatory studies are needed.

Efficacy of ertapenem for consolidation therapy of extended-spectrum beta-lactamase-producing gram-negative infections: a case series report.

BACKGROUND: Infections caused by extended-spectrum beta-lactamase (ESBL)-producing gram-negative organisms are becoming increasingly common and present significant challenges in terms of treatment. Carbapenems is the antibiotic class of choice for treatment of these types of infections. Ertapenem is the newest carbapenem, capable of being dosed once daily, and has some in vitro but little in vivo evidence supporting its use for the treatment of these resistant infections. OBJECTIVE: To examine the clinical and microbiologic outcomes associated with ertapenem therapy of ESBL-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis infections. METHODS: This was a retrospective case series that examined the clinical and microbiologic outcomes of 22 patients who received ertapenem for treatment of an ESBL infection at Rush University Medical Center in Chicago, IL, during 2003-2005. RESULTS: The majority (16/22) of patients received ertapenem for consolidation rather than initial therapy. Different antibiotics most commonly used were other carbapenems, piperacillin/tazobactam, and aminoglycosides. The most common infections treated were lower urinary tract infections and osteomyelitis. Clinical efficacy was determined in all 22 patients, with 20 (91%) patients having a positive outcome, defined as either clinical improvement or clinical cure. The best clinical cure rate was seen with wound infections, where all 3 patients examined were found to be clinically cured. Microbiologic efficacy was determined in 7 patients, with 6 (85.7%) defined as microbiologic cure. One patient was found to be both a clinical and microbiologic failure and was also found to have developed an ertapenem-resistant strain of E. coli. CONCLUSIONS: These results demonstrate potential microbiologic and clinical efficacy of ertapenem for treatment of ESBL-producing infections and the need for a prospective, randomized study examining its efficacy versus that of other carbapenems.

Faropenem medoxomil.

OBJECTIVE: To review the literature concerning the in vitro activity, pharmacokinetic properties, in vivo efficacy, and adverse events associated with a new penem antibiotic, faropenem medoxomil. DATA SOURCES: We conducted a search of MEDLINE/PubMed and International Pharmaceutical Abstracts databases for articles or abstracts using the terms faropenem, faropenem daloxate, faropenem medoxomil, SUN5555, SY5555, WY49605, RU67655, ALP201, BLA 857, and YM 044 and published through July 2007. Information on poster presentations was obtained from the drug's manufacturer. Additional articles were identified from citations in the bibliographies of review articles. Articles written in languages other than English were excluded. STUDY SELECTION AND DATA EXTRACTION: All published reports that evaluated faropenem (or its chemical synonyms) and faropenem medoxomil were used in this review. Abstracts subsequently published as full reports were excluded, and only the resulting reports were included. Abstracts without subsequently published reports were included. DATA SYNTHESIS: The in vitro activity of faropenem has been evaluated extensively against respiratory pathogens and less extensively against aerobic gram-positive, gram-negative, and anaerobic organisms. Prospective, randomized, multicenter clinical trials have demonstrated noninferiority of faropenem to comparators for the treatment of acute bacterial sinusitis, community-acquired pneumonia, acute exacerbation of chronic bronchitis, and uncomplicated skin and skin structure infections. Adverse events associated with faropenem appear to be minimal and include nausea, vomiting, and diarrhea. CONCLUSIONS: Faropenem has demonstrated excellent in vitro activity against common respiratory pathogens, many aerobic gram-positive organisms, and anaerobes. Activity against gram-negative organisms is more reserved. In vivo data suggest that faropenem is efficacious in treating community-acquired infections including uncomplicated skin and skin structure infections; however, more data may help to characterize faropenem's place in antimicrobial therapy. Replidyne, Inc., the manufacturer of faropenem, is conducting studies to address the Food and Drug Administration's concerns that resulted in a nonapprovable letter in October 2006.