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September 2016
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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.  Five Days of Antibiotics for Community-Acquired Pneumonia: Good Enough?
Reviewed by Christopher J. Graber, MD, MPH, FIDSA 

The 2007 guidelines for management of community-acquired pneumonia (CAP) endorsed by IDSA and the American Thoracic Society recommend a “minimum” of five days of antibiotic therapy for CAP and that patients must meet clinical stability criteria (afebrile for at least 48 hours, stable vital signs) for antibiotics to be discontinued. A recent study published in JAMA Internal Medicine evaluated whether five days of therapy is indeed sufficient for patients meeting clinical stability criteria.

In the study, 312 patients hospitalized for CAP in four teaching hospitals in Spain were randomized to either have antibiotic therapy stopped at five days if clinical stability criteria were met or to have their antibiotics continued for longer at the discretion of their treating physicians. Patients who were immunosuppressed, had health care exposure within 14 days, received antibiotics within 30 days, or were admitted to the intensive care unit were excluded. Forty percent of patients had Pneumonia Severity Index (PSI) scores of IV or greater; 80 percent were treated with fluoroquinolones.

In the intervention arm, 162 patients received a median of five days of therapy (interquartile range [IQR] 5-6.5); 150 patients in the control arm received a median of 10 days (IQR 10-11). In the intention-to-treat analysis, clinical success was similar in both arms at day 10 (56.3 percent vs. 48.6 percent) and day 30 (91.9 percent vs. 88.6 percent), as was improvement in CAP symptom questionnaire scores at day 10. Among patients with PSI scores of IV and greater, clinical success at day 30 was significantly higher in the intervention arm (93.1 percent vs. 80.3 percent, p=0.04). In the per-protocol analysis, readmission at 30 days was lower in the intervention arm (1.4 percent vs. 6.6 percent). 

This study adds to a slowly enlarging group of studies across many common infectious conditions that show, when compared to longer courses, shorter courses of antibiotic therapy are typically at least equivalent. It provides strong impetus for antimicrobial stewardship initiatives to reduce duration of therapy for CAP to five days for patients meeting clinical stability criteria.

(Uranga et al. JAMA Intern Med. 2016;176(9):1257-1265.)

 
BDG Serum Testing and Invasive Fungal Infections in Stem Cell Transplant Patients
Reviewed by Erica Kaufman West, MD

Patients receiving both allogeneic and autologous hematopoietic stem cell transplantation (HSCT) are at high risk for invasive fungal infections (IFI). (1 -> 3)-β-D-glucan (BDG) is a polysaccharide cell wall component found in most pathogenic fungal species, such as Aspergillus, Candida, Pneumocystis, and Fusarium. A single-center study recently published in Transplant Infectious Disease looked at HSCT recipients (current or within the last year) and followed BDG twice weekly until resolution of risk factors for developing an IFI. 

The early phase was determined to start at the beginning of myeloablative therapy up to 30 days after HSCT. Late phase was defined as >30 days but <1 year after HSCT. The Fungitell® assay was used, with positive results noted at ≥80 pg/mL. Samples were classified as “no evidence” for IFI or “possible,” “probable,” or “proven” IFI based on the definitions provided by the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group and the Mycoses Group.  

The researchers obtained 308 samples from 45 patients, with about 75 percent drawn in the early phase. Most patients (73 percent) were allogeneic HSCT patients. Notably, almost all (78.6 percent) were on anti-fungal prophylaxis (medication not specified). Only 16 samples were obtained during a “possible” or “probable” IFI, and these had significantly higher BDG levels than those with “no evidence” (median 170 pg/mL vs. 15.4 pg/mL, p<0.001). They found the sensitivity of “possible” or “probable” IFI was 81 percent, specificity was 98 percent, negative predictive value (NPV) was 99 percent, and positive predictive value was 65 percent. 

From this study, BDG has an excellent NPV (>99 percent) and thus is a helpful tool in ruling out IFI in adult HSCT patients. This is a good “real-world” study where patients were likely taking medications noted to give false positive BDG results, making the high NPV worth noting. In addition, almost all of the patients were on antifungal prophylaxis, which has been shown to decrease sensitivity. This study provides some evidence that BDG is a reliable test for ruling out IFI in the adult HSCT population, which can prove helpful in avoiding empiric antifungal therapy.

(Reischies et al. Transpl Infect Dis. 2016;18:466-470.)

 
Zero HIV Transmissions with a Suppressed Viral Load: Is the Risk Zero?
Reviewed by Brian R. Wood, MD

The true risk of HIV transmission from an infected partner with routinely suppressed HIV RNA level on antiretroviral therapy (ART) to an uninfected partner remains unknown. The topic is highly clinically relevant because it affects counseling for serodifferent partners, particularly when considering pre-exposure prophylaxis, conception options, and other factors. The PARTNER study, recently published in JAMA, provides compelling evidence, but some questions linger.

