May 2011 FAQs
May 2011 FAQs
Is Fidaxomicin an Effective Future Treatment for Clostridium difficile Infection?
Is Fidaxomicin an Effective Future Treatment for Clostridium difficile Infection?
Clostridium difficile -associated diarrhea (CDAD) is becoming an increasing problem among hospitalized patients, with a reported tripling of the incidence since 1996. 1 Several risk factors have been identified for CDAD, including advanced age, antimicrobial exposure, cancer chemotherapy, and manipulations of the gastrointestinal tract (eg, surgery or tube feedings).2 Because of the morbidity and mortality associated with CDAD, effective and complete treatment is important.
Current Treatment Options for CDAD
Guidelines on the treatment of CDAD were published by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) in 2010.2 In addition to describing measures such as apppropriate infection control and antimicrobial stewardship, the guidelines provide specific recommendations for treatment of CDAD (see Table). However, treatment options are limited for patients with frequent relapses or with refractory CDAD. Probiotics, nitazoxanide, intravenous immunoglobulins, and rifaximin have been used with varying success.
Table. Current Treatment Recommendations for CDAD.2
CDAD episode Treatment Initial, mild to moderate Metronidazole 500 mg 3 times daily for 10 to 14 days Initial, severe Vancomycin 125 mg 4 times daily for 10 to 14 days Severe, complicated Vancomycin 500 mg 4 times daily with or without intravenous metronidazole 500 mg every 8 hours May be given orally or as a retention enema every 6 hours (in 100 mL normal saline) First recurrence Same regimen as for initial episode, stratified by severity Metronidazole should not be used beyond the first recurrence or for long-term treatmetn because of the risk of cumulative neurotoxicity Second or later recurrences Vancomycin with tapered or pulsed dosing
Fidaxomicin (Dificid, Optimer Pharmaceuticals) is a macrocyclic antibiotic currently under investigation for the treatment of C difficile infections in adults.3,4 In April 2011, the Anti-Infective Drugs Advisory Committee of the Food and Drug Administration (FDA) reviewed data on the safety and efficacy of fidaxomicin and recommended fidaxomicin for treatment for patients with severe CDAD.5 The New Drug Application (NDA) for fidaxomicin is expected to be reviewed by the FDA by May 30, 2011, under a 6-month priority review, for treatment of C difficile infection and for reducing the risk of recurrence of infection. Fidaxomicin was granted orphan status in December 2010 for treatment of C difficile in children 16 years and younger.3
The macrocyclics are a new class of antibiotics that exert their effects through inhibition of bacterial protein synthesis.4 Fidaxomicin is active against gram-positive aerobes and gram-negative anaerobes, similar to vancomycin. Reported minimum inhibitory concentrations (MICs) for fidaxomicin against C difficile have ranged from less than 0.016 to 0.25 mcg/mL. Fidaxomicin is poorly absorbed, with one pharmacokinetic study reporting near undetectable levels in 50% of enrolled patients.6 Over 90% of patients had serum concentrations of fidaxomicin of less than 20 ng/mL. Higher concentrations of the metabolite, OP-1118, were found but were still low. In contrast, fecal concentrations of the drug exceeded 90% MICs by 2000- to 10,000-fold, depending on the dose of fidaxomicin (100 to 400 mg/day).
One of 2 clinical trials on the efficacy of fidaxomicin in the treatment of C difficile infection has been published.7 This multicenter, double-blind, randomized trial enrolled 629 patients 16 years or older with a diagnosis of C difficile infection. Enrolled patients had diarrhea and stool specimens positive for C difficile toxin A, B, or both. Use of vancomycin or metronidazole (up to 4 doses) in the 24 hours prior to enrollment was allowed, but patients receiving other possible effective treatments, with life-threatening CDAD, or with more than one occurrence of C difficile infection in the previous 3 months were excluded. Randomized treatment consisted of fidaxomicin 200 mg every 12 hours (with vancomycin-placebo) or vancomycin 125 mg every 6 hours for 10 days. The primary outcome was the rate of clinical cure, defined as resolution of diarrhea, which was maintained for the duration of treatment with no additional treatments needed. Recurrence of C difficile infection (defined as return of diarrhea within 4 weeks, stool cultures positive for C difficile toxins, and need for retreatment) was a secondary outcome along with global cure. The primary outcome was assessed for noninferiority of fidaxomicin to vancomycin, based on a margin of -10% in the lower boundary of the confidence interval (CI) for clinical cure difference. Post-hoc analyses were used for the secondary outcomes.
Clinical cure was seen in 88.2% of the fidaxomicin group and in 85.8% of the vancomycin group, using a modified intention to treat approach; non-inferiority criteria was met based on the CI lower boundary (-3.1%).7 Similar results were found for a per-protocol approach, as the criteria for non-inferiority was also met (-2.6% CI lower boundary). Recurrence rates were significantly lower with fidaxomicin compared with vancomycin (15.4% vs. 25.3%, p=0.005), and global cure rates were significantly higher with fidaxomicin (74.6% vs. 64.1%, p=0.006); both analyses were based on the intention to treat group. The per-protocol results were similar. Both treatments were well-tolerated; serious adverse events were reported in 25% and 24% of the fidaxomicin and vancomycin groups, respectively. The study also determined the MICs for both fidaxomicin and vancomycin. For the majority of isolates, the MIC with fidaxomicin was 0.25 mcg/mL or less compared with 2 mcg/mL for vancomycin. Fidaxomicin fecal concentrations were 4900 times the 90% MIC for C difficile.
Although not yet FDA-approved, fidaxomicin appears to be a promising treatment for C difficile infection and CDAD. Compared to vancomycin, fidaxomicin resulted in similar clinical cure rates and significantly lower recurrence rates. As a member of a new class of antibiotics-the macrocyclics-fidaxomicin may offer an effective treatment, in addition to metronidazole and vancomycin, for patients with CDAD.
