In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.
The Evidence Is In: Two Doses of Varicella Vaccine Are Better Than One
Reviewed by Christian B. Ramers, MD, MPH
After a varicella vaccine was licensed in the U.S. in 1995, disease incidence, hospitalizations and mortality all fell significantly. However, outbreaks occurred in schools and daycare settings despite high vaccination rates, and even immunized children continued to contract “breakthrough” varicella. Based on data showing better antibody responses, but without controlled data on comparative clinical efficacy, the Centers for Disease Control and Prevention recommended a second vaccine dose for children aged 4-6 years old in 2006. A report in the February 1 issue of The Journal of Infectious Diseases fills this gap in evidence.
Investigators conducted a case-control study (71 cases and 140 matched controls) drawing from 28 pediatric practices in southern Connecticut. They identified cases using active surveillance and confirmed varicella zoster virus (VZV) with DNA PCR on vesicular fluid. Authors verified vaccination status using a thorough medical records review.
Among the 71 PCR-confirmed cases, 5 (7 percent) had not received varicella vaccine, 66 (93 percent) had received one dose, and none had received two doses. Among the 140 controls, one (0.7 percent) had not received the varicella vaccine, 117 (83.6 percent) had received one dose, and 22 (15.7 percent) had received two doses. The authors calculated an effectiveness of 86.0 percent for one dose of vaccine and 95 percent for two doses (p < 0.001). Further, the odds of developing varicella disease in those who had received two doses were 95 percent lower than those who had received only one.
This study provides strong evidence supporting the recommendation for routine administration of two doses of varicella vaccine. Continued surveillance for all forms of VZV disease, including reactivation disease, will be essential because latent infection with wild-type VZV is likely to decline with ongoing vaccination and long-term efficacy of the vaccine is unknown.
(Shapiro et al. J Infect Dis. 2011 Feb; 203(3): 312-5.)
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Yet Another Potential Use for Rifaximin: Irritable Bowel Syndrome
Reviewed by Christopher J. Graber, MD MPH
Rifaximin, a rifamycin antibiotic with low systemic absorption following oral administration, has emerged as a viable treatment option for hepatic encephalopathy and travelers’ diarrhea. An article published in the January 6 issue of the New England Journal of Medicine may add irritable bowel syndrome (IBS) without constipation to this list.
This study, funded by the manufacturer of rifaximin, enrolled 1,260 patients into one of two identical randomized trials in which participants who had a diagnosis of IBS without constipation and active symptoms received a two-week course of rifaximin 550 mg or placebo twice daily for 14 days. Patients in the rifaximin arm had statistically significant (though moderate) improvement relative to placebo in most endpoints over the following 10 weeks (improvement in global IBS symptoms, bloating, abdominal pain, and stool consistency), an effect that diminished over time with respect to some symptoms.
Infectious diseases practitioners should be aware of IBS as an additional potential indication for rifaximin use, as rifaximin’s high cost (more than $20 per 550 mg pill) and the potential for IBS patients to receive multiple two-week courses may strain antibiotic formulary budgets. What is less clear is how widespread rifaximin use may contribute to rifamycin resistance. While significant increases in rifamycin resistance among gut flora with rifaximin use have largely not been seen to date, a study in the January 2011 issue of Journal of Infection examines whether rifaximin use in healthy volunteers predisposed to rifampin resistance among staphylococci colonizing their skin.
Of the 11 volunteers who took a seven-day course of rifaximin (none of whom were colonized with rifampin-resistant staphylococci at baseline), seven were colonized with rifampin-resistant staphylococci at some point during their 10-week follow up. Resistance was seen earliest among isolates colonizing the perianal region. While the rifampin-resistant staphylococci, all of which were coagulase-negative, constituted only 2 percent of all of the staphylococci isolated throughout the study, this study highlights potential danger ahead, as rifampin is frequently used in adjunctive treatment of certain invasive staphylococcal diseases.
(Pimentel et al. New Engl J Med 2011; 364(1):22-32 and Valentin et al. J Infect 2010;62(1):34-38)
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HIV Pre-Exposure Prophylaxis with Tenofovir/FTC: iPrEx Study Proves Concept
Reviewed by Nina Kim, MD, MSc
The past year has witnessed encouraging advancement in HIV prevention. The CAPRISA 004 study showed a 39 percent reduction in the risk of HIV acquisition among women who used a tenofovir-based vaginal gel before and after sex. Joining these data are the long-awaited results of the landmark trial on the efficacy of oral antiretroviral therapy (ART) for the prevention of HIV (the Preexposure Prophylaxis Initiative, or iPrEx, study), published in the December 30 issue of the New England Journal of Medicine.
The trial randomized 2,499 HIV-seronegative men who have sex with men to receive the oral once-daily coformulation of tenofovir-emtricitabine (TDF/FTC) or placebo. Participants also received condoms and underwent adherence and risk-reduction counseling as well as rapid serum HIV testing by enzyme-linked immunoassay every four weeks.
Of the 100 HIV infections that occurred during the median 1.2 years of follow-up, 64 occurred in the placebo group and 36 in the treatment group with an overall risk reduction of 44 percent (95 percent confidence interval, 15-63 percent, P=0.005). As in the CAPRISA study, efficacy correlated with greater drug exposure, with a 73 percent risk reduction at the highest adherence category. Subjects tolerated TDF/FTC well; adverse events and discontinuations were similar between groups, though reversible elevations in serum creatinine occurred more often in those in the treatment than placebo arm (25 versus 14 subjects). Emtricitabine resistance was noted in three men who had acute HIV infection at enrollment; two of these were in the TDF/FTC group.
