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March 2015
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IDSA Journal Club
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, FIDSA, in each issue of Clinical Infectious Diseases.

Screening for Incident Hepatitis C in Persons with HIV: A Call for Action
Reviewed by Brian R. Wood, MD

Around one-third of individuals with HIV infection in the United States are also infected with hepatitis C, with high rates of coinfection in injection drug users and rising incidence in men who have sex with men (MSM). Timely diagnosis of hepatitis C permits effective counseling, prevention efforts, and informed treatment decisions. So, how well are we meeting the need for screening in this high-risk population?

In a recent article in Clinical Infectious Diseases, investigators examined hepatitis C screening rates in 17,090 HIV-seropositive adults between 2000 and 2011 in a retrospective cohort study. Most (85 percent) received screening at entry into care; however, only about half (55.6 percent) of the 9,077 individuals who screened negative at baseline ever received repeat testing. Even those with ongoing risk or elevated transaminases were not uniformly retested. Of participants with first-time alanine aminotransferase (ALT) elevations >100 IU/L or >400 IU/L, only 26.7 percent and 20.3 percent, respectively, were tested within 12 months. The authors astutely call for concrete guidelines on screening for incident hepatitis C in the United States, as have been developed elsewhere.

Two recent analyses examined potential new methods that could arm providers with additional tools for hepatitis C screening and diagnosis. The first, a small, single-center study from the United Kingdom described in Clinical Infectious Diseases, found hepatitis C core antigen, which is not an approved assay in the United States, to be a sensitive and specific marker of acute hepatitis C in HIV-infected persons with abnormal ALT. This test could provide a cost-effective and rapid means (results generally available the same day) for detecting incident hepatitis C, especially where RT-PCR is not available.

Another study, also reported in Clinical Infectious Diseases, evaluated antibody dynamics in 63 HIV-seropositive MSM with acute hepatitis C in the Netherlands, most of whom received early treatment. Median time to seroconversion was 74 days and only 59 percent seroconverted by three months after infection. Notably, reinfection rates in this cohort were high (18 of 63 participants became reinfected, including one individual who became reinfected three times). Investigators noted a significant decrease in hepatitis C antibody reactivity following viral clearance, and a significant subsequent increase upon reinfection, even though only 44 percent of reinfection cases had elevated ALT. This provocative article confirms that MSM are at high risk for hepatitis C reinfection and reinforces the need for ongoing monitoring, perhaps using antibody reactivity levels.

Together, these studies highlight the challenge of diagnosing incident hepatitis C infection and the responsibility that ID providers have in ensuring that HIV-infected individuals at risk are routinely tested, as well as in propagating this best practice to other HIV primary care practitioners. The findings also underscore the need to develop and disseminate specific guidelines for incident hepatitis C screening in high-risk individuals and to consider novel approaches to testing.

(Freiman et al. Clin Infect Dis. 2014;59(12):1686-1693, Vanhommerig et al. Clin Infect Dis. 2014;59(12):1678-1685, and Cresswell et al. Clin Infect Dis. 2015;60(2):263-266.)

Combination Therapy for Invasive Aspergillosis: Better Than Monotherapy?
Reviewed by Zeina Kanafani, MD, MS

While voriconazole is now considered the drug of choice for the primary treatment of invasive aspergillosis (IA), it is still not clear whether combination with an echinocandin agent would be beneficial.

A recent article in the Annals of Internal Medicine describes a randomized double blind study comparing voriconazole monotherapy to combination therapy with voriconazole and anidulafungin in patients with suspected or documented IA in the setting of hematologic malignancy or hematopoietic stem cell transplantation. All patients received voriconazole for six weeks (intravenously during the first week at 6 mg/kg every 12 hours on day one then 4 mg/kg every 12 hours, with possible switching to oral formulation afterwards at 300 mg every 12 hours). In addition, patients were randomized to receive either intravenous anidulafungin at 200 mg on day one, then 100 mg every 24 hours, or placebo every 24 hours for two to four weeks.