1. Kelly CP, LaMont JT. Clostridium difficile-more difficult than ever. N Engl J Med. 2008;359(18):1932-1940.
2. Cohen S, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
3. Optimar Pharmaceuticals. Product pipeline. Dificid. Available at : http://www.optimerpharma.com/fidaxomicin. Accessed April 27, 2011.
4. Sullivan KM, Spooner LM. Fidaxomicin: a macrocyclic antibiotic for the management of Clostridium difficile infection. Ann Pharmacother. 2010;44:352():352-359.
5. Medscape News. FDA panel gives new antibiotic fidaxomicin 2 thumbs up. Available at: http://www.medscape.com/viewarticle/740296?src=rss. Accessed April 28, 2011.
6. Louie T, Miller M, Donskey C, Mullane K, Goldstein EJC. Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2009;53(1):223-228.
7. Louie T, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
What is the Efficacy of Intravenous Levetiracetam for Acute Seizure Management in Adults and Children?
What is the Efficacy of Intravenous Levetiracetam for Acute Seizure Management in Adults and Children?
Status epilepticus is defined as an uninterrupted seizure that lasts for more than 30 minutes or multiple seizure episodes without recovery of consciousness between episodes.1 Since prolonged status epilepticus can result in permanent neurologic damage and death, this is considered a medical emergency that should be promptly treated with the goal of ending seizure activity. In adult patients, first-line treatment consists of a benzodiazepine such as lorazepam, diazepam, or midazolam, closely followed by a second-line anticonvulsant such as phenytoin, fosphenytoin, or phenobarbital. Multiple agents and repeat doses may be required for complete seizure control. Status epilepticus is considered refractory if seizure activity continues for more than 60 minutes despite appropriate therapy or fails to respond to first- or second-line therapy. Treatment options for refractory status epilepticus include continuous infusions of benzodiazepines, anticonvulsants, or propofol, or the addition of alternative anticonvulsants such as lacosamide, topiramate, levetiracetam, or ketamine. Management of initial and refractory status epilepticus in pediatric patients is similar to adult management.2 In neonates, status epilepticus is usually treated with phenobarbital, midazolam, phenytoin, or lidocaine.3
Rapid Levetiracetam Administration
Levetiracetam is available in both oral and injectable formulations. The injection is indicated for adjunctive therapy of partial onset and primary generalized tonic-clonic seizures and myoclonic seizures when oral therapy is temporarily not feasible.4 For these indications, levetiracetam is usually infused over 15 minutes. However, since the approval of the injectable formulation, numerous reports have been published describing its use for status epilepticus in adults, children, and neonates, often as a 5-minute infusion.5-29 Several studies have evaluated the safety of shorter infusion times in both adults and pediatrics, and minimal adverse reactions associated with the rate of administration have been reported.5-7 In one study, the most common adverse effects were dose-related dizziness and somnolence, which occurred in 53% an 33% of patients, respectively.7 These limited data suggest that rapid administration of IV levetiracetam over 5 minutes is well-tolerated.
Intravenous Levetiracetam for Status Epilepticus in Adults
Only one prospective study has evaluated the efficacy and safety of IV levetiracetam for refractory status epilepticus in adults.8 This non-randomized, evaluator-blinded study allocated 82 patients with continuing seizure activity despite therapy with IV lorazepam and phenytoin to either IV levetiracetam 30 mg/kg or IV valproate 30 mg/kg. Both drugs were administered at a rate of 5 mg/kg/min. At baseline, patients in the levetiracetam group were a mean age of 21 years and had been experiencing seizures for a median of 5 hours (range 2 to 84 hours). The valproate group was older (mean age 26 years) and had been experiencing seizures for a median of 4 hours (range 1 to 48 hours) at the time of study drug administration. The primary endpoint, seizure cessation after receipt of study drug, was achieved in 73.2% of patients in the levetiracetam group and 68.3% of patients in the valproate group (p=NS). Hospital length of stay was similar in both groups (p=0.903) and no adverse events were reported in either group. The authors concluded that levetiracetam appears to be a promising therapeutic option for refractory status epilepticus, but that larger studies are needed to confirm their findings.
Numerous retrospective studies support the use of IV levetiracetam in adult patients with status epilepticus.9-19 These studies are mostly limited to single-center observations in primarily elderly patients. The largest retrospective study involved 43 elderly patients (mean 67 years; range. 43 to 92 years) with primarily new-onset seizures due to acute conditions such as stroke, hypoxia, and dementia. In this study, IV levetiracetam 1000 or 2000 mg was effective for simple focal, complex focal, and myoclonic seizures (overall termination rate of 44.2%).9 No generalized tonic-clonic seizures were successfully terminated. Serious adverse effects were not reported, but prolonged somnolence was observed in patients older than 80 years of age.
Another retrospective study included 40 patients (mean 63.5 years; range, 19 to 92) with status epilepticus who received IV levetiracetam in addition to a standard protocol of a benzodiazepine and either phenytoin or valproate.10 Most patients received a levetiracetam loading dose (mean 1275 mg) followed by maintenance therapy. Termination of seizures was seen in 57.5% of patients after an average of 14.4 hours. Seizure termination was more likely when IV levetiracetam was given second-line after benzodiazepines rather than third-line after other anticonvulsants (78% efficacy vs. 46%, p=0.048). The most common adverse effect was somnolence, but the proportion of patients experiencing this effect was not reported.
