Nadim G. El Chakhtoura

Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae: can we apply "precision medicine" to antimicrobial chemotherapy?

ABSTRACT Introduction: For the past three decades, carbapenems played a central role in our antibiotic armamentarium, trusted to effectively treat infections caused by drug-resistant bacteria. The utility of this class of antibiotics has been compromised by the emergence of resistance especially among Enterobacteriaceae. Areas covered: We review the current mainstays of pharmacotherapy against infections caused by carbapenem-resistant Enterobacteriaceae (CRE) including tigecycline, aminoglycosides, and rediscovered ‘old’ antibiotics such as fosfomycin and polymyxins, and discuss their efficacy and potential toxicity. We also summarize the contemporary clinical experience treating CRE infections with antibiotic combination therapy. Finally, we discuss ceftazidime/avibactam and imipenem/relebactam, containig a new generation of beta-lactamase inhibitors, which may offer alternatives to treat CRE infections. We critically evaluate the published literature, identify relevant clinical trials and review documents submitted to the United States Food and Drug Administration. Expert opinion: Defining the molecular mechanisms of resistance and applying insights about pharmacodynamic and pharmacokinetic properties of antibiotics, in order to maximize the impact of old and new therapeutic approaches should be the new paradigm in treating infections caused by CRE. A concerted effort is needed to carry out high-quality clinical trials that: i) establish the superiority of combination therapy vs. monotherapy; ii) confirm the role of novel beta-lactam/beta-lactamase inhibitor combinations as therapy against KPC- and OXA-48 producing Enterobacteriaceae; and, iii) evaluate new antibiotics active against CRE as they are introduced into the clinic.

Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

ABSTRACT Introduction: Non-fermenting Gram-negative bacilli are at the center of the antimicrobial resistance epidemic. Acinetobacter baumannii and Pseudomonas aeruginosa are both designated with a threat level to human health of ‘serious’ by the Centers for Disease Control and Prevention. Two other major non-fermenting Gram-negative bacilli, Stenotrophomonas maltophilia and Burkholderia cepacia complex, while not as prevalent, have devastating effects on vulnerable populations, such as those with cystic fibrosis, as well as immunosuppressed or hospitalized patients. Areas covered: In this review, we summarize the clinical impact, presentations, and mechanisms of resistance of these four major groups of non-fermenting Gram-negative bacilli. We also describe available and promising novel therapeutic options and strategies, particularly combination antibiotic strategies, with a focus on multidrug resistant variants. Expert commentary: We finally advocate for a therapeutic approach that incorporates in vitro antibiotic susceptibility testing with molecular and genotypic characterization of mechanisms of resistance, as well as pharmacokinetics and pharmacodynamics (PK/PD) parameters. The goal is to begin to formulate a precision medicine approach to antimicrobial therapy: a clinical-decision making model that integrates bacterial phenotype, genotype and patient’s PK/PD to arrive at rationally-optimized combination antibiotic chemotherapy regimens tailored to individual clinical scenarios.

Influence of Aging and Environment on Presentation of Infection in Older Adults

In older adults, pathophysiologic, clinical, and environmental factors all affect the presentation of infections. We explore how age-related changes influence the manifestation and evaluation of infections in this population. Specific topics include immunosenescence, age-related organ-specific physiologic changes, and frailty. We also describe clinical factors influencing infection risk and presentation in older adults, including temperature regulation, cognitive decline, and malnutrition. Finally, we discuss the influence of the setting in which older adults reside on the clinical evaluation of infection. Understanding the influence of all these changes may facilitate the prevention, early recognition, and treatment of infections in older adults.

A 17-Year Nationwide Study of Burkholderia cepacia Complex Bloodstream Infections Among Patients in the United States Veterans Health Administration

Background Burkholderia cepacia complex (Bcc) are a group of multidrug-resistant gram-negative bacteria rarely reported in patients without cystic fibrosis (CF) or immunocompromising conditions. We investigated Bcc bloodstream infections (BSIs) in a cohort of non-CF patients from the US Veterans Health Administration (VHA). Methods Using VHA databases, we identified patients with Bcc BSI at facilities nationwide from 1999 through 2015. We ascertained clinical characteristics, treatments, and outcomes and identified factors associated with 30-day mortality in logistic regression analysis. Results We identified 248 patients with Bcc BSI, who were of advanced age (mean, 68 years), chronically ill, and had severe disease. The most common sources were central venous catheters (41%) and pneumonia (20%). Most cases were hospital-acquired (155 [62%]) or healthcare-associated (70 [28%]). Mortality at 14, 30, and 90 days was 16%, 25%, and 36%, respectively. Trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones were active against 94% and 88% of isolates, respectively. Susceptibility to ceftazidime and meropenem occurred in approximately 70% of the isolates. The most prescribed antibiotics were fluoroquinolones (35%), followed by carbapenems (20%), TMP-SMX (18.5%), and ceftazidime (11%). In regression analysis, age (OR, 1.06 [95% confidence interval {CI}, 1.02-1.10], per added year) and the Pitt bacteremia score (OR, 1.65 [95% CI, 1.44-1.94], per unit increase) were associated with higher 30-day mortality. Conclusions In this large cohort of BSIs caused by Bcc, cases were mostly hospital-acquired and we observed high mortality, significant resistance to ceftazidime, and limited use of TMP-SMX. These observations add to our understanding of Bcc infection in non-CF patients and highlight the need for interventions to improve their outcome.

Disseminated Histoplasmosis in Patients Receiving Tumor Necrosis Factor-α Inhibitors: A Case Series and Review

AbstractSince their introduction in the late 1990s, tumor necrosis factor (TNF)-&agr; inhibitors have proven effective in the treatment of several inflammatory disorders, and their use has become increasingly common. Tumor necrosis factor-&agr; blockade is nonetheless associated with an increase in the risk of infection by intracellular, granuloma-forming pathogens, such as Histoplasma capsulatum. We performed a query of our medical records for all cases of disseminated histoplasmosis in patients receiving TNF-&agr; inhibitors between the years 1999 and 2014 at University Hospitals Case Medical Center in Cleveland, Ohio, an area of moderate histoplasmosis endemicity. A total of 357 cases of disseminated histoplasmosis were identified, 8 (2.2%) of whom were receiving TNF-&agr; inhibitor therapy at the time of diagnosis. Five patients were receiving infliximab, and 3 were receiving adalimumab. All patients had generalized, nonspecific presenting symptoms, and all but one had a complete response to antifungal treatment and the cessation of the inciting TNF-&agr; inhibitor. Five of the patients eventually resumed TNF-&agr; inhibitor therapy a year after their initial diagnosis with disseminated histoplasmosis. The only patient who succumbed to the infection had a delayed diagnosis. The increasing use of TNF-&agr; inhibitors should come with an increased awareness of its association with opportunistic infections including disseminated histoplasmosis and by other endemic fungi. This case series highlights the importance of early diagnosis of such infections to achieve a favorable outcome. Further research will need to focus on determining the best long-term treatment strategies in managing these patients after the resolution of the acute infection.