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IDC Snapshots

Snapshots of ID Week 2019

Ho, Jeffrey Manleung MB BCh, BAO; Attar, Sana S. MD; Al Robeh, Hussain MBBS; Louie, Ted MD

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Infectious Diseases in Clinical Practice: March 2020 - Volume 28 - Issue 2 - p 58-60
doi: 10.1097/IPC.0000000000000824
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1. Poster 2307 Imlay I, Dasgupta S, Boeckh M, Stapleton R, Rubenfeld G, Chen Y, Limaye A. Risk factors for CMV reactivation and association with clinical outcomes in critically ill adults with sepsis: a pooled analysis of prospective studies

The authors performed a secondary pooled analysis of 2 prospective observational cohorts. One was an observational cohort of intensive care unit (ICU) patients (n = 40),1 and another was a placebo cohort from a randomized double blind trial of ganciclovir to prevent CMV reactivation in acute critical illness (n = 66) [2]. They extracted demographic information, receipt of transfusion, APACHE, cytomegalovirus (CMV) viral load at peak and average area under the curve, odds of death, ventilator free, ICU-free, and hospital-free days at day 28. In this population, they found that 44% had detectable CMV viremia, 20% with viral load of greater than 1000 IU/mL. CMV viremia was associated with increased odds of hospitalization/death at 28 days, fewer ventilator-free days, ICU-free days, or hospital-free days. The association appeared stronger with higher levels of viremia.

Comment by Dr. Ho: Whether CMV reactivation causes worse outcomes in immunocompetent patients experiencing critical illness is an interesting question, and this study demonstrates a dose-dependent association between clinical outcomes and CMV viremia. However, correlation does not equal causation, and CMV viremia could be a marker of more severe illness rather than a driver of it. One of the cohorts used for this study was part of a trial looking at the effect of prophylactic ganciclovir on interleukin (IL)-6 levels. That study (n = 160)2 showed no difference in IL-6 levels, slightly more ventilator-free days, and no significant difference in ICU length of stay, secondary bacteremia or fungemia, or mortality. Tissue invasive CMV disease was not reported. The authors are planning an efficacy study of CMV prevention to improve clinical outcomes, and those results may help answer that question.

2. Poster 240 Nomura J, Tsai T. The Clinical Utility of Molecular Testing in the Diagnosis and Management of Infectious Diseases- Plasma-Based Next Generation Sequencing (PNGS)

The authors performed a retrospective chart review from February 2017 to January 2019 of 164 PNGS (Karius) tests done on 125 patients at their institution to determine utility of the test. Clinical relevance was defined by the clinician making a management decision based on the result, which included stopping antibiotics for a negative test. A false positive was defined as a positive test that was not treated. They found an assay failure rate of 4.9% and positive result in 34% (53/156). Of these positives, 23 were false positives (43% of positive results). Of the 28 clinically relevant positive results (18% of total tests), 2 were unnecessary because blood cultures were also positive. The test was most commonly ordered to assess for Mycobacterium chimaera infection (94 tests). The test was able to detect approximately 50% of patients with M. chimaera infection. It did not detect sternal M. chimaera infection. The second most common indication was in suspected endocarditis (total 18 cases). Eight of these had a clinically relevant PNGS result that was used to direct antibiotic therapy. The remaining 44 tests were for a variety of infectious syndromes including fever of unknown origin, eosinophilic meningitis, febrile neutropenia, lung and brain lesions in immunocompromised hosts, and septic arthritis. Ten of these results were used to guide clinical management, and there were 15 false-positive results. There were also 4 false-negative results reported.

Comment by Dr. Ho: New molecular-based diagnostic testing was a prominent feature at IDweek 2019. The authors describe the real-world impact of one of these (Karius) on clinical practice. They highlight some of the challenges interpreting the results. They do not report the false-negative rate nor give a sense of why clinicians did not act according to Karius results. The cost of the test was also not mentioned. Clinical outcomes were not reported. Nevertheless, for endocarditis, Karius testing did provide clinically relevant information beyond what could be obtained by routine cultures in 44% of cases. The authors concluded that Karius testing should not be performed until standard blood cultures are negative. As more experience with these new diagnostic modalities accrue, we should expect to hear more about the role of these tests in clinical practice.

3. Session 227: Novel antimicrobials and approaches against MDR organisms

Wiederhold N, Najvar L, Shaw K, Jaramillo R, Patterson H, Olivo M, Catano G, Patterson T. In Vivo Efficacy of Delayed Therapy With the Novel Inositol Acyltransferase Inhibitor Fosmanogepix (Apx001) in a Murine Model of Candida auris Invasive Candidiasis.

