MRSA: Once The Exception, Now The Rule

MRSA is a relative newcomer to the bacterial pathogen scene, being first identified in the 1960s. A decade ago, clinicians thought of MRSA as a typically hospital-acquired pathogen, and rarely identified it from healthy persons in the ambulatory setting. Today, the epidemiologic presence of MRSA in both hospital settings and among ostensibly healthy patients without risk factors in the ambulatory setting calls for enhanced clinician awareness of this pathogen and its appropriate treatment.

Moran et al sought to characterize the prevalence of MRSA from diverse communities around the United States. They studied bacterial isolates from adult patients presenting to emergency rooms with skin or soft tissue infections in 11 different cities across the United States: Albuquerque, Atlanta, Charlotte, Kansas City, LA, Minneapolis, New Orleans, New York, Philadelphia, Phoenix, and Portland.

Of the 422 patients presenting with skin/soft-tissue infections at these sites, 76% were caused by Staphylococcus, over half of which (59%) were MRSA. In over half the cases, prescribed antibiotics would not have been successful based upon culture and sensitivity results. MRSA was sensitive to clindamycin, trimethoprim/sulfamethoxazole, or tetracycline more than 90% of the time.

Because of the high prevalence and evolving resistance pattern of MRSA, clinicians would be wise to routinely culture patients with skin and soft-tissue infections, and consider antibiotic choices based upon prevailing sensitivity data.

Source: Moran GJ, et al. N Engl J Med. 2006;355:666-674.

From: Internal Medicine Alert

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HBV With De Novo Adefovir Resistance

Newer data suggest that ~2% of naturally occurring HBV may exhibit de novo resistance to adefovir. The authors describe cases of a variant HBV with primary resistance to Adefovir that remained sensitive both in vivo and in vitro to tenofovir (Viread, Gilead Sciences). The 3 patients, 2 of whom were married, were initially treated, and failed lamivudine as part of a clinical trial involving ~80 persons. All 3 subsequently received adefovir without any virologic response, but later responded to tenofovir.

The 3 strains of HBV proved to have the same unique amino acid substitute in the reverse transcriptase domain (rtI233v). The mutation was independent of lamivudine resistance, and remained stable for up to 220 weeks, even in the absence of selective pressure from adefovir. All 3 strains were typed a genotype D, which has a worldwide distribution and is the most common HBV genotype. A GenBank search found only 3 of 500 previously sequenced strains containing this mutation (2 from southeast Asia, both genotype C, and one from a Gibbon).

The initial significance of this mutation was not clear. Strains containing the mutation exhibited reduced in vitro sensitivity to adefovir by a factor of about 6 to 10, compared with wild type virus. Site-directed mutagenesis, whereby the isoleucine group at position 233 was converted back to wild type virus containing valine, demonstrated adefovir-sensitive virus.

Separately, another clinical trial compared the effectiveness of entecavir and lamivudine in patients with HBV infection. Eight patients receiving entecavir were found to be infected with a rtI233V mutant strain. Seven of the 8 patients developed undetectable viral loads, and 6 of 6 with available histologic data had histologic improvement. Although these patients did not have pre-existing lamivudine resistant, entecavir may be a good therapeutic option for patients with this variant mutation. Although tenofovir is not approved for use in patients with HBV, HIV providers have been using it successfully as part of an antiretroviral regimen for HBV/HIV co-infected persons.

Sources: Schildgen O, et al. Variant of Hepatitis B Virus with Primary Resistance to Adefovir. N Engl J Med. 2006,354: 1807-1812; Chang TT, Lai CL. N Engl J Med. 2006;355:322-323.

From: Infectious Disease Alert

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Statins And ACE Inhibitors Work Help Prevent Stokes

A newly published study showed that 80 mg per day of atorvastatin reduced the overall incidence of recurrent stroke, and a meta-analysis of several large studies of ACE inhibitors showed a reduction in all stroke types, as well as a reduction in overall cardiovascular mortality.

Until now, practitioners have relied on large studies of patients with coronary atherosclerosis and hyperlipidemia who were treated with statins and were found, as a secondary outcome, to have a reduced risk of ischemic stroke. While the role of cholesterol as a stroke risk factor has remained controversial, the benefit of statins in reducing the risk of ischemic stroke has been compelling. Other mechanisms than reduction of LDL cholesterol have been postulated, such as the antithrombotic, anti-inflammatory, and plaque-stabilizing effects of statins.

Now, Amarenco and colleagues have reported for the first time convincing evidence regarding the efficacy of atorvastatin in a direct study of secondary prevention of ischemic stroke in a selected population of patients with stroke or TIA. In a double-blind, placebo-controlled trial of atorvastatin 80 mg. per day, 4731 patients who had a stroke or transient ischemic attack (TIA) within one to 6 months had low-density lipoprotein cholesterol levels (LDL) of 100 to 190 mg/dL, and no known coronary disease, were enrolled in the study, and followed for a median of 4.9 years. During the trial, the mean LDL cholesterol was reduced to 73 mg/dL among patients receiving atorvastatin and 129 mg/dL in those receiving placebo. Two hundred sixty-five patients (11.2 %) receiving atorvastatin and 311 patients (13.1%) receiving placebo had a fatal or non-fatal stroke There was a small increase in hemorrhagic stroke, and elevated liver enzymes were more common in the atorvastatin group.