The primary end point (all cause-mortality at six weeks in the modified intent-to-treat population) was achieved in 19.5 percent of patients in the combination therapy arm compared to 27.8 percent in the monotherapy arm (p=0.087). Mortality at 12 weeks was 29.3 percent with combination therapy and 39.4 percent with voriconazole monotherapy (p=0.077). A low Karnofsky score, low platelet count, and high serum galactomannan antigen index at baseline were the only independent risk factors for mortality at six weeks.

In addition, a post hoc analysis was performed in patients where the diagnosis of IA was made based on radiographic abnormalities and galactomannan antigen positivity in serum or bronchoalveolar lavage. Combination therapy in this subgroup was associated with an all-cause mortality rate of 15.7 percent versus 27.3 percent with monotherapy (p=0.037). Combination therapy was safe and well tolerated in the majority of patients.

The study suggests that treatment with voriconazole/anidulafungin for IA may be associated with improved outcomes compared to voriconazole alone, although the difference did not reach statistical significance. The exact benefit of combination therapy is yet to be determined in further trials.

(Marr et al. Ann Intern Med. 2015;162(2):81-9.)

Antibiotics for Travelers’ Diarrhea Increase Risk of Colonization by ESBL-Producing Enterobacteriaceae
Reviewed by Manie Beheshti, MD

Rising rates of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) globally pose significant risks of increased morbidity and mortality. Travelers’ diarrhea, use of antibiotics, and travel to areas with high prevalence have previously been identified as risk factors for colonization with ESBL-PEs. In a recent study published in Clinical Infectious Diseases, investigators studied these travelers’ risks of colonization in the largest inquiry on the matter to date.

Utilizing a questionnaire, 430 Finns traveling outside of Scandinavia were evaluated for travelers’ diarrhea and antibiotic use directed at travelers’ diarrhea. In addition, stool samples were analyzed before and after travel to assess for colonization by ESBL-PE. Overall, 21 percent of travelers became colonized by ESBL-PE during travel. Travelers’ diarrhea, use of antibiotics, and travel destination were identified as notable risk factors accounting for rates as high as 80 percent in those traveling to South Asia. Of interest, use of antimalarials alone, including doxycycline, was not identified as a risk factor.

Rates of colonization with ESBL-PE were as follows:

No Antibiotics for TD
Antibiotics for TD
No Travelers’ Diarrhea (TD)
TD in South Asia

This study highlights travelers’ diarrhea and antimicrobials as independent risk factors for acquisition of ESBL-PE. Noting the complexities in the management of travelers’ diarrhea, the authors contend that efforts should focus on measures to avoid travelers’ diarrhea and to limit the use of antibiotics. Perhaps the most reasonable first step would be to eliminate use of antibiotics for mild to moderate travelers’ diarrhea, which resolves spontaneously.

(Kantele et al. Clin Infect Dis. 2015; published online January 21, 2015, doi:10.1093/cid/ciu957)

Thrice-Weekly Therapy for Nodular-Bronchiectatic Pulmonary MAC
Reviewed by Michael T. Melia, MD

Treatment of pulmonary Mycobacterium avium complex (MAC) infection is complicated by the need for long-term antimicrobial therapy and attendant risks of medication side effects and intolerance. Treatment modifications associated with enhanced medication tolerability may be associated with greater response rates owing to a greater likelihood of completing therapy.

In a recent issue of the American Journal of Respiratory and Critical Care Medicine, investigators retrospectively reviewed 217 treatment-naïve patients with nodular-bronchiectatic, macrolide-susceptible pulmonary MAC infection (NB-MAC) treated at a single center in Seoul, Korea. Ninety-nine patients were treated with daily macrolide (88 percent clarithromycin) + rifamycin (96 percent rifampin) + ethambutol; 61 percent received thrice-weekly (TIW) streptomycin for three months. Owing to a protocol change, as of January 2011 patients with NB-MAC were treated with thrice-weekly macrolide (97 percent azithromycin) + rifampin + ethambutol without an aminoglycoside. More TIW cohort patients were treated with azithromycin because it was approved for nontuberculous mycobacterial infection treatment in Korea in 2011.