Fosmanogepix (APX001) is a novel agent that inhibits inositol acyltransferase Gwt1, preventing glycosylphosphatidylinositol-anchored protein maturation in a manner selective for fungi. It has demonstrated in vitro activity against Candida species (excluding Candida krusei), Cryptococcus species, Aspergillus, Fusarium, and Scedosporium. It has also shown in vivo efficacy in murine models of invasive fungal infections. These authors evaluated the in vivo efficacy of fosmanogepix after delayed initiation in a murine model of Candida auris infection. Mice were made neutropenic with fluorouracil and inoculated with a standardized dose of Candida auris. Treatment was initiated 1 day after inoculation and continued for 7 days. There were 10 mice in each arm of treatment, which included control, fosmanogepix at 3 different doses, fluconazole, and supratherapeutic caspofungin. Survival after 21 days was 90% to 100% in the fosmanogepix arms, 90% with caspofungin, and 10% in fluconazole and control arms. They also demonstrated reductions in fungal burden in kidney and brain tissue.

Comment by Dr. Ho: The azoles, echinocandins, and polyenes are the 3 main classes of antifungals available in clinical practice. With the emergence of multidrug-resistant strains, such as Candida auris, there is urgent need for development of new antifungals. Fosmanogepix seems to be a promising novel class of antifungal agent to meet this need. There is currently a phase 2 efficacy and safety study ongoing in nonneutropenic patients with candidemia, which started October 2018, anticipated completion August 2020. Another novel antifungal agent with one poster at IDweek 2019 was ibrexafungerp (SCY-078), which is also in phase 2 studies.

4. Poster 1539 Abdul-Mutakabbir J, Kebriaei R; Stamper K, Massen P, Michael J. Rybak MJ. Dalbavancin, Vancomycin, and Daptomycin Alone and in Combination with Cefazolin Against Vancomycin Intermediate Resistant (Visa) and Daptomycin Non-Susceptible (DNS) Staphylococcus Aureus

This study was to evaluate the activity of dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP), alone and in combination with cefazolin (CFZ) in a pharmacokinetic/pharmacodynamic model.

Daptomycin Nonsusceptible–vancomycin intermediate Staphylococcus aureus strain, D712, was evaluated in 8 different regimens in duplicate via a 1-compartment 7-day pharmacokinetic/pharmacodynamic model. In this model, the combinations DAP + CFZ and VAN + CFZ combination models demonstrated bactericidal activity at 4 and 24 hours, respectively. Although DAL alone did demonstrate bactericidal activity, the DAL + CFZ combination was more rapidly bactericidal, achieving a more than 3-log reduction from baseline in 8 hours versus 48 hours (P < 0.05). The combination of DAL, VAN, or DAP with CFZ demonstrated significantly improved activity against this multidrug-resistant S. aureus strain.

Comment by Dr. Al Robeh: With the continued emergence of multidrug-resistant pathogens, alternative regimens are urgently needed. In this poster, DAL showed good bactericidal activity at 48 hours; however, DAP + CFZ achieved this faster by more than threefold. That is an exciting finding for DAP + CFZ, as you would expect that the DNS-vancomycin intermediate Staphylococcus aureus strain would be resistant to this combination. Furthermore, the combination of DAP + CFZ is cheaper and more readily available. More research, both in vivo and in vitro, is needed to explore the synergistic capabilities of anti-MRSA drug therapy in combination with β-lactams.

5. SYMPOSIUM 2, OCTOBER 2, 2019: ANTIMICROBIAL STEWARDSHIP AND RESISTANCE ACROSS THE GLOBE

Moderators: C. Ohl, K. Tateda. Speakers: A. Dreser, M. Ishikane, R. Smith, B. Zayed.

This symposium focused on antibiotic resistance (AR) and antibiotic stewardship (AS) initiatives in Japan, the Eastern Mediterranean, and Mexico, including resource-limited settings (RLSs). In RLS, the main drivers of inappropriate antibiotic use are over-the-counter availability of antibiotics and frequent empiric antibiotic use in the absence of cultures, often in the context of poor sanitation and high infection rates. Complicating the situation is a lack of AS. The Centers for Disease Control and Prevention introduced its core elements document for RLS in 2018 and has assisted with data collection and analysis in Senegal and Kenya.

