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February 2016
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.
  • Antibiotics: Meant to Heal, but also Conferring Risk for C. difficile
  • Is the Joint Involved? Staphylococcus aureus Bacteremia among Patients with Joint Prostheses
  • Isavuconazole: A New Alternative for the Treatment of Invasive Aspergillosis
  • A Pan-Hepatitis C Medication with Excellent Safety and Efficacy
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.
Antibiotics: Meant to Heal, but also Conferring Risk for C. difficile
Reviewed by Terri Stillwell, MD
Despite multidisciplinary efforts, health care-associated C. difficile infections (HA-CDI) continue to cause significant morbidity and mortality. While it is well known that antibiotic exposure increases risk of HA-CDI, a recent Infection Control and Hospital Epidemiology article took the analysis of antibiotic exposure a step further, looking at antibiotic use in both inpatient and outpatient settings.
This retrospective cohort study included all patients older than 18, with an inpatient admission from January 2011 through December 2012, comparing those with incident HA-CDI to non-HA-CDI patients. Data regarding all antibiotics, inpatient and outpatient, within three months prior to admission were gathered. The authors separated antibiotics into 27 categories on the inpatient review and 10 categories in the outpatient review, allowing for a more in-depth look at the impact of specific antibiotic classes.
Approximately 400,000 patients were admitted at least once during the study period; 2,638 had incident HA-CDI, 0.7 percent of the study population, equivalent to a rate of 14.98/10,000 patient days. Outpatient fluoroquinolone and lincosamide use was associated with increased risk of HA-CDI, while outpatient macrolide use seemed protective. Nearly all inpatient antibiotic classes exhibited an association with HA-CDI, except first-generation cephalosporins and tetracyclines, which appeared to reduce HA-CDI risk. Interestingly, inpatient metronidazole and PO vancomycin was also associated with increased risk of HA-CDI, which the authors hypothesized may be due to empiric treatment with delay in testing versus the potential that, like other antibiotic classes, these antibiotics too disrupt gut flora in colonized, but otherwise uninfected, patients, ultimately leading to disease.  
Authors of another recent article, in The Journal of Infectious Diseases, aimed to explore that very question by assessing the impact of metronidazole and vancomycin on gut microbiota in mice, which were treated with three days of metronidazole, vancomycin, or both. The mice were then challenged with C. difficile. Mice with no antibiotic pre-treatment did not exhibit colonization/infection with C. difficile. Those treated with metronidazole showed presence of C. difficile spores, but at decreasing levels; baseline colonization was restored within two weeks. Those receiving vancomycin were found to be heavily colonized, but nearly all had undetectable spore levels near the end of the study. However, those receiving metronidazole plus vancomycin had severe gut disruption, with nearly 80 percent having continued C. difficile growth at three weeks post antibiotic cessation. 
Metronidazole caused minor shifts in commensals, returning to pre-treatment flora in one to two weeks, while vancomycin and metronidazole plus vancomycin created more significant changes.  Finally, the authors also challenged mice with vancomycin-resistant Enterococcus (VRE), carbapenem-resistant K. pneumoniae, and E. coli. Those treated with metronidazole exhibited these bacteria early, with quick return to baseline; those receiving vancomycin were susceptible throughout the study period, with the exception of VRE. The authors extrapolated that treatment with these antibiotics could potentially create susceptibility to nosocomial infections by resistant organisms.  
Antibiotics, though intended to benefit our patients, continue to place them at harm, increasing their risk for HA-CDI. Even those antibiotics meant to treat C. difficile can cause disruption in the gut microbiota, lending susceptibility to C. difficile infection itself, as well as potential for infections by resistant organisms, showing that empiric therapy carries its own inherent risks. 
Is the Joint Involved? Staphylococcus aureus Bacteremia among Patients with Joint Prostheses
Reviewed by Michael T. Melia, MD
When caring for patients with Staphylococcus aureus bacteremia, infectious diseases physicians are often asked whether previously placed joint prostheses are foci of hematogenously spread infection. Identifying variables that can distinguish patients for whom diagnostic testing for prosthetic joint infection (PJI) is warranted from those for whom watchful waiting might be pursued may advance patient care.
A recent article in the American Journal of Medicine provides data that helps facilitate decision-making. The authors retrospectively identified 97 patients with S. aureus bacteremia who had previously undergone 166 joint knee, hip, shoulder, and/or elbow arthroplasties. Twelve of these patients had only primary or indeterminate PJI, leaving a study population comprising 85 patients with 143 arthroplasties. Fifty (59 percent) of these patients had no PJI and 35 (41 percent) had a hematogenous PJI in at least one arthroplasty. All but one PJI manifested at least one clinical feature suggestive of infection. Joint pain (97 percent) was most commonly present, with other features including periarticular swelling or effusion (62 percent) and periarticular warmth (46 percent).
The study also found increased odds of PJI among patients with community-acquired S. aureus bacteremia as compared with nosocomial infection (odds ratio [OR] 21.39; 95 percent confidence interval [CI] 2.92-infinity; P = .001); no patient with nosocomial S. aureus bacteremia developed PJI. The presence of three or more arthroplasties was associated with increased odds of hematogenous PJI as compared with one or two arthroplasties (OR 8.55; 95 percent CI 1.44-95.71; P = .012). Previously revised joints were more likely to develop hematogenous PJI, and knees were more likely than hips to get infected.
PJIs are common among patients with S. aureus bacteremia and previous joint arthroplasty. Nearly all patients with PJI in this setting manifest with at least one sign or symptom consistent with PJI, suggesting that patients without such signs or symptoms might forego further evaluation for possible occult PJI.
Isavuconazole: A New Alternative for the Treatment of Invasive Aspergillosis
Reviewed by Sheila Mitsuma, MD
Isavuconazonium sulfate was approved for treatment of invasive aspergillosis and invasive mucormycosis in the U.S. in March 2015. This approval was based on a randomized-controlled, phase III trial of 527 adults with invasive mold disease recently published in The Lancet.
Diagnostic classification was based on definitions from the 2008 EEORTC/MSG Consensus Group. Patients with hepatic or moderate-severe renal dysfunction were excluded. Block randomization was used to stratify patients by active malignant disease at baseline, allogenic hematopoietic stem cell transplantation, and geographic region. Trial participants were randomized to receive either:
  •  isavuconazonium sulfate 372 mg intravenously (IV) three times daily for two days, then IV or orally once daily; or
  • voriconazole 6 mg/kg IV twice daily for one day, then 4 mg/kg IV twice daily for one day, then 4 mg/kg twice daily or 200 mg orally twice daily. 

