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  • 1
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    Novel Combination Therapy for Extensively Drug-Resistant Acinetobacter baumannii Necrotizing Pneumonia Complicated by Empyema: A Case Report
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. 4 ( 2022-04-01)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. 4 ( 2022-04-01)
    Abstract: We report our clinical and laboratory experience treating a 50-year-old patient who was critically ill with extensively drug-resistant Acinetobacter baumannii necrotizing pneumonia complicated by empyema in Detroit, Michigan. A precision medicine approach using whole-genome sequencing, susceptibility testing, and synergy analysis guided the selection of rational combination antimicrobial therapy.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac092
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    1422. A Multi-Center Evaluation of Omadacycline for Multi-Drug Resistant Infections
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: Multi-drug resistant (MDR) pathogens are a continuously evolving threat for which there are limited effective treatment modalities. Omadacycline (OMC) is a novel oral and intravenously administered aminomethylcycline with potent in-vitro activity against MDR gram-negative and gram-positive pathogens. Post-marketing data investigating its potential place in the antibiotic armamentarium is limited. This study aimed at describing the clinical success and tolerability of patients receiving OMC for various infections. Methods This was a multicenter, retrospective, observational study conducted from January 2020 to March 30, 2022. We included all patients ≥ 18 years of age that received OMC for any infection not related to Mycobacterium spp. for ≥72 hours. The primary outcome was clinical success at 30 days, defined as survival, the absence of persistence or re-emergence of infection during or after therapy, and the absence of escalation or alteration of OMC. Incidence of adverse effects while on OMC and reasons for OMC utilization were also analyzed. Results This analysis included 19 patients from 10 distinct academic centers. The median age was 50 years (IQR, 37-63), 58% were male, 63% were Caucasian, and the median APACHE II, Charlson and SOFA scores were 10 (IQR 5-12.5), 4 (IQR 2-6.3), and 1 (IQR 0 – 2.25), respectively. Most patients had a bone and joint (8/19, 42.1%) or intra-abdominal infections (4/19, 21.1%), all with positive cultures. Eight patients (44.1%) had a polymicrobial infection and 4 (22.2%) had bacteremia. The most common pathogens encountered were Carbapenem-resistant A. baumannii (5/19, 27.8%), E. coli (5/19, 27.8%), Vancomycin-resistant Enterococcus spp. (4/19, 22.2%), and K. pneumoniae (3/19, 16.7%). Clinical success was observed in 14 patients (74%) and 7 (36.8%) received combination therapy. Adverse drug reactions were reported in 3 patients (15.8%) and of those patients, none discontinued therapy. Reasons for prescribing OMC were mostly attributed to oral availability (12/14, 85.7%) and resistance to other agents (7/14, 50%). Conclusion OMC demonstrated clinical effectiveness and safety against a large number of MDR pathogens. More robust, prospective, comparative studies are needed to confirm our preliminary findings. Disclosures P. Brandon Bookstaver, PharmD, Spero Therapeutics: Advisor/Consultant.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.1251
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
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    High-dose Cefepime vs Carbapenems for Bacteremia Caused by Enterobacterales With Moderate to High Risk of Clinically Significant AmpC β-lactamase Production
    Oxford University Press (OUP) ; 2023
    In:  Open Forum Infectious Diseases Vol. 10, No. 3 ( 2023-03-03)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 10, No. 3 ( 2023-03-03)