The World Health Organization focused on its Eastern Mediterranean Region spanning Pakistan to Morocco, with a population of approximately 600 million. Some of these countries are afflicted with humanitarian crises and/or disease outbreaks. The World Health Organization encouraged collection and reporting of AR data. Some of the included areas have striking rates of resistance, with several regions that have high incidences of carbapenem-resistant gram negatives in their blood isolates.

Comment by Dr. Attar: This symposium presented the growing acknowledgment of the alarming issue of antimicrobial resistance by major world organizations. The issue of antimicrobial resistance spreads across many ecosystems and impacts the health of the environment, humans, and animals. It will require a concerted long-term and sustainable effort by multiple disciplines and industries. The Global Action Plan on AR is an important development toward the global concerted effort toward beginning to address this issue.

6. Poster 2261 Hefler JL, Perez KK, Lewing B, Musick WL. Oral Fosfomycin Compared With Standard IV Therapy for Multi-Drug Resistant Urinary Tract Infections

Urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE) have limited treatment options. Oral fosfomycin achieves high urinary concentrations and has in vitro activity against many of these highly resistant strains.

The authors conducted a retrospective cohort review of hospitalized adult patients for a 15-month period, in a 7-hospital system. They compared outcomes with oral fosfomycin and standard intravenous (IV) therapy for UTI caused by ESBL and CRE. Standard IV therapy included colistin, aminoglycosides, ceftolazone/tazobactam, or ceftazidime/avibactam. The oral fosfomycin group had 39 patients and the standard IV therapy group had 31 patients. Isolates included ESBL Escherichia coli and Klebsiella pneumonia, as well as CRE E. coli, and K. pneumoniae. The oral fosfomycin group and the standard IV therapy group had similar functional cure rates of 94.9% and 96.8% (P = 0.59). Only 28 of 69 patients had repeat urine cultures for evaluation, but microbiologic cure was seen in all 28 patients. By a multivariate regression analysis, the authors also found that oral fosfomycin was independently associated with decreased time for hospital discharge.

Comment by Dr. Attar: Extended-spectrum β-lactamase and CRE organisms are on the rise globally, given the widespread use of broad-spectrum antibiotics, and the increasingly complex patient population. Urine isolates account for most resistant organisms. Oral fosfomycin offers a good alternative to IV antibiotic therapy for these multidrug-resistant urinary pathogens.

7. Poster 754 Shihadeh K, Young H, Wyles D, Jenkins T. Evaluation of Standardized Dalbavancin Use to Facilitate Early Hospital Discharge for Outpatient Parenteral Antibiotic Therapy

The authors did a retrospective study of all patients receiving DAL. Of these 16 patients, a great majority were homeless and many were IV drug users. The majority had MRSA or methicillin sensitive Staphylococcus aureus, for a variety of conditions, including endocarditis and osteomyelitis. No adverse reactions were noted. The authors estimate saving an average of 7 hospital days per patient, with a total cost savings to the hospital of US $159,000 (the estimated cost of 1 hospital day was US $1800, whereas the cost of the standard dose of 1500 mg DAL was US $3000).

8. Poster 1028 Streifel AC, Sikka M, Lewis J. Dalbavancin Use in Complicated Infections and Associated Cost Savings

For a 4-year period, the authors retrospectively studied 46 patients who received DAL. Reasons for use of DAL included intravenous drug users and other issues that prevented patients from reliably receiving standard outpatient parenteral antibiotics. The conditions treated included osteomyelitis, bacteremia, and skin and soft tissue infections. Over this time, the authors estimate that there was a mean cost avoidance of US $40,988 per patient, for a total of US $1,885,479.

Comment by Dr. Louie: Dalbavancin is Food and Drug Administration approved for skin and soft tissue infection. In addition, there is a growing body of literature supporting the safe, effective use of DAL for bone and joint infections, and bacteremia, including endocarditis. Because of the long half-life of DAL, the previously mentioned conditions are generally treatable with 1 or 2 doses. The second dose, if necessary, is given a week later, and can sustain efficacious levels in the bloodstream and tissue for up to 6 weeks. The spectrum of activity mimics that of VAN.

This antibiotic is a potential game changer. In the right population, it can shorten hospital stay and avoid the problems associated with IV lines. We would like to see a randomized prospective trial in patients with gram-positive endocarditis.

REFERENCES

1. Limaye AP, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–422.
2. Limaye AP, Stapleton RD, Peng L, et al. Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA. 2017;318(8):731–774.
Keywords:

dalbavancin; vancomycin-resistant Staphylococcus aureus; antimicrobial stewardship; fosfomycin; cytomegalovirus reactivation; plasma-based next-generation sequencing; fosmanogepix

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