In a complementary study reported in Lancet by Dagenais and colleagues, the benefit of using an angiotensin-converting-enzyme inhibitor (ACEI) to prevent stroke in a population of patients with stable coronary artery disease was supported by a meta-analysis of 3 large clinical trials (HOPE, EUROPA, PEACE) that looked at cardiovascular outcomes and total mortality in 29,805 patients randomized to treatment with an ACEI (ramipril, perindopril, trandolapril). In prior studies of patients with overt heart failure, use of an ACEI did not demonstrate a significant reduction in stroke risk. The lack of efficacy was attributed to the relatively low blood pressures that these patients had at time of enrollment. Because high blood pressure is such a powerful risk factor for stroke, use of an ACEI without a significant lowering of blood pressure would not be expected to have much benefit.

Dagenais et al's analysis, however, demonstrated that when the findings of the studies were combined, ACEI significantly reduced all-cause mortality (7.8% vs 8.9%, P = 0.0004), cardiovascular mortality (4.3% vs 5.2%, P = 0.0002), and all stroke (2.2% vs 2.8%, P = 0.0004). The baseline mean blood pressures, before treatment, ranged from 134-139 systolic and 78-82 diastolic, and were reduced during treatment by 4-6 systolic and 3-4 diastolic.

Sources: Amarenco P, et al (SPARCL). High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med. 2006;355:613-615; Dagenais GR, et al. Angiotensin-Converting-Enzyme Inhibitors in Stable Vascular Disease without Left Ventricular Systolic Dysfunction or Heart Failure: A Combined Analysis of Three Trials. Lancet. 2006;368:581-588.

Breast Cancer Risk In WHI Estrogen-Progestin Trial Arm

The Women's Health Initiative (WHI) reports an increase in breast cancer is concentrated in prior hormone users, but the overall adjusted risk of breast cancer is not statistically significant.

Anderson and colleagues from the WHI performed subgroup analyses focusing on how prior hormone therapy use influenced the risk of breast cancer found in the estrogen-progestin trial arm. Prior hormone users totaled 4311 participants (26%), with 42% reporting less than 2 years of use (17% used hormones 5 to 10 years previously, and 26% more than 10 years before enrolling in the WHI study). Prior users had an increased hazard ratio compared to placebo (1.96; CI = 1.17-3.27) in contrast to no increase among never users (1.02; CI = 0.77-1.36). The WHI concluded that this difference could reflect an increasing risk with cumulative exposure to hormone therapy. The subgroup analysis suggested that no increase in breast cancer was seen in never users, perhaps because of insufficient duration of exposure.

Many of the factors associated with a reduced risk of breast cancer were slightly but significantly more prevalent in the group of prior hormone users, such as younger age, more education, lower body mass, and more physically active, notes Leon Speroff, MD professor of obstetrics and gynecology at Oregon Health and Science University, Portland. "On the other hand, some factors associated with an increased risk of breast cancer were more common in prior users (smoking, alcohol use, vasomotor symptoms, and lower bone density). The overall risk of breast cancer in the treated estrogen-progestin group was the same as previously reported by the WHI (1.24; CI = 1.02-1.50)." Speroff says that after adjusting for the multiple factors recognized to influence the risk of breast cancer, the hazard ratio was 1.20, and no longer statistically significant, CI = 0.94-1.53). "Remarkably, the authors comment that the adjustment 'did not substantially alter this risk estimate.' Is it not substantial if the risk goes from significant to nonsignificant? Is it appropriate for the WHI in its conclusion to say 'the significant increase in breast cancer risk found in the trial overall …?'," he asks.

A year-by-year analysis of prior users and never users is provided. Every single line in this figure, with one exception, crosses 1.0, is not statistically significant, and the confidence intervals are very wide, Speroff says. "The only statistically significant line is for prior users at year 5 of the study, and this confidence interval is the widest of all, 1.18-10.73. When the adjusted overall risk is no longer statistically significant, how confident can we be in the results of subgroup analyses with smaller numbers?

"This report from the WHI is promoting the idea that increasing duration of exposure is necessary for an increasing risk. Yet, they provide this result: 'Duration of prior hormone therapy use, and specifically duration of prior combined hormone use, did not significantly modify the risk of breast cancer.'"

How does all this fit with the idea that the data reflect the effect of hormone therapy on pre-existing tumors? Interestingly, the prior users who ended up in the placebo group had a lower incidence of breast cancer per year compared to the women without prior exposure, Speroff says. "After adjustment for the various risk factors, this reduction was not statistically significant (0.66; CI = 0.41-1.05). The WHI recognized that this was a 'puzzle.' It seems to me that this is tantalizing, a result consistent with early detection of pre-existing tumors. The WHI concludes that the results are consistent with the hypothesis that the risk of breast cancer increases with longer exposure; however, the data do not answer the question: are we seeing effects on pre-existing tumors.

"Most importantly, the overall result of an increased risk of breast cancer in the estrogen-progestin arm was no longer statistically significant after adjusting for risk factors," Speroff says. "This is good news! The WHI results are not consistent with a large effect, and the findings are finding it hard to escape the influence of differences in risk factors and personal characteristics."

Source: Anderson GL, et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006 Sep 20;55(2):103-15.

From: OB/GYN Clinical Alert

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