William A. Prescott

Incidence of Carbapenem-Associated Allergic-Type Reactions among Patients with versus Patients without a Reported Penicillin Allergy

This retrospective analysis sought to determine the comparative incidence of cross-reactivity associated with carbapenem antibiotic treatment among patients with versus those without penicillin allergy. We sought to determine whether the incidence of cross-reactivity is different between imipenem-cilastatin and meropenem. A total of 211 patients were treated with a carbapenem antibiotic. Included were 100 patients with and 111 patients without a documented or reported penicillin allergy. Within each group, subgroups of penicillin-allergic and penicillin-nonallergic patients were balanced equally between imipenem-cilastatin and meropenem. The incidence of patients with a reported or documented penicillin allergy experiencing an allergic-type reaction to a carbapenem was 11%, which is 5.2 times greater than the risk in patients who were reportedly not allergic to penicillin (P=.024). No difference in the occurrence of allergic-type reactions was observed between the 2 carbapenems.

Antiinflammatory therapies for cystic fibrosis: past, present, and future.

Inflammation is a major component of the vicious cycle characterizing cystic fibrosis pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Antiinflammatory drugs for cystic fibrosis lung disease appear to have beneficial effects on disease parameters. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possesses antiinflammatory properties. Inhaled corticosteroids, colchicine, methotrexate, montelukast, pentoxifylline, nutritional supplements, and protease replacement have not had a significant impact on the disease. Therapy with oral corticosteroids, ibuprofen, and fish oil is limited by adverse effects. Azithromycin appears to be safe and effective, and is thus the most promising antiinflammatory therapy available for patients with cystic fibrosis. Pharmacologic therapy with antiinflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred.

Cost Effectiveness of Respiratory Syncytial Virus Prophylaxis: A Critical and Systematic Review

Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization in the US. The economic burden of severe disease is substantial, including hospitalization costs and out-of-pocket expenses. RSV prophylaxis with either RSV immune globulin intravenous (RSV-IGIV) or palivizumab has been shown to be effective in reducing RSV-related hospitalizations. Motavizumab, a new enhanced-potency humanized RSV monoclonal antibody, is presently in clinical trials. RSV-IGIV and palivizumab are associated with high acquisition costs. Cost-effectiveness analyses are therefore of great importance in helping to determine who should receive RSV prophylaxis. Six studies have analysed the cost effectiveness of RSV-IGIV, 14 have analysed the cost effectiveness of palivizumab and five have analysed the cost effectiveness of both agents, two of which directly compared palivizumab with RSV-IGIV. The cost effectiveness of motavizumab has not been studied.Significant variation exists in the modelling used in these analyses. Many studies have examined short-term benefits such as reducing hospitalizations and associated costs, while fewer studies have examined long-term benefits such as QALYs or life-years gained. The payer and society have been the most common perspectives used. The endpoints examined varied and generally did not account for the potential impact of RSV prophylaxis on RSV-related complications such as asthma. While some studies have reported acceptable cost-effectiveness ratios for RSV prophylaxis, the majority failed to show cost savings or cost-effectiveness ratios below commonly accepted thresholds for either RSV-IGIV or palivizumab. Cost effectiveness of RSV prophylaxis tended to be more favourable in populations with specific risk factors, including premature infants ≤32 weeks’ gestational age, and infants or children aged <2 years with chronic lung disease or congenital heart disease.Comparing the results of economic analyses of the two agents suggests palivizumab may be the more cost-effective option in the population for which RSV prophylaxis is recommended. Over time, the acquisition cost of RSV prophylaxis agents, a major cost driver, may decrease, and more acceptable outcomes of economic analyses may result. Albeit important, the results of economic analyses are not the only tool that decision makers rely on, as population-specific risk factors, and efficacy and safety data must be considered when developing treatment guidelines and making clinical decisions.

Safety of ceftriaxone sodium at extremes of age

Background: Isolated reports of neonatal and infant deaths associated with ceftriaxone–calcium precipitation in the lungs and kidneys have prompted a recommendation from the US FDA in June 2007 advising that in patients of all ages, calcium-containing solutions should not be administered simultaneously or within 48 h of the last ceftriaxone dose. Objective: To provide a comprehensive review of the literature surrounding the safety of ceftriaxone in the neonatal (≤ 28 days) and geriatric populations (≥ 65 years). Methods: Multi-database literature search for original research articles, review articles and case reports pertaining to safety of ceftriaxone in the neonatal and geriatric populations. Results/conclusions: Ceftriaxone should be avoided or significantly minimized in neonates (especially those treated concomitantly with intravenous calcium solutions and those with hyperbilirubinemia), and potentially restricted in the geriatric population treated concomitantly with intravenous calcium.

The Potential Role of HMG-CoA Reductase Inhibitors in Pediatric Nephrotic Syndrome

OBJECTIVE To evaluate the safety and efficacy of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as a potential treatment option for the dyslipidemia associated with childhood nephrotic syndrome. DATA SOURCES Searches of MEDLINE (1966–April 2004), Cochrane Library, International Pharmaceutical Abstracts (1977–April 2004), and an extensive manual review of journals were performed using the key search terms nephrotic syndrome, familial hypercholesterolemia, dyslipidemia, and HMG-CoA reductase inhibitor. STUDY SELECTION AND DATA EXTRACTION Two prospective uncontrolled studies evaluating the safety and efficacy of statin therapy in pediatric nephrotic syndrome were included. DATA SYNTHESIS While an extensive amount of data is available in adult nephrotic syndrome in which statin therapy decreases total plasma cholesterol 22–39%, low-density lipoprotein cholesterol (LDL-C) 27–47%, and total plasma triglycerides 13–38%, only 2 small uncontrolled studies have been conducted evaluating the utility of these agents in pediatric nephrotic syndrome. These studies indicate that statins are capable of safely reducing total cholesterol up to 42%, LDL-C up to 46%, and triglyceride levels up to 44%. CONCLUSIONS Lowering cholesterol levels during childhood may reduce the risk for atherosclerotic changes and may thus be of benefit in certain patients with nephrotic syndrome. Statins have demonstrated short-term safety and efficacy in the pediatric nephrotic syndrome population. Implementing pharmacologic therapy with statins in children with nephrotic syndrome must be done with care until controlled studies are conducted in this population.