Several retrospective studies have commented on risk factors for response or lack of response to IV levetiracetam therapy.11,12 Moddel and colleagues conducted a chart review of 36 patients (mean 70.5 years, range 34 to 96 years) with persistent status epilepticus despite therapy with at least one anticonvulsant (benzodiazepines, phenytoin, or valproate).11 Seizure termination was successfully achieved in 69% of patients after IV levetiracetam therapy (median dose 3000 mg/day). In this cohort, response was more likely when a levetiracetam loading dose was administered (p=0.002 vs. no loading dose) and when study drug was given within 48 hours of symptom onset (p<0.001 vs. starting after 48 hours). In contrast, lack of response to IV levetiracetam was associated with age >80 years old, subtle status epilepticus, periodic lateralized epileptiform discharges, acute lesions such as stroke and intracranial hemorrhage, previous failure to respond to phenytoin or valproate, and need for intubation (all p<0.05). A similar study in 34 patients (mean 64 years, range 11 to 90 years) with status epilepticus who failed to respond to one or more anticonvulsants identified cryptogenic and primarily generalized status epilepticus, presence of brain anoxia, and previous use of IV phenytoin or valproate as potential risk factors for lack of response to IV levetiracetam.12
Of note, many clinicians have an interest in using IV levetiracetam for patients with status epilepticus because it is not associated with many of the issues that complicate use of other parenteral anticonvulsants. For example, sedation is less likely with levetiracetam than benzodiazepines, and levetiracetam has a lower potential for drug interactions than phenytoin due to lack of hepatic metabolism.4 In particular, IV levetiracetam may be safer than first- and second-line anticonvulsants in elderly patients. Many elderly patients were included in the studies previously discussed. 9-12 In addition, 2 retrospective studies specifically evaluated efficacy and safety of IV levetiracetam in elderly patients for whom clinicians wanted to avoid use of conventional treatments.16,17 A small retrospective cohort study included 9 patients with status epilepticus and concomitant respiratory failure, cardiac arrhythmia, or hepatitis C.16 The mean patient age was 76 years (range, 65 to 91 years). In these patients, IV levetiracetam 1500 mg resulted in seizure cessation in 8 (89%) of the 9 patients, and there were no notable adverse events. In contrast, sedation and somnolence were reported by 4 (28.6%) of 14 elderly patients (mean 73.9 years, range 61 to 97 years) who received IV levetiracetam for emergent seizures in a retrospective study conducted by Beyenburg and colleagues. However, these adverse neurological effects may have been partially due to prior use of IV benzodiazepines and IV valproate.17 Although further data are needed, currently available studies support the efficacy and safety of IV levetiracetam for acute seizure management in elderly patients.
Patients with Critical Illness
Two retrospective studies describe the use of IV levetiracetam in critically ill patients.18,19 Nau and colleagues evaluated a cohort of 29 patients (mean55.1 ± 18.5 years) with acute seizures in the intensive care unit (ICU).18 At baseline, 34.5% of these patients had elevated serum creatinine levels, 37.9% had elevated bilirubin, and 58.6% had elevated liver function tests, making use of first-line anticonvulsants undesirable. After administration of IV levetiracetam, 93% experienced seizure cessation, and no major adverse events were noted. Another retrospective study included 50 patients in the ICU (mean 59.7 ± 17.8 years) who received IV levetiracetam 20 mg/kg for status epilepticus or other acute seizures in addition to lorazepam (40%), phenytoin (36%), and/or valproate (32%).19 Seven patients received levetiracetam prophylactically. In this study, the drug was given parenterally because patients were unable to take oral medications. Seizures stopped in 67% of patients, and no serious adverse effects were reported. These studies suggest that IV levetiracetam appears to be an effective and safe anticonvulsant option in critically ill patients.
Intravenous Levetiracetam for Pediatric Seizures
Although the parenteral formulation is not approved for use in pediatric patients, several studies support the use of IV levetiracetam for acute seizures in neonates, infants, and children.20-29
The largest prospective study with IV levetiracetam in pediatric patients was an uncontrolled, open-label evaluation in 38 neonates with EEG-confirmed seizures.20 All patients were in the neonatal intensive care unit at the time of the study, and groups were stratified according to gestational age (GA) at the time of enrollment. Nineteen extremely premature infants (median GA 26 weeks, median birth weight 842 g), 6 premature infants (median GA 31 weeks, median birth weight 1442 g), and 13 term infants (median GA 41 weeks, median birth weight 3495 g) were enrolled. Seizures were described as status epilepticus in 7 patients and as repetitive seizures in the remaining 31 patients. Levetiracetam was administered IV at an initial dose of 10 mg/kg twice daily followed by dose titration over 3 days to 30 mg/kg twice daily. At the end of the first week the dose could be further increased to a maximum of 60 mg/kg if needed. Concurrent phenobarbital was used in 42% of the extremely premature group, 67% of the premature group, and 54% of the term group; no other anticonvulsants were permitted. Intravenous levetiracetam was switched to oral therapy when patients were able to tolerate oral feeding. After 1 week of levetiracetam monotherapy, 79%, 75%, and 50% of patients in the extremely premature, premature, and term groups, respectively, were seizure-free. At the same time, only 21%, 25%, and 50% of patients who had also received phenobarbital were seizure-free, indicating that these patients may have had more treatment-resistant seizures. The only adverse effect noted was drowsiness, which occurred most commonly during the titration phase in patients receiving concurrent phenobarbital. This study suggests that IV levetiracetam monotherapy effectively reduces neonatal seizures, but further data are needed to confirm the efficacy and safety in combination with phenobarbital.
A retrospective study by Khan and colleagues evaluated 22 term neonates who received IV levetiracetam during the first 28 days of life.21 The mean GA was 39.3 ± 1.03 weeks and the mean birth weight was 3.419 ± 0.57 kg. Hypoxic ischemia was noted as the seizure etiology in 55% of patients, and most experienced partial seizures with or without secondary generalization. A levetiracetam 50 mg/kg IV loading dose was administered to 20 patients, and all 22 patients received maintenance doses of 10 to 25 mg/kg every 8 to 12 hours. Other anticonvulsants (most commonly phenobarbital) were administered to 86% of patients, and levetiracetam was initiated a mean of 1.5 ± 2.28 days (range 0 to 9 days) after these other therapies. Efficacy of IV levetiracetam add-on therapy was high, as 86% of patients experienced immediate seizure cessation within 1 hour, and 64% were completely seizure-free by 24 hours. Only one patient experienced an adverse effect (increased irritability) attributable to study medication , highlighting the safety of IV levetiracetam in term neonates.
