A clinical review of echinocandins in pediatric patients.

OBJECTIVE: To identify and evaluate available data on pediatric echinocandin use. DATA SOURCES: A PubMed search, limited to English-language articles, was conducted (1990-August 2009) using the search terms echinocandin, pediatric, child, pharmacokinetics, caspofungin, micafungin, and anidulafungin. Additional articles were retrieved from citations of selected references. STUDY SELECTION AND DATA EXTRACTION: Relevant information on the pharmacology, pharmacokinetics, efficacy, and safety of echinocandins in children was selected. Clinical trials, retrospective reviews, and case series were identified and evaluated. Data from these sources were included in this review. DATA SYNTHESIS: Caspofungin is the only echinocandin approved by the Food and Drug Administration for use in children. Pediatric pharmacokinetics has been evaluated with all 3 echinocandins but is limited with anidulafungin. Micafungin is the most well-studied agent in prospective clinical trials for antifungal prophylaxis in stem cell transplantation and treatment of invasive fungal infections. Caspofungin has been studied prospectively for febrile neutropenia and treatment of invasive fungal infections, but most published data are from retrospective reviews or case reports. One case report of anidulafungin for neonatal candidiasis has been published. The role of echinocandins in the management of invasive pediatric fungal infections has expanded. Micafungin and caspofungin are recommended as primary or alternative treatment of candidemia and esophageal or invasive candidiasis, and as salvage therapy for invasive aspergillosis. Micafungin is recommended for neutropenic prophylaxis in stem cell transplantation, while caspofungin may be used in febrile neutropenia as an alternative to azoles. Dosing has been well established for caspofungin only in children 3 months of age and above. Anidulafungin should be avoided in children until more pharmacokinetic and clinical data become available. CONCLUSIONS: Further comparative trials are needed to more clearly define the role of echinocandins, either as monotherapy or in combination for difficult-to-treat infections, in the pediatric population.

Pertussis resurgence: diagnosis, treatment, prevention, and beyond.

The introduction of routine vaccination against Bordetella pertussis more than a half century ago led to a drastic decline in the number of reported cases of pertussis. It was originally believed that lifelong immunity was afforded after vaccination. Unfortunately, this belief is flawed, as the highest number of pertussis cases since 1959 was reported in 2004. This significant increase has led to additional research on immunity, vaccination, and treatment of B. pertussis in all age groups. We performed a MEDLINE search of literature from 1966-2006 to evaluate and review the existing data on immunity to and prevention or treatment of B. pertussis infections. Additional articles were identified from the bibliographies of reviewed literature. Numerous articles pertaining to these topics have been published recently. The most significant changes in the management of this infectious disease surround the new recommendations by the Advisory Committee on Immunization Practices for adult and adolescent immunizations to assist in preventing outbreaks of B. pertussis. The Centers for Disease Control and Prevention recently published guidelines updating the recommended pharmacologic agents for treatment or prevention of B. pertussis. Despite decades of successful vaccination programs, pertussis continues to be a problematic disease. Fortunately, data and vaccines are now available that make development of a pertussis booster vaccination campaign reasonable. However, until widespread compliance with such programs is achieved, clinicians need to maintain vigilance against pertussis.

Antibiotic lock technique: review of the literature.

Central venous catheters (CVCs) are frequently used for patients requiring long-term venous access. Catheter-related infection is a serious complication associated with extended use of a CVC and can result in catheter removal. The antibiotic lock technique, a controversial method for sterilizing the catheter lumen, involves instilling high concentrations of antibiotics with or without heparin into the catheter lumen for extended periods of time. Studies differ regarding the choice and concentrations of antibiotics, dwell times in the catheter lumen, presence of heparin in the antibiotic lock technique solution, use of systemic antibiotics with the technique, and use of the technique for prevention or treatment of catheter-related infections. Results of in vitro studies demonstrate that many antibiotic combinations are stable and maintain high drug concentrations for prolonged periods of time. In vivo studies report the success of multiple combinations for both prevention and treatment with antibiotic lock technique in salvaging these catheters.

