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.

• Fidaxomicin for Treatment of Clostridium difficile Infection: A Welcome Addition
• Nontuberculous Mycobacterial Cervicofacial Lymphadenitis in Children: Wait and See 
• Benefits of HPV Vaccination in Males
• Stem Cell Transplantation as HIV “Cure”: An Update

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.

Fidaxomicin for Treatment of Clostridium difficile Infection: A Welcome Addition
Reviewed by George R. Thompson III, MD

Recent observations have noted reduced clinical response rates and increased recurrence rates in patients with Clostridium difficile infection (CDI). These findings have prompted a search for more efficacious treatment regimens. A phase III trial published in the Feb. 3 issue of The New England Journal of Medicine examined the potential role of fidaxomicin in treating adults with CDI.

Fidaxomicin is a recently discovered macrocylic antibiotic with limited in vitro activity against normal gut flora, greater in vitro activity than vancomycin against C. difficile, minimal systemic absorption, and no cross-resistance with other antibiotic classes. This agent is also bactericidal against C. difficile, while vancomycin is bacteriostatic. 

To further evaluate this compound, the authors performed a prospective, double-blind, randomized trial comparing fidaxomicin (200 mg orally every 12 hours) to vancomycin (125 mg orally every six hours) in the treatment of a first or second episode of CDI.  The clinical cure rate was not significantly different between treatment groups. However, CDI recurrence rates were significantly fewer in the group treated with fidaxomicin in both the modified intention-to-treat analysis (P=0.005) and the per-protocol analysis (P=0.004). Global cure rates (clinical cure and lack of relapse) were also found to significantly favor the fidaxomicin treatment group (P=0.006).  Adverse events were similar between treatment groups as well, and no patients discontinued the study due to intolerance or side effects.

Although both medications exhibited similar efficacy in respect to clinical resolution, the authors observed a more sustained, durable response in the group treated with fidaxomicin. The additional benefit of decreasing overall vancomycin use and the subsequent development of vancomycin-resistant enterococcus suggest this agent will be a welcome addition in the treatment of such a difficult pathogen.

(Louie et al. N Engl J Med. 364;5:422-431.)

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Nontuberculous Mycobacterial Cervicofacial Lymphadenitis in Children: Wait and See
Reviewed by Khalil Ghanem, MD, PhD

A conservative “wait and see” approach resulted in similar healing times compared to combination antibiotic therapy among children with advanced nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis. Published in the Jan. 15 issue of Clinical Infectious Diseases, the findings are from a randomized non-inferiority study conducted in the Netherlands.

Immunocompetent children with microbiologically-proven advanced NTM cervical lymphadenitis characterized by fluctuation of the lymph node and discoloration of the skin were randomized to receive either clarithromycin plus rifabutin for 12 weeks or no pharmacologic intervention. The primary outcome was regression of lymph node enlargement by 75 percent with cured fistula and total skin healing. The secondary outcome was medication adverse events.

The study included 50 children with a median age of 35 months and an NTM infection lasting approximately nine weeks. The majority were infected with M. avium (70 percent) and M. hemophilum (24 percent).  Median times to resolution of lymphadenitis were 36 weeks for the treatment group and 40 weeks for the non-intervention group (p=0.4). No recurrences were noted in either group after two years of follow-up.  The most common adverse events in the treatment group included abdominal pain (28 percent) and extrinsic tooth discoloration (64 percent).

Most children with early NTM cervical infections undergo surgery, which is curative. This study confirms case reports and case series that suggest that withholding antibiotic treatment of advanced NTM cervical infections in children is reasonable. One major limitation is the sample size of the study, which may not have detected small, but clinically meaningful differences in healing times.

(Lindeboom. Clin Infect Dis. (2011) 52 (2): 180-184.)

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Benefits of HPV Vaccination in Males
Reviewed by Jason Weinberg, MD

Human papillomavirus (HPV) causes genital infection in both sexes.  A quadrivalent HPV vaccine provided protection against HPV infection and HPV-related disease in males in a study published in the Feb. 3 edition of The New England Journal of Medicine.

In a placebo-controlled, double-blind study, 4,065 males 16 to 25 years old were randomized to receive three doses of quadrivalent vaccine (active against HPV-6, 11, 16, and 18) or placebo.  Vaccination had an overall efficacy of 60.2 percent in preventing external genital lesions, although predominantly condyloma accuminata and not penile, perianal, or perineal intraepithelial neoplasia.  Efficacy was 65.5 percent when the lesions were associated with HPV-6, 11, 16, or 18.  When individual HPV types were considered, significant reductions were seen only in lesions associated with HPV-6 and HPV-11. Vaccination had an efficacy of 47.8 percent in reducing the incidence of persistent infection (detection of the same HPV type in an anogenital swab or biopsy specimen over at least six months). 

Vaccination was also effective in reducing the detection of HPV DNA of any type at any time.  Improved vaccine efficacy was observed in a per-protocol population that was initially seronegative and DNA negative and received all vaccinations within one year.

The results suggest that quadrivalent HPV vaccination protects against infection and some forms of HPV-associated genital disease in males, although effects on other relevant outcomes, such as anogenital and oropharyngeal cancer or respiratory papillomatosis, were not reported.  Indirect effects of HPV vaccination of males on preventing HPV transmission to sexual partners were also not assessed.  Ultimately, additional data demonstrating the efficacy of vaccination in protecting against multiple forms of HPV-associated disease in males and in preventing transmission to sexual partners will likely be needed to support the cost effectiveness of universal HPV vaccination in both sexes.

(Giuliano et al. N Engl J Med. 2011;364(5):401-411.)

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Stem Cell Transplantation as HIV “Cure”: An Update
Reviewed by Kathryn E. Stephenson, MD, MPH

In Germany in 2007, a patient with HIV and acute myeloid leukemia (AML) received a stem cell transplant (SCT) with donor cells that were homozygous for the HIV-resistance gene (the CCR5-delta32 deletion). The case garnered significant attention at the time because of the potential for this transplant to eradicate HIV in the patient while also treating the AML.

More than three years later, an update on this pioneering case published in the Jan. 14 issue of AIDS states that the patient remains off of antiretroviral therapy with no evidence of active HIV replication. In addition, the patient’s CD4 cell count now exceeds 800/µL. Investigation of cells derived from the transplant, including gut macrophages, has shown these cells to all be CCR5 negative, suggesting that all infectable target cells and reservoirs have been replaced with CCR5-negative cells. This evidence supports the notion that the patient is now cured of HIV.

The case provides an exciting proof of principle. However, the authors have been unable to repeat their findings in a second patient. Despite an international search over a three-year period, the authors have been unable to identify any additional HIV-infected patients who are both eligible for transplant and have a HLA-matched donor who is homozygous for the CCR5-deletion. This failure underscores that the chance to perform such transplants will be exceedingly rare going forward, and thus, the relevance of this strategy to treat HIV remains in question. Still, the authors argue that the successful outcome in their patient suggests that at the very least, gene therapy for HIV is worth exploring further. 

(Hutter and Thiel. AIDS 2011:25:273-5.)

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