    Abstract: Limited data suggest that serious infections caused by Enterobacterales with a moderate to high risk of clinically significant AmpC production can be successfully treated with cefepime if the cefepime minimum inhibitory concentration (MIC) is ≤2 µg/mL. However, isolates with a cefepime-susceptible dose-dependent (SDD) MIC of 4–8 µg/mL should receive a carbapenem due to target attainment and extended-spectrum β-lactamase (ESBL) concerns. Methods This was a retrospective cohort study of hospitalized patients with E. cloacae, K. aerogenes, or C. freundii bacteremia from January 2015 to March 2022 receiving high-dose cefepime or a carbapenem. Cox regression models were used with incorporation of inverse probability of treatment weighting and time-varying covariates. Results Of the 315 patients included, 169 received cefepime and 146 received a carbapenem (ertapenem n = 90, meropenem n = 56). Cefepime was not associated with an increased risk of 30-day mortality compared with carbapenem therapy (adjusted hazard ratio [aHR], 1.45; 95% CI, 0.79–2.14), which was consistent for patients with cefepime SDD isolates (aHR, 1.19; 95% CI, 0.52–1.77). Multivariable weighted Cox models identified Pitt bacteremia score & gt;4 (aHR, 1.41; 95% CI, 1.04–1.92), deep infection (aHR, 2.27; 95% CI, 1.21–4.32), and ceftriaxone-resistant AmpC-E (aHR, 1.32; 95% CI, 1.03–1.59) to be independent predictors associated with increased mortality risk, while receipt of prolonged-infusion β-lactam was protective (aHR, 0.67; 95% CI, 0.40–0.89). Conclusions Among patients with bacteremia caused by Enterobacterales with moderate to high risk of clinically significant AmpC production, these data demonstrate similar risk of 30-day mortality for high-dose cefepime or a carbapenem as definitive β-lactam therapy.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofad034
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 4
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    Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam
    Oxford University Press (OUP) ; 2023
    In:  Clinical Infectious Diseases Vol. 76, No. 3 ( 2023-02-08), p. e1444-e1455
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 76, No. 3 ( 2023-02-08), p. e1444-e1455
    Abstract: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). Methods We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan–Meir analysis to assess the time to nephrotoxicity between the 2 groups. Results We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560–6.993). Results of the stratified Kaplan–Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). Conclusions Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Article
    DOI: 10.1093/cid/ciac670
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 5
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    679. Traditional vs. Alternative Agents in Patients with Lower Respiratory Tract Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa Susceptible to Traditional Agents
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: Comparative effectiveness studies to guide treatment decisions for infections caused by carbapenem-resistant P. aeruginosa (CRPA) susceptible to traditional agents (non-carbapenem β-lactams and fluoroquinolones) are unavailable. This study aims to compare clinical outcomes between patients treated with traditional and alternative treatment regimens for lower respiratory tract infection (LRTI) caused by CRPA that remain susceptible to traditional agents. Methods Multi-center, retrospective cohort from January 2016 to December 2019. We included adults with CRPA (resistant to ≥ 1 carbapenem; meropenem or imipenem) that were susceptible to ≥1 traditional agent (piperacillin-tazobactam, cefepime, ceftazidime, ciprofloxacin, or aztreonam) by CLSI breakpoints isolated from an LRTI sample. All other antibiotics were considered alternative agents. We excluded patients with known colonization, cystic fibrosis, or who expired ≤24 hours after antibiotic receipt. Primary outcome was 30-day mortality and secondary outcomes included 30-day readmission and 30-day recurrence. Results In total, 87 patients, ‘traditional’ treatment (n=53) and ‘alternative’ treatment (n=34), were included from 2 institutions in Detroit, MI, USA: median(IQR) age 59(20) years, 64.4% male, and 59.8% African American. Median(IQR) APACHE II and Charlson Comorbidity index scores were 24(10) and 4(5), respectively. Most patients received traditional therapy (n=53), most commonly with cefepime (60.4%) or piperacillin-tazobactam (41.5%). While 34(39.0%) were treated with alternative agents, most commonly ceftolozane-tazobactam (64.7%) or an aminoglycoside (29.4%) alone or in combination. Thirty-day mortality was not significantly different between traditional and alternative therapy groups (22.6% and 11.8%), respectively. There was no significant difference between 30-day recurrence (17.0% and 20.6%) or 30-day readmission (22.6% and 17.6%) between groups. Conclusion Clinical outcomes did not differ significantly between patients receiving traditional vs. alternative agents for LRTI caused by CRPA susceptible to traditional agents. Traditional agents may be considered for these infections. Further comparative studies are needed to guide treatment decisions for CRPA. Disclosures All Authors: No reported disclosures.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.731
