ABSTRACT
BACKGROUND: Real-world data assessing outcomes of immunocompromised patients treated with ceftolozane/tazobactam (C/T) are limited. This study evaluated treatment and clinical outcomes of immunocompromised patients receiving C/T for multidrug-resistant (MDR) Pseudomonas aeruginosa. METHODS: This was a 14-center retrospective cohort study of adult immunocompromised inpatients treated for ≥24 hours with C/T for MDR P. aeruginosa infections. Patients were defined as immunocompromised if they had a history of previous solid organ transplant (SOT), disease that increased susceptibility to infection, or received immunosuppressive therapies. The primary outcomes were all-cause 30-day mortality and clinical cure. RESULTS: Sixty-nine patients were included; 84% received immunosuppressive agents, 68% had a history of SOT, and 29% had diseases increasing susceptibility to infection. The mean patient age was 57 ± 14 years, and the median (interquartile range) patient Acute Physiology and Chronic Health Evaluation II and Charlson Comorbidity Index scores were 18 (13) and 5 (4), respectively, with 46% receiving intensive care unit care at C/T initiation. The most frequent infection sources were respiratory (56%) and wound (11%). All-cause 30-day mortality was 19% (n = 13), with clinical cure achieved in 47 (68%) patients. Clinical cure was numerically higher (75% vs 30%) in pneumonia patients who received 3-g pneumonia regimens vs 1.5-g regimens. CONCLUSIONS: Of 69 immunocompromised patients treated with C/T for MDR P. aeruginosa, clinical cure was achieved in 68% and mortality was 19%, consistent with other reports on a cross-section of patient populations. C/T represents a promising agent for treatment of P. aeruginosa resistant to traditional antipseudomonal agents in this high-risk population.
ABSTRACT
Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i.e., without poisoning it. Surprisingly, these compounds are more effective in inhibiting the catalytic activities of human and bacterial topoisomerase I. The National Cancer Institute's 60 human tumor cell lines screen revealed significant anti-proliferative activities with 217 and 227 against the majority of 60 cancer cell lines. A proof of concept in vivo efficacy study using an HT-29 xenograft model of human colorectal cancer showed that 217 could inhibit the proliferation of human colorectal cancer cells to a degree comparable to fluorouracil in mice. Although 227 also exhibited anti-proliferative activity, it was not as effective as 217 in this xenograft model. These novel fluoroquinolones may serve as promising lead compounds for the development of new anticancer drugs.