Infants and Children
One prospective study has evaluated the use of IV levetiracetam in children, with a focus on safety.22 Thirty pediatric patients (mean 6.3 years, range 0.5 to 14.8 years) with a need for acute add-on anticonvulsant therapy were included; patients deemed clinically unstable were excluded. The most common seizure types were symptomatic generalized (n=9) and idiopathic generalized (n=8). At enrollment, patients were receiving a mean of 1.3 other anticonvulsants. Vital signs were monitored for 2 hours after administration of levetiracetam 50 mg/kg (maximum 2500 mg) IV over 15 minutes. The overall rate of seizure cessation was 57.7%, and an additional 38.5% experienced a reduction in seizure activity of at least half. Adverse effects included feelings of sleepiness or fatigue in 3 patients. Overall, the investigators felt that IV levetiracetam was effective and well-tolerated.
The 2 largest retrospective pediatric studies with IV levetiracetam included 73 and 32 patients, respectively.23,24 In the larger study by Reiter and colleagues, patients received IV levetiracetam within 30 minutes of an acute seizure after concurrent therapy with benzodiazepines (83.4%), phenytoin (17.8%), and/or other anticonvulsants (8.3%). Most patients required treatment for a series of seizures (79%), and 8% of patients had status epilepticus. The median age was 3.92 years (range, 1 day to 17.8 years). The mean IV levetiracetam dose was 29.4 ± 13.5 mg/kg (range, 6.6 to 89 mg/kg). When the odds of remaining seizure-free after IV levetiracetam were compared, patients with a single seizure were more likely to remain seizure-free compared to those with repetitive seizures or status epilepticus. Adverse effects reported in this study included aggression, irritability, mood swings, gastrointestinal upset, ataxia, and increased hunger. Response to IV levetiracetam in the setting of status epilepticus in children was also observed in a retrospective study of 32 patients (range,2 months to 18 years).24 Most patients in this study (69%) had complex partial seizures, and 57% had received initial treatment with lorazepam and phenytoin. The authors stated that all patients responded to levetiracetam clinically and on EEG within 25 to 30 minutes. Two patients experienced adverse effects that may have been related to treatment (rash and unspecific behavioral issues).
Numerous studies describe the use of IV levetiracetam for acute seizure management in adult and pediatric patients. Although prospective data are lacking and most studies are relatively small, retrospective data suggest that IV levetiracetam effectively terminates acute seizures/status epilepticus in 44% to 89% of adults and 50% to 79% of pediatric patients. These data should be interpreted cautiously due to the lack of control groups in all of the retrospective trials. Also, seizure cessation cannot be definitively attributed to levetiracetam alone since most patients received concurrent anticonvulsants. Few adverse effects were reported with IV levetiracetam but larger studies are needed to confirm the safety of this treatment strategy. Until further data are available, IV levetiracetam should be reserved as a third-line anticonvulsant in adults with acute seizure who do not respond to more established therapies such as benzodiazepines and phenytoin. In pediatric patients, IV levetiracetam may be an appropriate option in patients with contraindications (such as hepatic dysfunction) to first-line treatments, but its role in combination with other drugs such as phenobarbital remains the subject of future study.
1. Tesoro EP, Brophy GM. Pharmacological management of seizures and status epilepticus in critically ill patients. J Pharm Pract. 2010;23(5):441-454.
2. Owens J. Medical management of refractory status epilepticus. Semin Pediatr Neurol. 2010;1(3):176-181.
3. Lawrence R, Inder T. Neonatal status epilepticus. Semin Pediatr Neurol. 2010;17(3):163-168.
4. Keppra injection [package insert]. Smyrna, GA: UCB, Inc.; 2008.
5. Uges JWF, van Huizen MD, Engelsman J, et al. Safety and pharmacokinetics of intravenous levetiracetam infusions as add-on in status epilepticus. Epilepsia. 2009;50(3):415-421.
6. Wheless JW, Clarke D, Hovinga CA, et al. Rapid infusion of a loading dose of intravenous levetiracetam with minimal dilution: a safety study. J Child Neurol. 2009;24(8):946-951.
7. Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomized, placebo-controlled safety and pharmacokinetic study. Epilepsia. 2006;47(7):1128-1135.
8. Tripathi M, Vibha Dr. Choudhary N, et al. Management of refractory status epilepticus at a tertiary care centre in a developing country. Seizure. 2010;19(2):109-111.
9. Eue S, Grumbt M, Muller M, Schulze A. Two years of experience in the treatment of status epilepticus with intravenous levetiracetam. Epilepsy Behav. 2009;15(4):467-469.
10. Aiguabella M, Falip M, Villanueva V, et al. Efficacy of intravenous levetiracetam as an add-on treatment in status epilepticus: a multicentric observational study. Seizure. 2011;20(1):60-64.
11. Moddel G, Bunten S, Dobis C, et al. Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus. J Neurol Neurosurg Psychiatry. 2009;80(6):689-692.
12. Gamez-Leyva G, Aristin JL, Fernandez E, Pascual J. Experience with intravenous levetiracetam in status epilepticus. CNS Drugs. 2009;23(11):983-987.
13. Berning S, Boesebeck F, van Baalen A, Kellinghaus C. Intravenous levetiracetam as treatment for status epilepticus. J Neurol. 2009;256(10):1634-1642.
14. Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodiazepine refractory status epilepticus. J Neurol Neurosurg Psychiatry. 2008;79(5):588-589.
15. Patel NC, Landan IR, Levin J, Szaflarski J, Wilner AN. The use of levetiracetam in refractory status epilepticus. Seizure. 2006;15(3):137-141.
16. Fattouch J, Di Bonaventura C, Casciato S, et al. Intravenous levetiracetam as first-line treatment of status epilepticus in the elderly. Acta Neurol Scand. 2010;121(6):418-421.
17. Beyenburg S, Reuber M, Maraite N. Intravenous levetiracetam for epileptic seizure emergencies in older people. Gerontology. 2009;55(1):27-31.
18. Nau KM, Divertie GD, Valentino AK, Freeman WD. Safety and efficacy of levetiracetam for critically ill patients with seizures. Neurocrit Care. 2009;11(1):34-37.
19. Ruegg S, Naegelin Y, Hardmeier M, Winkler DT, Marsch S, Fuhr P. Intravenous levetiracetam: treatment experience with the first 50 critically ill patients. Epilepsy Behav. 2008;12(3):477-480.
20. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011;15(1):1-7.
21. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol. 2011;44(4):265-269.
22. Ng Y, Hastriter EV, Cardenas JF, Khoury EM, Chapman KE. Intravenous levetiracetam in children with seizures: a prospective safety study. J Child Neurol. 2010;25(5):551-555.
23. Reiter PD, Huff AD, Knupp KG, Valuck RJ. Intravenous levetiracetam in the management of acute seizures in children. Pediatr Neurol. 2010;43(2):117-121.
24. Kirmani BF, Crisp ED, Kayani S, Rajab H. Role of intravenous levetiracetam in acute seizure management of children. Pediatr Neurol. 2009;41(1):37-39.
25. Goraya JS, Khurana DS, Valencia I, et al. Intravenous levetiracetam in children with epilepsy. Pediatr Neurol. 2008;38(3):177-180.
26. Michaelides C, Thibert RL, Shapiro MJ, et al. Tolerability and dosing experience of intravenous levetiracetam in children and infants. Epilepsy Res. 2008;81(2-3):143-147.
27. Abend NS, Monk HM, Licht DJ, Dlugos DJ. Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures. Pediatr Crit Care Med. 2009;10(4):505-510.
28. Gallentine WB, Hunnicutt AS, Husain AM. Levetiracetam in children with refractory status epilepticus. Epilepsy Behav. 2009;14(1):215-218.
29. Depsitario-Cabacar DT, Peters JM, Pong AW, et al. High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy. Epilepsia. 2010;51(7):1319-1322.
What are the Latest Guidelines for Prevention of Intravascular Catheter-related Infections?
What are the Latest Guidelines for Prevention of Intravascular Catheter-related Infections?
Updated guidelines for the prevention of intravascular catheter-related infections have been published ahead of print (April 1, 2011) on the Infectious Diseases Society of America's (IDSA) website.1 The guidelines replace the previous version (published in 2002). The guidelines were developed by a working group led by the Society of Critical Care Medicine in collaboration with the following organizations:
- American Academy of Pediatrics (AAP)
- American College of Chest Physicians (ACCP)
- American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.)
- American Society of Critical Care Anesthesiologists (ASCCA)
- American Thoracic Society (ATS)
- Association for Professionals in Infection Control and Epidemiology (APIC)
- Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention (CDC)
- Infectious Diseases Society of America (IDSA)
- Infusion Nurses Society (INS)
- Oncology Nursing Society (ONS)
- Pediatric Infectious Diseases Society (PIDS)
- Society for Healthcare Epidemiology of America (SHEA)
- Society of Interventional Radiology (SIR)
- Surgical Infection Society (SIS)
The guidelines focus on 5 key content areas including education and training of healthcare providers; sterile barrier precautions during insertion; use of > 0.5% chlorhexidine gluconate skin preparation with alcohol; avoidance of routine catheter replacement; and use of antiseptic/antibiotic impregnanted short-term central venous catheters (CVCs) and chlorhexidine gluconate-impregnated sponge dressings if rate of infection is not decreasing despite other strategies.1 This summary will provide a general overview, but focus on issues that relevant to pharmacists. The reader is encourage to view the entire document for further information: http://cid.oxfordjournals.org/content/early/2011/04/01/cid.cir257.full.pdf+html
Intravascular Catheter-related Infections
In terms of background, it is estimated that 15 million CVC-days occur in intensive care units (ICUs) in the United States annually.1 About 80,000 catheter-related bloodstream infections (CRBSIs) occur in ICUs every year, whereas the number increases to 250,000 when considering the entire hospital. Catheter-related bloodstream infection and central line-associated bloodstream infections (CLABSIs) are terms that are often used interchangeably; however, they have different meanings. To meet the definition of a CRBSI, there must be laboratory evidence that identifies the catheter as the source of infection. This term is not routinely used for surveillance purposes; in contrast, CLABSI is used by the CDC for such purposes. A CLABSI is a primary bloodstream infection in a patient who had a central line within 48 hours prior to the development of the infection. The most common pathogens implicated in CLABSIs include coagulase-negative staphylococci, Staphylococcus aureus, enterococci, and Candida species. The incidence of methicillin-resistant S aureus (MRSA) CLABSIs has declined in recent years. Catheter contamination is generally due to 1 of 4 reasons: skin organisms contaminating the catheter tip, direct contamination of the catheter or the hub, seeding from an infection at a different site, or infusate contamination (rare). The Table summarizes select recommendations from the guidelines that may be relevant to pharmacists.
