Updates by Carol A. Kemper, MD, FACP
Updates
By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Neuropsychiatric Symptoms with Efavirenz
Source: Gutierrez-Valencia A., et al Stepped-dose versus full-dose efavirenz for HIV infection and neuropsychiatric adverse events. Ann Intern Med. 2009; 151:149-156.
Neuropsychiatric side effects and sleep disturbances are among the more prominent and limiting features of efavirenz (EFV) therapy for HIV infection. These researchers from Spain examined the neuropsychiatric side effects in HIV+ patients receiving EFV for the first month. A total of 114 patients were randomized, in a double-blind fashion, to receive either standard-of-care (SOC) treatment with EFV 600 mg/day or a dose-escalation (DE) regimen of EFV 200 mg/day from days 1 through 7, 400 mg/day from days 8 through 13, and 600 mg/day thereafter; both groups received concurrent treatment with two nucleoside/tide agents.
Patients receiving SOC with full-dose therapy were more likely than those receiving DE to experience dizziness (66% vs. 33%, p = .001), hangovers (46% vs. 21%, p = .008), and hallucinations (6% vs. 0%, p = .056). There was also a trend toward increased sleep disturbances and nightmares in patients receiving SOC therapy. Side effects were more severe in patients receiving SOC beyond two weeks of therapy compared with the DE group, although the frequency of side effects was similar.
As expected, EFV plasma levels were significantly lower during the first two weeks in those receiving DE compared with those in the SOC group. Those receiving DE had mean plasma levels 12-hours post-dose of .73 (.05-4.79 mcg/mL) and .67 (.04-3.03 mcg/mL) at days 7 and 14 of therapy, respectively. In contrast, mean plasma levels in the SOC group were 1.23 (.06-3.96 mcg/mL) and 1.41 (.08-3.85 mcg/mL) at days 7 and 14, respectively. Individual patient variability was large, and there was no correlation between plasma levels and symptoms.
Virologic failure (> 200 copies/mL) occurred in six patients by week 24 of therapy, including two patients receiving DE and four in the SOC group. Genotype resistance (with at least a K103 mutation) occurred in one patient in each group by week 12 of therapy. Both patients admitted to missed doses.
Dose escalation of EFV for the first two weeks of therapy may be beneficial in limiting the frequency and severity of neuropsychiatric side effects and sleep disturbances in patients receiving EFV for the first time, but deserves further investigation.
Tamiflu in Children
Source: ProMEDmail post August 10 and 11, 2009; http://www.promedmail.org
These alerts present some of the controversy generated by a recent British Medical Journal article, published online, examining evidence from seven published articles of oseltamivir treatment of children with influenza.1
The authors suggest that a risk-benefit meta-analysis does not support the widespread use of antiviral therapy, with either oseltamivir or zanamivir, in children ages 1 to 12 years with documented or suspected influenza. These results, they suggest, should be extrapolated to the current H1N1 epidemic.
Studies have demonstrated that the use of antivirals in children and adults with seasonal influenza can reduce the duration of illness by up to 0.5 to 1.5 days. These data were not considered sufficient evidence to support the widespread use of drugs in otherwise healthy children with ordinary seasonal influenza. The primary concern was the frequency of side effects to therapy, including vomiting and dehydration, which could result in an increase in the severity of illness, as well as hospitalization. No apparent benefit was observed in children with asthma exacerbation, ear infection, or in the frequency of antibiotic use. Data also showed that the empiric administration of antivirals to children with influenza-like illness (ILI) may result in significant over-treatment; one study suggested that only one in four children with ILI actually had the flu.
The researchers did acknowledge that antiviral therapy may be of benefit in children with underlying disease, such as those with cystic fibrosis or hematologic malignancy.
In addition, analysis of prophylactic therapy in children suggested that at least 13 children would need to be treated to prevent infection in one. There are additional concerns that the widespread use of these agents will result in futher resistance.
The Canadian health authorities have since announced they will continue to recommend the use of Tamiflu in children, including children less than one year of age. The United States DPH provided a curious response, indicating "while there is doubt about how swine flu affects children," they advocate a "safety-first approach of offering antivirals" and "to suggest otherwise is potentially dangerous." (Never mind the data, I guess.)