While the results of the iPrEx study represent a major step in HIV prevention research, it is uncertain how ART-based pre-exposure prophylaxis will play out in real-world settings. The optimal administration of TDF/FTC in the context of other prevention tools, the benefit to other risk groups, and the extent of drug resistance and nephrotoxicity with widespread implementation all remain unclear. In the wake of this study, the Centers for Disease Control and Prevention (CDC) has issued interim guidance on the use of pre-exposure prophylaxis (PrEP) as an HIV prevention strategy among men who have sex with men.
(Grant et. al. N Engl J Med 2010; 363:2587-99.)
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An Update on the Impact of Foodborne Illnesses
Reviewed by Rachel Simmons, MD
Two recent studies illustrated the significant impact of foodborne illnesses locally and nationally. In the December 15 issue of Clinical Infectious Diseases, researchers report on a raw milk-related outbreak of E. coli 0157:NM associated with a farm in Connecticut where the sale of raw milk is legal. The investigation identified seven definite and seven probable cases, and the median age of the cases was 5. One adult was hospitalized with thrombotic thrombocytopenic purpura (TTP), and three children were hospitalized with hemolytic uremic syndrome (HUS).
The investigation revealed no major regulatory infractions on the farm, and E. coli O157:NM was isolated from the stool of an asymptomatic cow. The estimated cost of the outbreak was $413,402. An advisory at the point of sale described the risks of consuming unpasteurized milk, and at least in the case-control portion of the study, the cases (or their parents) stated they knew that the unpasteurized milk can contain harmful bacteria.
In the January 2011 issue of Emerging Infectious Diseases, researchers report on the overall burden of foodborne illness in the United States. They estimated that 31 pathogens cause 9.4 million foodborne illnesses (59 percent due to viruses, 39 percent due to bacteria, and 2 percent due to parasites) leading to 55,961 hospitalizations and 1,351 deaths annually. In a second study, the investigators estimated that unknown or unspecified foodborne pathogens acquired in the U.S. cause 38.4 million illnesses, 71,878 hospitalizations, and 1,686 deaths each year. In combination, 47.8 million foodborne illnesses occur in the U.S. each year.
These studies indicate that the food supply remains an important and costly cause of morbidity and mortality. In early January, President Obama signed food safety legislation into law giving the Food and Drug Administration greater authority to both prevent and manage foodborne outbreaks. Adequately funding the implementation of the bill may be challenging, but these studies underscore the urgent need for better food safety practices.
(Guh et al. Clin Infect Dis. 2010; 51:1411-7, Scallan et al. Emerg Infect Dis. 2011;17:7-15, and Scallan et al. Emerg Infect Dis. 2011;17:16-22.)
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Short- Versus Long-Term Antimicrobial Treatment for AHOM in Children
Reviewed by Ed Dominguez, MD
Acute hematogenous osteomyelitis (AHOM) in childhood has traditionally been treated for four or more weeks, initially with intravenous antibiotics. A study published in the December 2010 issue of the Pediatric Infectious Disease Journal has evaluated the duration and route of therapy in a prospective, randomized trial for the first time.
Investigators evaluated short-term (20 days) versus long-term (30 days) therapy in 131 culture-positive patients from 1993 to 2005. The children ranged in age from 3 months to 15 years old. Patients were randomized to receive either clindamycin or first-generation cephalosporin therapy, intravenously for two to four days, followed by oral therapy until the termination date. Erythrocyte sedimentation rate, peripheral white blood count, and C-reactive protein (CRP) level were also monitored.
Sixty-seven patients were in the short-term group, 64 in the long-term group. Staphylococcus aureus accounted for 89 percent (n=117) isolates; all were methicillin-susceptible. At the end of therapy, there were no significant deviations between the groups in the parameters measured. Although more patients received clindamycin than cephalosporins, there was no difference in response. Seventy-six percent of patients required surgical intervention, but there was no difference in the need for surgery between groups. After 12 months, no patient required corrective osteotomy. The authors conclude that 20-day therapy for AHOM, initially intravenously for several days with high doses of a highly absorbable antibiotic, is appropriate if there is symptomatic improvement and normalization of the CRP within 10 days.
An adjoining editorial notes that the lack of community-acquired methicillin-resistant (CA-MRSA) in this study is important. A number of AHOM studies in children infected with such strains show that these patients are more likely to have prolonged bacteremia and fever, and have more than one bone or joint involved. They are also more likely to require intensive care. Additionally, the CRP may take 19 days or longer to normalize in these patients. Before employing short-term therapy, the clinician must rule out infection with these virulent strains.
(Peltola et al. Ped Inf Dis J. 2010;29:1123-1128 and Kaplan. Ped Inf Dis J. 2010;29:1128-1129.)
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For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases:
- Eliminating Leprosy
- A Carbapenemase From Abroad: NDM-1
- Oseltamivir Resistance—Mutations Hiding in the Background Account for its Spread
- Non-Antibiotic Therapy of Uncomplicated Cystitis
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