Clinical importance of carbapenem hypersensitivity in patients with self-reported and documented penicillin allergy.

The risk of carbapenem hypersensitivity in patients with self‐reported or documented penicillin allergy needs to be determined so that practitioners can make better‐informed decisions regarding antibiotic therapy for this patient population. The risk of cross‐reactivity between penicillin and carbapenem antibiotics initially was reported to approach 50%. Recent retrospective studies have suggested that the clinical risk of cross‐hypersensitivity between these two drug classes is 9.2–11%, which is significantly lower than initially reported. Patients whose history of penicillin allergy is self‐reported and is not type 1 may be at moderate risk for hypersensitivity when treated with a carbapenem antibiotic. The risk of hypersensitivity appears to be higher in patients whose penicillin allergy was documented by a health care provider, those with several antibiotic allergies, and those with a positive penicillin skin test result or a history of type 1 penicillin hypersensitivity.

Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis.

Extended‐interval once‐daily dosing with the aminoglycoside tobramycin has been proven to be equally efficacious as traditional thrice‐daily dosing for treatment of the pulmonary exacerbations of cystic fibrosis in adults and children older than 5 years. The frequencies of acute ototoxicity and nephrotoxicity do not appear to be significantly different between patients treated with once‐versus thrice‐daily dosing, and the risk of acute nephrotoxicity may actually be lower in pediatric patients when once‐daily dosing is used. Long‐term studies are needed to fully assess the impact that cumulative treatments with once‐daily dosing have on renal and auditory function. An increase in antimicrobial resistance has been suggested with once‐daily dosing in the cystic fibrosis population. The extended‐interval aminoglycoside dose should be determined based on previous therapeutic drug monitoring. If the patient is aminoglycoside (tobramycin) naïve, a dose of 10 mg/kg once/day is suggested, with the dose adjusted by using therapeutic drug monitoring to individualize therapy.

Tacrolimus Toxicity Associated with Concomitant Metoclopramide Therapy

Subtherapeutic tacrolimus trough concentrations were noted in a 52‐year‐old woman who had undergone liver transplantation. Her tacrolimus dosage was increased from 7 to 28 mg twice/day, and ketoconazole therapy was added; however, her tacrolimus concentration remained undetectable. Metoclopramide 10 mg 4 times/day was begun to control the patients new‐onset nausea and vomiting. Within 48 hours of increasing the dosage to 20 mg 4 times/day, her tacrolimus trough concentration exceeded 30 ng/ml. Signs and symptoms were suggestive of tacrolimus nephrotoxicity and neurotoxicity. According to the Naranjo scale, this adverse drug event was probably the result of improved absorption of tacrolimus secondary to metoclopramide therapy. The patients subtherapeutic tacrolimus concentration at baseline was probably secondary to poor absorption due to impaired gastric emptying. Coadministration of metoclopramide significantly improved gastric motility and delivery of tacrolimus to the small intestine, increasing tacrolimus bioavailability, thus resulting in acute‐onset tacrolimus toxicity. When tacrolimus is administered with metoclopramide in patients with gastric dysmotility, tacrolimus concentrations should be monitored closely to minimize the risk of toxicity.

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV1%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden. Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications. Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.

National Survey of Extended-Interval Aminoglycoside Dosing in Pediatric Cystic Fibrosis Pulmonary Exacerbations

OBJECTIVES The Cystic Fibrosis Foundation recently deemed the use of extended-interval dosing (EID) of aminoglycosides acceptable for the treatment of cystic fibrosis (CF) pulmonary exacerbations, but current practices across United States (US) pediatric CF accredited care centers and affiliate programs are unknown. The objectives of this research are to characterize the practice trends, dosing strategies, therapeutic drug monitoring practices, and adverse drug reaction monitoring of EID of aminoglycosides in the treatment of pulmonary exacerbations across US pediatric CF programs. METHODS A 38-question online survey was distributed on behalf of the author by the CF Foundation to all US pediatric CF accredited care centers and affiliate programs. RESULTS Of the 70 participating CF programs (42.2% survey response rate), 94.3% reported using EID of aminoglycosides (as once-daily or twice-daily dosing), whereas 84.3% reported using once-daily EID in their pediatric CF population. The frequency of EID use increased with patient age. Tobramycin dosed 10 mg/kg per day every 24 hours, infused over the course of 30 minutes, in combination with an antipseudomonal beta-lactam, was the most commonly cited regimen. Monitoring of aminoglycoside serum concentrations was reported by 98.5% of programs, with a tobramycin peak of 25 to 30 mg/L and trough of less than 1 mg/L targeted most frequently. Nephrotoxicity was commonly monitored through serum creatinine measurements, whereas ototoxicity was monitored by audiometry in approximately one-half of programs. CONCLUSIONS This study indicates that the use of EID of aminoglycosides across US pediatric CF accredited care centers and affiliate programs is common, particularly among adolescents, with tobramycin being the preferred agent.