Table. Select Recommendations for Prevention of Intravascular Catheter-related Infections.1
Section Recommendation Comments CVCs No recommendation can be made as to whether or not a designated lumen should be used for parenteral nutrition. This is considered an unresolved issue with no consensus. Skin preparation Peripheral venous catheters: prepare skin with 70% alcohol, tincture of iodine, an iodophor, or chlorhexidine gluconate. A meta-analysis suggested that skin preparation with chlorhexidine gluconate reduced the incidence of catheter-related infection by 49% compared to povidone-iodine. CVCs and peripheral arterial catheters: prepare skin with >0.5% chlorhexidine gluconate with alcohola; if the patient has a contraindication to chlorhexidine gluconate, tincture of iodine, an iodophor, or 70% alcohol can be used. Catheter site dressing regimens Topical antibiotic ointments/creams are not recommended for use on catheter insertion sites, with the exception of dialysis catheters. Use of such products can promote the occurrence of fungal infections and antimicrobial resistance. Antibiotic/ antiseptic ointments Povidone-iodine or bacitracin/gramicidin/polymyxin B ointment can be used at the hemodialysis catheter exit site after insertion and at the end of each dialysis session. Follow the manufacturer of the hemodialysis catheter's recommendations in terms of interactions with such solutions/ointments. Antimicrobial/ antiseptic impregnanted catheters and cuffs If the rate of CLABSIs is not declining despite the implementation of a comprehensive strategy to reduce such infections, the use of chlorhexidine/silver sulfadiazine or minocycline/rifampin impregnated CVCs are recommended for patients whose catheters are expected to remain in place for >5 days. There are 3 components to the comprehensive strategy:
1. Education for professionals who insert and maintain catheters
2. Maximal use of sterile barrier precautions
3. >0.5% chlorhexidine gluconate preparation with alcohol for skin antispepsis (CVC insertion)
No such catheters are marketed at this time for infants who weigh less than 3 kg.
Prophylactic systemic antibiotics Routine administration of systemic antibiotics is not recommended for use as prophylaxis prior to insertion or during use of a catheter. Insufficient data exist to support any value to routine use of systemic antibiotics for this purpose. Antibiotic-lock prophylaxis Prophylactic antimicrobial-lock solutions can be used in patients with long-term catheters who have a history of multiple line infections despite adherence to aseptic technique. No specific agent or combination of agents is recommended. Several antibiotics have been used including vancomycin, gentamicin, amikacin, ciprofloxacin, minocycline, cefazolin, cefotaximine, and ceftazidime.
An anticoagulant (eg heparin or EDTA) is commonly given with the antibiotic in the lock solution.
Umbilical catheters Low-dose heparin (0.25 to 1 unit/mL) should be added to fluid infused through umbilical catheters. Pharmacists can play a role in ensuring that the proper concentration of heparin is available in the NICU. Administration set replacement Tubing used to administer blood or blood products or fat emulsion should be replaced within 24 hours after starting the infusion. In general, administration sets are recommended to be changed every 7 days. However, patients receiving blood products, lipids, or propofol require more frequent changes due to the risk for infection with these agents. Tubing used to administer propofol should be changed every 6 or 12 hours, when the vial is changed. This recommendation is according to the manufacturers' labeling and an FDA MedWatch alert.
Abbreviations: CLABSI(s), central line-associated bloodstream infection(s); CVCs, central venous catheters; FDA, Food and Drug Administration; IV, intravenous; NICU, neonatal intensive care unit.
a Alcohol increases the effectiveness of chlorhexidine gluconate, and the alcohol begins to kill bacteria and inactivate viruses immediately.2
The updated guidelines for prevention of intravascular catheter-related infections, a collaborative effort among many stakeholders, have been published. Pharmacists are encouraged to become familiar with the new guidelines, especially sections that are relevant to drug therapy. One area that requires further investigation is the use of antibiotic-lock solutions. Although such practice is supported by the guidelines, data are too limited to allow for recommendation of specific agents.
1. O'Grady NP, Alexandar M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis. 2011;52. http://cid.oxfordjournals.org/content/early/2011/04/01/cid.cir257.full.pdf+html . Accessed April 25, 2011.
2. Stokowski LA. Chlorhexidine in healthcare: your questions answered. http://www.medscape.com/viewarticle/726075. Accessed April 26, 2011.
What are the Efficacy and Safety Data Supporting the Use of Roflumilast in the Treatment of COPD?
What are the Efficacy and Safety Data Supporting the Use of Roflumilast in the Treatment of COPD?
Chronic obstructive pulmonary disease (COPD) is defined as airflow limitation that is progressive and not fully reversible.1 Chronic obstructive pulmonary disease is caused by chronic inflammation that causes structural changes in the peripheral airways, lung parenchyma, and pulmonary vasculature. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, there are 4 stages of COPD based on forced expiratory volume in 1 second (FEV1). The severity of COPD, which ranges from mild to very severe, will help determine what medications should be used in treatment. Medications currently used in the treatment of COPD aim to prevent and control symptoms and reduce frequency of exacerbations but do not modify the long-term progression of the disease. Short-acting bronchodilators are used on an as needed basis in all stages of COPD. In patients with moderate disease, long-acting bronchodilators can be added to improve symptoms. Inhaled corticosteroids are used in patients with severe or very severe COPD to decrease the rate of exacerbations. Roflumilast (Daliresp) is the first oral agent indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.2 The dose of roflumilast is 500 mcg orally once daily and can be taken without regard to meals. Roflumilast and its active metabolite, roflumilast N-oxide, are selective phosphodiesterase-4 (PDE4) inhibitors and inhibit all subtypes of PDE4.3,4 Even though the exact mechanism of roflumilast in COPD is unknown, it is thought that by inhibiting PDE4 expressed on immune and pro-inflammatory cells, roflumilast will result in multiple anti-inflammatory effects. There is no evidence to suggest that roflumilast has any bronchodilation effect.5 Roflumilast is metabolized by cytochrome (CYP) 3A4 and CYP1A2 and is a weak inducer of CYP2B6.2-5 Unlike the non-selective PDE inhibitor, theophylline, there are few drug-drug interactions with roflumilast. The adverse effects associated with roflumilast include nausea, diarrhea, weight loss, and psychiatric side effects such as suicide, insomnia, anxiety, and depression. In April 2010, the Food and Drug Administration (FDA) advisory committee recommended against the approval of roflumilast in COPD due to the adverse effects of the medication outweighing the modest improvement of lung function.6 However, the FDA did not take the recommendation and roflumilast was FDA-approved in March 2011.7 A summary of the literature is provided below.