In this prospective, multinational European investigation, researchers enrolled serodifferent adult couples (61.7 percent heterosexual, 38.3 percent men who have sex with men [MSM]) in which the HIV-infected partner had a suppressed viral load on ART; all couples reported condomless sex (for a median 2 years prior to enrollment). Overall, 1,166 couples contributed a median 1.3 years of follow-up (1,238 couple-years total), including 58,000 condomless sex acts (36,000 heterosexual and 22,000 MSM). Notably, zero phylogenetically linked HIV transmissions occurred within couples.

This result is remarkable and has stirred much discussion regarding the best interpretation. On one hand, it confirms findings of HPTN 052 regarding the drastically reduced HIV transmission risk with a suppressed viral load (defined liberally as less than 200 copies/ml in this trial) and fills in data gaps by including condomless sex (whereas reported condom use was very high in HPTN 052) and a large proportion of MSM couples (HPTN 052 included mostly heterosexual couples). On the other hand, as the authors point out, follow-up time and power are limited, and thus 95 percent confidence intervals make it difficult to definitively state that transmission risk is zero (particularly for anal sex with ejaculation, for which the upper limit is 20 percent over 10 years). Furthermore, as editorialists comment, a degree of selection bias may be present, and results are primarily generalizable to stable couples in which the positive partner has had excellent ART adherence for many years. 

So, how should we incorporate this data into counseling for serodifferent couples?  For most couples, this will involve an explanation of what we know and don’t know about HIV transmission risk and an individualized decision. Results of this study will add significantly to the counseling discussion and help us guide our patients and their partners to an informed decision, though we will likely still need to include small disclaimers when sharing the results. Outcomes of the PARTNER2 study, which will add data for MSM, are eagerly awaited.

(Rodger et al. JAMA. 2016 Jul 12;316(2):171-81.)

(Daar, Corado. JAMA. 2016 Jul 12;316(2):149-51.)

(Cohen et al. N Engl Med. 2016 Sep 1;375(9):830-9.)

Procalcitonin-Guided Therapy in Critically-Ill Patients
Reviewed by Zeina Kanafani, MD, MS

Antibiotics are frequently prescribed to critically ill patients for the treatment of various infections. It is often challenging for the clinician to determine the adequate duration of treatment, and antibiotics may be administered for a prolonged period of time, adding cost and contributing to antimicrobial resistance. Procalcitonin is an inflammatory maker with higher sensitivity and specificity than C-reactive protein; it has been used successfully in several studies to shorten the duration of treatment in the setting of respiratory tract infections and sepsis, although the safety of such an approach has not been fully vetted.

A recent article in Lancet Infectious Diseases describes an open-label, prospective, multicenter, randomized controlled trial conducted in the Netherlands. Adult patients in the intensive care unit with presumed infections requiring antibiotics were randomized to receive either procalcitonin-guided (n=761) or standard-of-care (n=785) antibiotic discontinuation. The intervention consisted of providing a non-binding advice to discontinue antibiotics once the procalcitonin concentration had decreased by 80 percent or more of its peak value or to £0.5 mg/L. The two primary endpoints of the trial were antibiotic daily defined doses (DDD) and duration of antibiotic treatment.

The investigators found a significantly lower median consumption of antibiotics in the procalcitonin-guided group compared to the standard-of-care group (7.5 vs. 9.3 DDD; p<0.0001). The median duration of treatment was also shorter in the procalcitonin-guided group (5 vs. 7 days; p<0.0001), thereby achieving the primary endpoints of the trial. In addition, the 28-day mortality was 20 percent in the procalcitonin-guided group and 27 percent in the standard-of-care group (p=0.0154), while the one-year mortality was 36 percent with procalcitonin and 43 percent with standard-of-care (p=0.0188).

The investigators therefore concluded that using guidance by procalcitonin for the discontinuation of antibiotics in critically ill patients is effective in reducing antibiotic usage. Not only was the safety of this approach confirmed, procalcitonin guidance was associated with a reduction in mortality rates.

(de Jong et al. Lancet Infect Dis. 2016; 16: 819–27.)

 

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:

September 15
  • Bacillus cereus Containing a Bacillus Anthracis Toxin Causing a Skin Legion
  • CANDIPOP: Is Fluconazole Effective as Initial Therapy in Patients With Candidemia Due to Candida glabrata?
September 1
  • Ophthalmology Consultation for Patients with Candidemia?
  • Is There Value in Antifungal Susceptibility Testing of Molds Other Than Aspergillus?
August 15
  • Aspergillosis Limited to the Orbit in Patients Without Identified Immunocompromise
  • Stenotrophomonas maltophilia: Antibiotic Choice


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