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
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    633. Eravacycline Use in Immunocompromised Patients: Multicenter Evaluation of Clinical and Safety Endpoints
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: Infections caused by multidrug-resistant (MDR) bacteria are an increasingly common public health threat associated with worse outcomes in immunocompromised patients. Eravacycline (ERV) has potent in-vitro activity against MDR Gram-negative and Gram-positive bacteria and has demonstrated non-inferiority to meropenem in the phase III IGNITE4 trial; however, the trial excluded immunocompromised patients. We aimed to evaluate clinical and safety endpoints of immunocompromised patients receiving ERV as definitive therapy. Methods Multicenter, retrospective, observational study conducted from October 2018 to April 2022. Adult hospitalized immunocompromised patients treated with ERV for ≥72 hours were included. Immunocompromised patients were defined as having any of the following: chemo or radiation therapy & lt; 30 days of hospital admission, HIV/AIDS with CD4 & lt; 200, chronic steroids ( & gt;40 mg prednisone or equivalent. The primary outcome was 30-day survival. Secondary outcomes were lack of 30-day infection recurrence and drug-related safety events. Results Overall, 75 immunocompromised patients treated with ERV were included from 17 United States medical centers. Median (IQR) age was 62 (53-70) and 61.6% were male. Hospital length of stay was 28 (13-42) days and 67% were admitted to the intensive care unit. SOFA and APACHE II scores were 3.5 (1-7) and 16 (11-20), respectively. Common infection sources were intra-abdominal (26%) and lower respiratory tract (18%); 24% were bacteremic. Most patients had cultured Enterobacterales (58.7%) and Enterococci (37%) spp. infections. Of those, 21.3% were CRE and 19% were VRE. Infectious diseases consult was obtained in 91.8% of cases. Time elapsed from index culture collection to ERV initiation was 4 (2-8) days and duration of ERV therapy was 7 (4-12) days. In total, 81.3% of immunocompromised patients achieved 30-day survival and 90.7% did not have 30-day infection recurrence. Probable drug-related adverse events occurred in 5.3% of patients (GI 4%, rash 1%). Conclusion A majority of immunocompromised patients receiving ERV as definitive therapy achieved 30-day survival and did not experience infection recurrence. ERV use in immunocompromised subpopulations will benefit from studies tailored to their specific characteristics. Disclosures Kimberly C. Claeys, PharmD, BioFire Diagnostics: Honoraria Bruce M. Jones, Pharm.D., FIDSA, BCPS, AbbVie: Advisor/Consultant|AbbVie: Honoraria|La Jolla: Honoraria|Melinta: Advisor/Consultant|Paratek: Honoraria|Regeneron: Honoraria.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.685
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Weighing the Odds: Novel β-Lactam/β-Lactamase Inhibitor Use in Hospital-Acquired and Ventilator-Associated Pseudomonas aeruginosa Pneumonia for Patients Who Are Morbidly Obese
    Oxford University Press (OUP) ; 2023
    In:  Open Forum Infectious Diseases Vol. 10, No. 9 ( 2023-09-01)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 10, No. 9 ( 2023-09-01)
    Abstract: Pseudomonas aeruginosa is a leading cause of hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). Novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations are often used for these infections; however, limited data exist to guide the dosing of BL/BLI in patients who are morbidly obese. Thus, we sought to evaluate the clinical and safety endpoints of patients who are morbidly obese (body mass index ≥35 kg/m2) and non–morbidly obese ( & lt;35 kg/m2) and receiving BL/BLI for P aeruginosa HABP/VABP. Methods This retrospective study was based on a cohort of patients hospitalized at 2 urban academic medical centers in Detroit, Michigan, from August 2014 through February 2021 