Roflumilast has been studied in 4 randomized, prospective, double-blind, placebo-controlled studies (see Table).8-11 The main endpoints of the 4 studies were change in FEV1 and rate of COPD exacerbations. Concomitant medications, such as inhaled corticosteroids or long-acting bronchodilators, allowed in each study varied. All 4 studies showed a significant difference in either pre-bronchodilator FEV1 or post-bronchodilator FEV1 when compared to placebo. The results for exacerbation rates in the studies were mixed. The studies performed by Calverley and colleagues (2009) and Rabe and colleagues showed a significant difference in exacerbation rate when comparing roflumilast to placebo, whereas the other 2 studies did not show a difference in exacerbation rates. Across the 4 studies, more patients on roflumilast discontinued treatment more often than the patients receiving placebo. The most common adverse effects reported include diarrhea, nausea, and weight loss. Insomnia was the only psychiatric side effect that occurred in significantly more patients on roflumilast compared to placebo, and this was the case only in one of the studies.9 There were also no differences in cardiovascular adverse events or pneumonia when comparing roflumilast to placebo, which are side effects of theophylline and inhaled corticosteroids.
Table. Studies Evaluating Roflumilast in the Treatment of COPD.8-11
Citation Design Population Intervention Outcomes and Conclusion Calverley 20098 Prospective, double-blind, randomized, placebo-controlled multicenter study
Results are a pooled analysis of 2 studies
- ≥ 40 years
- ≥ 20 pack-year history
- FEV1≤ 50% predicted
- COPD exacerbation within the previous year
- Chronic cough and sputum production
500 mcg oral ROF once daily (n=1537) or PLA (n=1554) for 52 weeks
Patients could remain on COPD medications except for ICSs or long-acting anticholinergics
- Change in pre-bronchodilator FEV1: difference of 48 mL (40 mL in ROF vs. -9 mL in PLA) (95% CI 35 to 62 mL) p<0.0001
- Moderate or severe exacerbations (mean rate, per patient per year): 1.14 ROF vs. 1.37 PLA; RR 0.83 (95% CI 0.75 to 0.92); p=0.0003
- Change in post-bronchodilator FEV1: 50 mL ROF vs -4 mL PLA; difference of 55 mL (95% CI 41 to 69); p<0.0001
- Time to mortality: 206.1 days ROF vs 211.7 days in PLA; HR 1.1 (95% CI 0.7 to 1.8) p=0.5452
- ADRs: more patients on ROF had diarrhea, weight loss (mean weight loss of 2.09 kg)
Fabbri 20099 Prospective, double-blind, placebo controlled multicenter study
Results are a pooled analysis of 2 studies
- > 40 years
- ≥ 10 pack-year history
- FEV1 of 40% to 70% predicted
- History of COPD for at least 12 months
- Chronic cough and sputum production (tiotropium study only)
- Frequent use as-needed short-acting β-agonist (≥ 28 puffs/week) (tiotropium study only)
2 different studies: 1. Oral ROF 500 mcg daily + salmeterol (n = 466) or PLA + salmeterol (n = 467) for 24 weeks 2. Oral ROF 500 mcg daily + tiotropium (n = 371) or PLA + tiotropium (n = 372) for 24 weeks
Patients were not allowed to use ICSs, short-acting anticholinergics, other long-acting bronchodilators, theophylline or other respiratory drugs
Salmeterol + ROF vs. salmeterol + PLA:
- Change in mean pre-bronchodilator FEV1: 39 mL ROF vs -10 mL PLA; difference of 49 mL (95% CI 27 to 71); p<0.0001
- Change is post-bronchodilator FEV1: 68 mL ROF vs 8 mL PLA; difference of 60 mL (95% CI 38 to 62); p<0.0001
- Change in pre-bronchodilator FVC: 32 mL ROF vs -14 mL PLA; difference of 47 mL (95% CI 10 to 84); p=0.0128
- Change in post-bronchodilator FVC: 67 mL ROF vs 10 mL PLA; difference of 58 mL (95% CI 20 to 95); p=0.0028
- Mild, moderate, or severe exacerbation (mean rate, per patient per year): 1.9 (95% CI 1.5 to 2.5) ROF vs 2.4 (95% CI 1.9 to 3.1); RR 0.79 (95% CI 0.58 to 1.08); p=0.1408
- ADRs: Mean change in bodyweight: -2.0 kg ROF vs +0.2 kg PLA
Tiotropium + ROF vs tiotropium + PLA:
- Change in mean pre-bronchodilator FEV1: 65 mL ROF vs -16 mL PLA; difference of 80 mL (95% CI 51 to 110); p<0.0001
- Change is post-bronchodilator FEV1: 74 mL ROF vs -7 mL PLA; difference of 81 mL (95% CI 51 to 110); p<0.0001
- Change in pre-bronchodilator FVC: 54 mL ROF vs -41 mL PLA; difference of 95 mL (95% CI 47 to 143); p=0.0001
- Change in post-bronchodilator FVC: 27 mL ROF vs -74 mL PLA; difference of 101 mL (95% CI 45 to 156); p=0.0004
- Mild, moderate, or severe exacerbation (mean rate, per patient per year): 1.8 (95% CI 1.3 to 2.5) ROF vs 2.2 (95% CI 1.7 to 2.9); RR 0.84 (95% CI 0.57 to 1.23); p=0.3573
- ADRs: Mean change in bodyweight: -1.8 kg ROF vs +0.3 kg PLA
Calverley 200710 Prospective, randomized, multicenter, double-blind, placebo- controlled, parallel group study
- ≥ 40 years old
- ≥ 10 pack year history
- Post-bronchodilator FEV1 ≤ 50% predicted
500 mcg oral ROF (n = 760) or PLA (n = 753) once daily in the morning for 52 weeks
Inhaled corticosteroids of 2000 mcg or less of beclomethas1dipropionate or equivalent and short-acting anticholinergics were allowed at constant dose if used prior to study
- Change in post-bronchodilator FEV1: 12 mL ROF vs -26 mL PLA; difference of 39 mL; p=0.001
- Change in pre-bronchodilator FEV1: 9 mL ROF vs -27 mL PLA; difference of 36 mL; p<0.002
- Change in post-bronchodilator FVC: -33 mL ROF vs -80 mL PLA; difference of 48 mL; p=0.091
- Moderate or severe exacerbation rate (per patient per year): 0.857 ROF vs 0.918 PLA; rate ratio 0.934; p=0.451
- Moderate or severe exacerbation requiring systemic corticosteroids (per patient per year): 0.474 ROF vs 0.549 PLA; rate ratio 0.864; p=0.183
- ADRs: Diarrhea (9.3%), nausea (5%) and headache (6.2%) were the most common treatment-related adverse events. The incidence of pneumonia was similar in each group.