Inter-group demographic data were similar, although more daily therapy patients had diabetes (11 percent vs. 3 percent). Forty-three percent of patients were acid-fast bacilli smear-positive at baseline. Daily therapy patients were treated longer (24.3 vs. 16.6 months).

Between-group treatment outcomes were similar; there were no differences in rates of symptom improvement (75-82 percent), radiographic (high-resolution chest computed tomography) improvement (68-73 percent), sputum culture conversion (67-76 percent), or time to sputum culture conversion. More daily therapy patients required a medication change (46 percent vs. 21 percent); this was driven almost entirely by different rates of ethambutol discontinuation (24 percent vs. 1 percent). There were no differences in emergence of macrolide resistance during treatment.

While the 2007 American Thoracic Society (ATS)/IDSA guidelines recommend TIW therapy for patients with NB-MAC, relatively few data support this recommendation, and heterogeneous populations were studied to produce those data. Although long-term patient follow-up was lacking in the present study, it provides compelling data supporting TIW treatment for treatment-naïve patients with NB-MAC.

(Jeong et al. Am J Respir Crit Care Med. 2015;191(1):96-103.)

Kicking the Can Down the Road: Delayed Infection and Antibiotic Prophylaxis for Transplant Recipients
Reviewed by Nirav Patel, MD

Pneumocystis jirovecii pneumonia (PCP) frequently develops in the immunocompromised patient. Although the risk has been mitigated with prophylaxis, there is no clear consensus on the duration or the risk factors that predispose infection in the modern era of widespread use of PCP prophylaxis. A study in the January 2015 issue of the American Journal of Transplantation attempts to answer these questions.

This retrospective case-control study included 1,895 adult transplant recipients (kidney, liver, and heart). All patients received six months of prophylactic antibiotics against PCP. Thirty-three patients met study inclusion criteria for diagnosis of PCP: 23 kidney recipients, five liver recipients, and five heart recipients. These cases were matched to two control patients who had negative bronchoalveolar lavage PCR testing for Pneumocystis jirovecii.

Notably, the incidence of PCP post-transplantation could be divided into three periods. Within one year of transplantation, only one case of PCP was diagnosed. During the second year, 11 patients were diagnosed, while 21 patients developed PCP between the third year and the 16th year post-transplantation, at a rate of about 1.6 cases per year.

Further, in multivariate analysis, age ≥ 65 (odds ratio [OR] 3.7, confidence interval [CI] 1.3-10.4, p=0.012), cytomegalovirus viremia (OR 5.2, CI 1.8-14.7, P=0.002), and total lymphocyte count <750/mm3 in the 50 days before PCP diagnosis (OR 3.9, CI 1.4-10.7, p=0.009) were all significant risk factors. Based on the analysis, PCP prophylaxis initiated 180 days prior to diagnosis of infection would benefit 70 percent of patients meeting all three criteria.

This study quantifies what many clinicians note in practice: Prophylaxis works, but what happens after stopping? The authors note that the “new” highest risk period is the second year post-transplantation. By identifying specific risk factors, clinicians can better target prophylaxis to those who would most benefit and reduce the unnecessary use in patients at lower risk.

(Iriart et al. Am J Transplant. 2015;15(1):190-9.)

Back to Top

For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases:

March 15
•    Does Ceftriaxone Therapy Eliminate Viable Borrelia burgdorferi?
•    Norovirus and Interferon
•    Chagas Disease in Texas

March 1
•    Risk of Active Tuberculosis–Exposed Contacts
•    Trimethoprim-Sulfamethoxazole: Be Careful!
•    Case Vignette: Blastomycosis Acquired in India

February 15
•    Bartonella Bacteremia in Veterinary Workers
•    Injectional Anthrax: A Look Back
•    Case Vignette: Cerebral and Meningeal Chagas Disease

February 1
•    Aspergillus terreus Infection
•    “You Dirty Rat … ” —Jimmy Cagney
•    Peripheral Neuropathy—Another Adverse Effect of Fluoroquinolone Therapy

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