with P aeruginosa HABP/VABP who were receiving BL/BLI (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam) for ≥72 continuous hours. The primary endpoint was presumed treatment failure, defined as the presence of all-cause in-hospital mortality or the continuation of infectious symptoms. Analyses were adjusted for possible confounding with inverse probability of treatment weighting. Multivariable regression was used to identify predictors of treatment failure. Results In total, 285 patients with HABP (61.4%) and/or VABP (56.1%) were enrolled (morbidly obese, n = 95; non–morbidly obese, n = 190). The median Acute Physiology and Chronic Health Evaluation II score was 23 (IQR, 13–26), and 60% of patients were admitted to the intensive care unit at index culture collection. Patients who were morbidly obese demonstrated significantly greater odds of presumed treatment failure vs those who were non–morbidly obese (58.9% vs 37.9%, respectively; adjusted odds ratio, 1.675 [95% CI, 1.465–1.979]). In multivariable analysis, morbid obesity (1.06; 95% CI, 1.02–1.79), prolonged time to BL/BLI initiation (1.47; 95% CI, 1.28–2.66), renal dose–adjusted BL/BLI in the first 48 hours of therapy (1.12; 95% CI, 1.09–1.75), and continuous renal replacement therapy during BL/BLI therapy (1.35; 95% CI, 1.06–1.68) were independently associated with increased odds of presumed treatment failure. Conclusions Among hospitalized patients receiving BL/BLI for P aeruginosa HABP/VABP, those who were morbidly obese had significantly greater odds of presumed treatment failure when compared with those who were non–morbidly obese.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofad454
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    1691. Bacteriophage and Protein Synthesis Pathway Inhibitor Combinations: Antibiotic mechanism of action drives antagonistic interactions
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: Bacteriophage (phage) to augment antibiotic efficacy is a possible therapeutic option in the era of antimicrobial resistance. Studies to date have assessed phage-antibiotic synergy (PAS), however, its efficacy may be dependent upon antibiotic mechanism of action. Here, we report our in-vitro evaluation of phage-antibiotic antagonism (PAA) among phage and protein synthesis inhibitor combinations in multidrug-resistant clinical strains of P. aeruginosa, S. aureus, and E. faecium. Methods The following bacteria (phage) regimens were evaluated: 10266 (EM) and R9010 (14207) (P. aeruginosa) against gentamicin (GEN), azithromycin (AZM), and ciprofloxacin (CIP); N315 and 494 (Intesti) (S. aureus), and R497 and HOU503 (NV-497) (E. faecium) against linezolid (LNZ), minocycline (MIN), and daptomycin (DAP). Modified checkerboard (CB) MIC assays were used for preliminary screening followed by 24h time kill analyses (TKA). For CB, synergy, additive activity, and antagonism were defined as an FIC index of ≤0.5, 1–4, and & gt;4, respectively. In 24h TKA, synergy and additivity were defined as a ≥2 and ≥1 log10 CFU/mL reduction from baseline, while antagonism was defined as phage-antibiotic combinations with CFU/mL higher than the most effective single treatment at 24h. Data were compared by one-way ANOVA and Tukey (HSD) test (P & lt; 0.05). Results In CB analyses and 24h TKA of S. aureus and E. faecium isolates, phage-LZD and phage-MIN combinations were antagonistic (FIC & gt;4) while phage-DAP was synergistic (FIC 0.5) (ANOVA range of mean differences 0.52 to 2.59 log10 CFU/mL; P & lt; 0.001). For P. aeruginosa, phage-AZM and phage-GEN were antagonistic (FIC & gt;4) and additive (FIC=1), respectively (ANOVA range of mean differences 1.04 to 1.95 log10 CFU/mL; P & lt; 0.001). Conclusion Our results suggest that antibiotics that act on the protein synthesis pathway may lead to PAA, however, PAA interactions may be highly dependent upon antibiotic mechanism of bacterial inhibition (i.e., location of ribosomal protein synthesis inhibition, bactericidal vs. bacteriostatic) protein synthesis inhibit. Studies assessing PAA in a wider array of phage-antibiotic combinations are warranted. Disclosures Cesar A. Arias, MD, PhD, Entasis Phramceuticals: Grant/Research Support|MeMed Diagnostics: Grant/Research Support|Merck: Grant/Research Support.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.1321
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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