Meanwhile, the current administration seems to be fueling fears about the dangers of this new strain of influenza virus, and the potential for "mutation," without good evidence for a significant difference in virulence between this and other seasonal flu strains. I feel like I'm watching a bad remake of "Outbreak," only it's the government scaring the public, not Hollywood.
Based on the rapidity of the emergence of resistance in circulating influenza viruses in Europe and the United States earlier this year, this discussion may soon be moot, especially with the widespread and random use of Tamiflu observed in our community. Oseltamivir-resistant H1N1 flu virus has already been isolated from individuals who have not received antiviral therapy.
Reference
- Shun-Shin M, at al. Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systemic review and meta-analysis of randomized controlled trials. BMJ. 2009; 339: b3172.
Updated Vancomycin Treatment Guidelines
Source: Rybak MJ, et al. Vancomycin therapeutic guidelines: A summary of consensus recommendations from the Infectious Disease Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis. 2009;49:325-327.
Failure of vancomycin therapy in patients with serious S. aureus infection with MIC values > 2-4 mcg/mL, and MIC "creep," prompted re-evaluation of current practices for vancomycin use and updated recommendations.
A summary of the key recommendations is as follows:
- Initial vancomycin dosing should be weight-based (actual body weight); subsequent dose adjustments should be based on actual serum-trough concentrations.
- For usual gram-positive infections, trough vancomycin concentrations should be maintained > 10 mg/dL; lower serum concentrations are associated with the development of S. aureus strains with vancomycin-intermediate susceptibility (VISA).
- For certain infections due to S. aureus (e.g., bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia), vancomycin-trough concentrations should be targeted at higher levels (15-20 mcg/mL).
- In order to more quickly reach target levels in seriously ill patients, a loading dose of vancomycin 25-30 mg/kg should be considered.
- Patients with S. aureus infections with MIC < 1 mcg/mL and normal renal function should receive vancomycin 15-20 mg/kg every q8-12 hours; however, it is not possible to attain an adequate AUC/MIC ratio in patients who have normal renal function and S. aureus infections with MIC > 2 mcg/mL; an alternate agent should be administered in these cases.
- Monitoring trough vancomycin levels is not warranted for short-course therapy (< 5 days) or for those individuals receiving usual dosing.
- Continuous infusions may be more effective than intermittent dosing in some patients.
Macrolide-resistant M. pneumoniae
Source: Li X, et al. Emerging macrolide resistance in Mycoplasma pneumoniae in children. Detection and characterization of resistant isolates. Pediatr Infect Dis J. 2009;28:693-696.
Two strains of m. pneumoniae isolated from two children hospitalized in Birmingham, Alabama, with severe community-acquired pneumonia have been found to be resistant to azithromycin (MIC 8-32 mcg/mL), erythromycin (MIC > 32 mcg/mL), and the ketolide, telith-romycin (MIC > 32 mcg/mL). Both children responded poorly to therapy with azithromycin, prompting further testing. Isolates from each child had a mutation (A2063G) in the 23S rRNA gene previously associated with macrolide resistance in M. pneumoniae (as has a A2064G mutation).
Limited information exists regarding macrolide resistance in M. pneumoniae in the United States. Prior to 1998, no macrolide resistance was detected among 58 US isolates tested at the CDC, although isolates from a New York patient failing macrolide therapy that year demonstrated the emergence of phenotypic resistance along with development of the A2064G mutation. Macrolide resistance was also detected in three of 11 M. pneumoniae isolates from an outbreak in Rhode Island also associated with the A2063G mutation in 2006-2007. Data suggest that macrolide resistance has been slowly increasing in Europe since 2005.
Increasing macrolide resistance in M. pneumonia presents a special challenge in children, since macrolides and azalides are considered safer choices than either fluoroquinolones or tetracyclines. More frequent macrobicide- and azalide-resistant M. pneumoniae infections in the United States are likely to occur
Neuropsychiatric side effects and sleep disturbances are among the more prominent and limiting features of efavirenz (EFV) therapy for HIV infection.Subscribe Now for Access
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