The effect of an antimicrobial restriction program on Pseudomonas aeruginosa resistance to beta-lactams in a large teaching hospital.

STUDY OBJECTIVES: To compare the use of beta-lactams and subsequent Pseudomonas aeruginosa sensitivity patterns before and after implementation of a clinical pharmacist-facilitated antimicrobial restriction program in August 1997. DESIGN: Retrospective consecutive data collection. SETTING: Large university-affiliated medical center. INTERVENTION: The study results are the accumulation of the daily intervention activities of the antimicrobial restriction program. Data on antimicrobial grams purchased/1,000 patient-days and susceptibility patterns were collected and analyzed retrospectively. MEASURES AND MAIN RESULTS: Annual grams of ceftazidime, piperacillin, piperacillin-tazobactam, and other antipseudomonal beta-lactams purchased/1,000 patient-days were compared during the 2 full calendar years before the antimicrobial restriction program (1995-1996) with the 4 full calendar years after the program was implemented (1998-2001). Pseudomonas aeruginosa resistance trends for the antipseudomonal beta-lactams, ciprofloxacin, and tobramycin also were compared for the 2 years before the program (1995-1996) with the last 2 years of the program (2000-2001). A 44% reduction in ceftazidime use was documented; ostensibly, minimal changes occurred in the overall use of piperacillin and piperacillin-tazobactam. During the same time period, ceftazidime resistance fell from 24% to 11.8% (p<0.001), whereas piperacillin resistance fell from 32.5% to 18.5% (p<0.001). Imipenem resistance declined from 20.5% to 12.3% (p<0.001) with an 18% reduction in use. Aztreonam resistance declined from 29.5% to 16.5% (p<0.001) despite a 57% increase in use. No changes in resistance to either ciprofloxacin or tobramycin were found. CONCLUSION: Through an antimicrobial restriction program, a dramatic reduction in ceftazidime use was achieved with judicious use of other antipseudomonal antimicrobials, which resulted in reduced resistance of P aeruginosa to other beta-lactams.

Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy.

STUDY OBJECTIVE: To evaluate risk factors for the development of arthralgias or myalgias associated with quinupristin-dalfopristin. DESIGN: Retrospective chart review and case-control analysis. SETTING: An 850-bed tertiary care medical center. PATIENTS: All adult and pediatric patients who had received quinupristin-dalfopristin through either a compassionate-use protocol (February 1996-October 1999) or in the year after quinupristin-dalfopristin was added to the hospital formulary (November 1999-October 2000) were included in this study. Case patients were those who developed arthralgias or myalgias while receiving quinupristin-dalfopristin therapy; control patients were those who received quinupristin-dalfopristin but did not develop arthralgias or myalgias. INTERVENTION: Medical records, pharmacy dispensing information, and microbiology data were reviewed by a physician and a pharmacist, both of whom specialized in infectious diseases. Presence or absence of arthralgias or myalgias was the primary outcome assessed. MEASUREMENTS AND MAIN RESULTS: Quinupristin-dalfopristin was administered to 68 patients during the period defined by the study. Arthralgias and myalgias could not be assessed in 18 of the 68 patients because they were sedated and paralyzed, or they were young children who could not communicate the presence of pain. Univariate analysis demonstrated that significant risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin were female sex, chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, major surgery, and receipt of either mycophenolate or cyclosporine. Multivariate analysis demonstrated a strong association with chronic liver disease, receipt of liver transplant, elevated bilirubin level at baseline, and receipt of either cyclosporine or mycophenolate. Of 50 evaluable patients receiving quinupristin-dalfopristin, 25 had pain that may have been associated with this antimicrobial agent. CONCLUSION: The mechanism for development of arthralgias or myalgias associated with quinupristin-dalfopristin remains unknown, but these adverse events are more likely to occur in patients with chronic liver disease and those who have received a liver transplant or are receiving cyclosporine or mycophenolate.

Pharmacology update in adolescents: contraception and human papillomavirus vaccination.