In the intention-to-treat analysis, no significant difference in 42-day all-cause mortality (the primary endpoint) was found, with 19 percent vs. 20 percent mortality (95 percent confidence interval [CI], -7.8 percent to 5.7 percent) in the isavuconazole vs. voriconazole groups. Similar mortality rates were found among the subset of patients with proven or probably invasive aspergillosis (82 percent of the total study population). Noninferiority, defined as the upper limit of 95 percent CI for a treatment difference ≤ 10 percent, was also met for 84-day all-cause mortality and clinical, mycologic, and radiographic response (the secondary endpoints, along with safety and tolerability). 

While overall adverse events did not differ between groups, drug-related adverse events were reported in fewer patients receiving isavuconazole when compared to voriconazole (42 percent vs. 60 percent, p<0.001). Specifically, there were fewer dermatologic reactions, visual abnormalities, and reports of hepatic dysfunction in the isavuconazole group. 
In sum, isavuconazole appears to be a promising new alternative for the treatment of invasive aspergillosis, with potentially fewer side effects than voriconazole. However, drug monitoring was not performed in this study, which is not reflective of clinical practice and raises the possibility that a portion of the voriconazole cohort was underdosed. It is also unclear whether these results can be extrapolated to the treatment of non-Aspergillus molds such as mucormycosis, which comprised 5 percent or less of the study cohort. Finally, the clinical response rate in both groups was low (62 percent for isavuconazole vs. 60 percent for voriconazole) highlighting the need for further drug research and development. 
A Pan-Hepatitis C Medication with Excellent Safety and Efficacy  
Reviewed by George R. Thompson III, MD
The advent of new hepatitis C virus (HCV) medications that directly interfere with HCV replication has revolutionized treatment. There are now regimens of direct-acting agents available for most patients. However, multiple variables impact the selection of an appropriate treatment regimen.
The results of four studies evaluating once daily sofosbuvir (a NS5B inhibitor) and velpatasvir (a new NS5A inhibitor with activity against all HCV genotypes) in the treatment of HCV were recently published in three articles in the New England Journal of Medicine. In two of these studies, ASTRAL-1 and ASTRAL-2, a sustained virologic response 12 weeks after the end of therapy was observed in 97 percent and 100 percent of patients with HCV genotypes 1a, 1b, 2, 4, 5, and 6. Efficacy was also demonstrated in those previously failing treatment and in those with compensated cirrhosis.   
The ASTRAL-3 study focused on those with HCV genotype 3, a genotype associated with more rapid disease progression and lower rates of response to treatment. A sustained virologic response 12 weeks after end of therapy was seen in 95 percent of patients (and was superior to patients treated with 24 weeks of sofosbuvir-ribavirin).
The ASTRAL-4 study evaluated outcomes in patients with HCV infection and decompensated cirrhosis, a group with no ribavirin-free regimen currently available. In this study, treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virology response (83 percent, 94 percent, and 86 percent, respectively).
Collectively in these studies, few serious adverse events, high study-completion rates, and rates of sustained virologic response superior to selected study comparators were seen. The presence of NS5A resistance-associated variants was also not a factor in treatment outcomes, although additional study in this area is needed.

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:

January 15

  • Pythiosis
  • MRSA Susceptible to Augmentin? mecC Is Not Your Mother's mecA
  • Case Vignette: A Patient With Severe Immunodeficiency Associated With a GATA2 Mutation

January 1

  • Coccidioidal Meningitis: Diagnosis by Antigen Detection
  • When Tuberculous Lymphadenitis Appears to Worsen During Treatment in Non-HIV-Infected Patients

December 15

  • Imaging of Prosthetic Valve Endocarditis and Infected Intracardiac Devices
  • Influenza (and Other Viruses) Causing Parotitis

December 1

  • Treatment of Infections due to Mycobacterium abscessus: Where Do We Go From Here?
  • Shedding Vaccine-Derived Poliovirus for Almost 3 Decades!
  • Case Vignette: Acute Hepatitis due to a Fruit Fly Endosymbiont


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