Rabe 200511 Prospective, randomized, multicenter, double-blind, placebo-controlled study
- ≥ 40 years old
- ≥ 10 pack year history
- History of COPD > 12 months
- Post-bronchodilator FEV1 of 30% to 80% predicted
250 mg ROF (n = 578), 500 mcg ROF (n = 555) or PLA (n = 280) once daily for 24 weeks
Salbutamol (rescue medication) and short-acting anticholinergics at a constant dose were allowed during the study
Change from baseline in post-bronchodilator FEV1:
- ROF 250 mcg = 29 mL; ROF 500 mcg = 51 mL; PLA = -45 mL
- Difference vs PLA: ROF 250 mcg = 74 mL (p<0.0001); ROF 500 mcg = 97 mL (p<0.0001)
Change in SGRQ Score:
- ROF 250 mcg = -3.4 units; ROF 500 mcg = -3.5 units; PLA = -1.8 units
- Differences in scores vs PLA were not statistically significant
Change in pre-bronchodilator FEV1:
- ROF 250 mcg = 24 mL; ROF 500 mcg = 49 mL; PLA = -39 mL
- Difference vs PLA: ROF 250 mcg = 64 mL (p=0.0006); ROF 500 mcg = 88 mL (p<0.0001)
Change in post-bronchodilator FVC
- ROF 250 mcg = -4 mL; ROF 500 mcg = 39 mL; PLA = -75 mL;
- Difference vs PLA: ROF 250 mcg = 71 mL (p=0.0193); ROF 500 mcg = 114 mL (p=0.0002)
- The percentage of patients who had any exacerbation was lower in the ROF 500 mcg (28%)group than in the 250 mcg (36%) or PLA (35%) group (p=0.0114)
- Mean number of exacerbations per patient: ROF 250 mcg = 1.03; ROF 500 mcg = 0.75; PLA = 1.13 (p=0.0029)
- Rate of total exacerbations was 34% lower in ROF 500 mcg group than in the PLA group
- Adverse events regarded as likely to related to study medication: diarrhea, nausea, and headache
Abbreviations: ADRs, adverse drug reactions; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, force expiratory volume in 1 second; FVC, force vital capacity; HR, hazard ratio; ICSs, inhaled corticosteroids; PLA, placebo; ROF, roflumilast; SGRQ, St. George's respiratory questionnaire; SGRQ is a disease-specific instrument used to assess health-related quality of life in patients with COPD.11
The place in therapy of roflumilast in the treatment of COPD is still uncertain. Roflumilast is currently indicated to reduce the risk of COPD exacerbations in patients with severe COPD. Inhaled corticosteroids are also used in COPD to decrease the risk of exacerbations. Compared to inhaled corticosteroids, roflumilast may be more advantageous in that it can be taken orally once a day, instead of inhaled twice daily like the corticosteroids. However, the adverse effect profile of roflumilast may limit its use in COPD patients. Due to the inconsistent rates of decreased exacerbation in clinical studies, roflumilast does not currently have a specific place in therapy in COPD. Head-to-head studies comparing roflumilast to inhaled corticosteroids are needed to determine if there is any benefit in using roflumilast over inhaled corticosteroids to decrease COPD exacerbations.
1. From the Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. http://www.goldcopd.org. Accessed March 29, 2011.
2. Daliresp [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2010.
3. Sanford M. Roflumilast: in chronic obstructive pulmonary disease. Drugs. 2010;70(12):1615-1627.
4. Gross NJ, Giembycz MA, Rennard SI. Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor. COPD. 2010;7(2):141-153.
5. Giembycz MA, Field SK. Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010;4:147-158.
6. Hitt E. Medscape Medical News. FDA panel votes against roflumilast for COPD. http://www.medscape.com/viewarticle/720010_print. Accessed March 25, 2011.
7. Forrest announces FDA approval of Daliresp (roflumilast) as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbation. [Press Release]. New York, NY: Business Wire; March 1, 2011. http://frx.com/news/PressRelease.aspx?ID=1534051. Accessed March 25, 2011.
8. Calverley, PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694.
9. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703.
10. Calverley PM, Sanchez-Toril F, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161.
11. Rabe KF, Bateman ED, O'Donnell D, et al. Roflumilast – an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563-571.
Prepared by: Brian Leav, PharmD Candidate