The ideal contraceptive agent remains elusive for the adolescent population. Contraceptive failure is often caused by inappropriate or inconsistent use, and discontinuation within the first year is not uncommon. Various methods have been explored within the adolescent population to increase efficacy rates, minimize side effects, and prevent unwanted pregnancies. The use of intrauterine devices and continuous use of combined oral contraceptives may lead to greater efficacy because of the ease of use and reduction in menstrual symptoms. Recent literature supports the continued use of medroxyprogesterone for adolescents without time limits, and advances in emergency contraception have increased access and use, but have not affected pregnancy rates. Human papillomavirus infection is the most common sexually transmitted infection and is associated with genital warts and the risk for cervical, penile, anal, and vulvovaginal cancer caused by persistent infection. A quadrivalent vaccine is indicated for both males and females to prevent genital warts and cancer, whereas the bivalent vaccine is indicated only for females and cancer prevention. Vaccination rates remain low among adolescents, and except in Virginia and the District of Columbia, vaccination is not a requirement for school entry. Research is ongoing for a 2-dose vaccine to improve vaccination rates while maintaining efficacy. Education is critical to prevent future infections and enhance vaccination rates.

Evaluation of serum concentrations achieved with an empiric once-daily tobramycin dosage regimen in children and adults with cystic fibrosis.

OBJECTIVES: To assess the ability of an empiric once-daily dosing (ODD) tobramycin regimen to achieve desired serum concentrations in patients with cystic fibrosis (CF); to determine an optimal dosage regimen, using pharmacodynamic parameters; and to evaluate clinical response, adverse effects, and patient/parent satisfaction with ODD. METHODS: This was a prospective single-center trial in patients with CF who are 5 years of age and older requiring intravenous antibiotics. Tobramycin, 10 mg/kg every 24 hours, was infused over 60 minutes, and two serum concentrations were analyzed using 1-compartment pharmacokinetic modeling. Simulations were performed to identify dosage regimens that maximized desired pharmacodynamic parameters. Other data included demographics, symptoms, spirometry, adverse events, and satisfaction with ODD. RESULTS: A total of 14 children and 11 adults completed the study. Empiric doses resulted in mean peak tobramycin concentrations of 28.7 ± 5.5 mg/L and undetectable trough concentrations. Only 42% of patients achieved desired peak serum concentrations (20-30 mg/L) with the empiric regimen. A regimen of 12 mg/kg every 24 hours would achieve modified pharmacodynamic goals with an acceptable peak range of 20 to 35 mg/L. Forced expiratory volume in 1 second improved in 15 of 20 (75%) patients with ODD. Two patients experienced reversible vestibular adverse effects attributed to tobramycin. All patients were satisfied or very satisfied with ODD because of convenience and ease of use. CONCLUSIONS: An empiric tobramycin regimen of 10 mg/kg every 24 hours did not achieve desired serum concentrations for most patients, although all patients demonstrated clinical improvement. Desired tobramycin concentrations with modified pharmacodynamic goals could be achieved by using an empiric dosage of 12 mg/kg every 24 hours. Prospective evaluation of this regimen with individualized patient monitoring is needed to ensure safety and efficacy and to monitor the effects on microbial resistance patterns.

Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists.

Aerosolized delivery of antimicrobial agents is an attractive option for management of pulmonary infections, as this is an ideal method of providing high local drug concentrations while minimizing systemic exposure. With the paucity of consensus regarding the safety, efficacy, and means with which to use aerosolized antimicrobials, a task force was created by the Society of Infectious Diseases Pharmacists to critically review and evaluate the literature on the use of aerosolized antiinfective agents. This article summarizes key findings and statements for preventing or treating a variety of infectious diseases, including cystic fibrosis, bronchiecstasis, hospital-acquired pneumonia, fungal infections, nontuberculosis mycobacterial infection, and Pneumocystis jiroveci pneumonia. Our intention was to provide guidance for clinicians on the use of aerosolized antibiotics through evidence-based pharmacotherapy. Further research with well-designed clinical trials is necessary to elucidate the optimal dosage and duration of therapy and, of equal importance, to appreciate the true risks associated with the use of aerosolized delivery systems.